Untested, unproven, and unethical: the promotion and provision of autologous stem cell therapies in Australia.

PubMed

McLean, Alison K; Stewart, Cameron; Kerridge, Ian

2015-02-09

An increasing number of private clinics in Australia are marketing and providing autologous stem cell therapies to patients. Although advocates point to the importance of medical innovation and the primacy of patient choice, these arguments are unconvincing. First, it is a stark truth that these clinics are flourishing while the efficacy and safety of autologous stem cell therapies, outside of established indications for hematopioetic stem cell transplantation, are yet to be shown. Second, few of these therapies are offered within clinical trials. Third, patients with chronic and debilitating illnesses, who are often the ones who take up these therapies, incur significant financial burdens in the expectation of benefiting from these treatments. Finally, the provision of these stem cell therapies does not follow the established pathways for legitimate medical advancement. We argue that greater regulatory oversight and professional action are necessary to protect vulnerable patients and that at this time the provision of unproven stem cell therapies outside of clinical trials is unethical.

A novel autologous stem cell procedure for the treatment of aplastic anaemia using reprogrammed mature adult cells: a pilot study

PubMed Central

Abuljadayel, Ilham Saleh; Mohanty, Dipika; Suri, Rajendar K.

2012-01-01

Background & objectives: Aplastic anaemia is a life threatening rare bone marrow failure disorder. The underlying haematopoietic cellular deficit leads to haemorrhage, infection and severe anaemia. The treatment of choice for this haematological condition is allogeneic bone marrow transplantation from fully matched HLA sibling. Though this procedure is curative in the majority of young patients with aplastic anaemia, extending this benefit to older patients or those lacking a family donor remains a major challenge. Herein, the safety and efficacy of infusing autologous retrodifferentiated haematopoietic stem cells (RHSC) into four patients with aplastic anaemia without the use of any pre- or post-conditioning regimen including immunosuppression is described. Methods: Un-mobilized, mononuclear cells were harvested from four patients with acquired aplastic anaemia by aphaeresis. Mononuclear cells of patients were cultured with purified monoclonal antibody against the monomorphic regions of the beta chain of MHC class II antigens (Clone CR3/43) for 3 h, to obtain autologous RHSC. Autologous RHSC were washed and infused into the four patients without the use of any pre- or post-conditioning regimen. Thereafter, the efficacy (engraftment) of autologous RHSC was assessed in these patients. Results: Following single infusion of the autologous RHSC, two of the four patients with aplastic anaemia become transfusion independent for more than seven years. Karyotyping and G-banding analysis prior and post-procedure in all patients remained the same. Interpretation & conclusions: The findings of this pilot study demonstrated the functional utility of reprogrammed fully differentiated adult cells into pluripotent stem cells with extensive repopulation potentials in a human setting and without any pre- or post-conditioning regimen, including immunosuppression. This autologous approach of stem cell creation may broaden the curative potentials of stem cell therapy to a wider

A novel autologous stem cell procedure for the treatment of aplastic anaemia using reprogrammed mature adult cells: a pilot study.

PubMed

Abuljadayel, Ilham Saleh; Mohanty, Dipika; Suri, Rajendar K

2012-06-01

Aplastic anaemia is a life threatening rare bone marrow failure disorder. The underlying haematopoietic cellular deficit leads to haemorrhage, infection and severe anaemia. The treatment of choice for this haematological condition is allogeneic bone marrow transplantation from fully matched HLA sibling. Though this procedure is curative in the majority of young patients with aplastic anaemia, extending this benefit to older patients or those lacking a family donor remains a major challenge. Herein, the safety and efficacy of infusing autologous retrodifferentiated haematopoietic stem cells (RHSC) into four patients with aplastic anaemia without the use of any pre- or post-conditioning regimen including immunosuppression is described. Un-mobilized, mononuclear cells were harvested from four patients with acquired aplastic anaemia by aphaeresis. Mononuclear cells of patients were cultured with purified monoclonal antibody against the monomorphic regions of the beta chain of MHC class II antigens (Clone CR3/43) for 3 h, to obtain autologous RHSC. Autologous RHSC were washed and infused into the four patients without the use of any pre- or post-conditioning regimen. Thereafter, the efficacy (engraftment) of autologous RHSC was assessed in these patients. Following single infusion of the autologous RHSC, two of the four patients with aplastic anaemia become transfusion independent for more than seven years. Karyotyping and G-banding analysis prior and post-procedure in all patients remained the same. The findings of this pilot study demonstrated the functional utility of reprogrammed fully differentiated adult cells into pluripotent stem cells with extensive repopulation potentials in a human setting and without any pre- or post-conditioning regimen, including immunosuppression. This autologous approach of stem cell creation may broaden the curative potentials of stem cell therapy to a wider population of patients with aplastic anaemia, including many patients suffering

Gastrocnemius tendon strain in a dog treated with autologous mesenchymal stem cells and a custom orthosis.

PubMed

Case, J Brad; Palmer, Ross; Valdes-Martinez, Alex; Egger, Erick L; Haussler, Kevin K

2013-05-01

To report clinical findings and outcome in a dog with gastrocnemius tendon strain treated with autologous mesenchymal stem cells and a custom orthosis. Clinical report. A 4-year-old spayed female Border Collie. Bone-marrow derived, autologous mesenchymal stem cells were transplanted into the tendon core lesion. A custom, progressive, dynamic orthosis was fit to the tarsus. Serial orthopedic examinations and ultrasonography as well as long-term force-plate gait analysis were utilized for follow up. Lameness subjectively resolved and peak vertical force increased from 43% to 92% of the contralateral pelvic limb. Serial ultrasonographic examinations revealed improved but incomplete restoration of normal linear fiber pattern of the gastrocnemius tendon. Findings suggest that autologous mesenchymal stem cell transplantation with custom, progressive, dynamic orthosis may be a viable, minimally invasive technique for treatment of calcaneal tendon injuries in dogs. © Copyright 2013 by The American College of Veterinary Surgeons.

Autologous Mesenchymal Stem Cell and Islet Cotransplantation: Safety and Efficacy.

PubMed

Wang, Hongjun; Strange, Charlie; Nietert, Paul J; Wang, Jingjing; Turnbull, Taylor L; Cloud, Colleen; Owczarski, Stefanie; Shuford, Betsy; Duke, Tara; Gilkeson, Gary; Luttrell, Louis; Hermayer, Kathie; Fernandes, Jyotika; Adams, David B; Morgan, Katherine A

2018-01-01

Islet engraftment after transplantation is impaired by high rates of islet/β cell death caused by cellular stressors and poor graft vascularization. We studied whether cotransplantation of ex vivo expanded autologous bone marrow-derived mesenchymal stem cells (MSCs) with islets is safe and beneficial in chronic pancreatitis patients undergoing total pancreatectomy with islet autotransplantation. MSCs were harvested from the bone marrow of three islet autotransplantation patients and expanded at our current Good Manufacturing Practices (cGMP) facility. On the day of islet transplantation, an average dose of 20.0 ± 2.6 ×10 6 MSCs was infused with islets via the portal vein. Adverse events and glycemic control at baseline, 6, and 12 months after transplantation were compared with data from 101 historical control patients. No adverse events directly related to the MSC infusions were observed. MSC patients required lower amounts of insulin during the peritransplantation period (p = .02 vs. controls) and had lower 12-month fasting blood glucose levels (p = .02 vs. controls), smaller C-peptide declines over 6 months (p = .01 vs. controls), and better quality of life compared with controls. In conclusion, our pilot study demonstrates that autologous MSC and islet cotransplantation may be a safe and potential strategy to improve islet engraftment after transplantation. (Clinicaltrials.gov registration number: NCT02384018). Stem Cells Translational Medicine 2018;7:11-19. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Clinical observation of the application of autologous peripheral blood stem cell transplantation for the treatment of diabetic foot gangrene

PubMed Central

XU, SHI-MIN; LIANG, TING

2016-01-01

The aim of the present study was to investigate the optimal mobilization plan in autologous peripheral blood stem cell transplantation for the treatment of diabetic foot and to observe its clinical curative effect. A total of 127 patients with diabetic foot were treated with different doses of granulocyte colony stimulating factor (G-CSF) to mobilize their hematopoietic stem cells. Subsequently, the extracted stem cell suspension was injected into the ischemic lower extremities along the blood vessels in the areas presenting with pathological changes. Following the treatment, the intermittent claudication distance, skin temperature, ankle brachial index and pain scores of the patients were evaluated. In addition, the associations among the mobilization time, doses and peripheral blood CD34+ level were analyzed. The collection efficiency of the stem cells was associated with the dose of G-CSF and the mobilization time. Following the injection of the autologous peripheral blood stem cell suspension, the ischemic area of the patients was improved significantly. In conclusion, autologous peripheral blood stem cell transplantation can promote the establishment of collateral circulation in patients with diabetic foot, and the optimal time for gathering stem cells is closely correlated with the peripheral blood CD34+ level. PMID:26889255

Preclinical Derivation and Imaging of Autologously Transplanted Canine Induced Pluripotent Stem Cells*

PubMed Central

Lee, Andrew S.; Xu, Dan; Plews, Jordan R.; Nguyen, Patricia K.; Nag, Divya; Lyons, Jennifer K.; Han, Leng; Hu, Shijun; Lan, Feng; Liu, Junwei; Huang, Mei; Narsinh, Kazim H.; Long, Charles T.; de Almeida, Patricia E.; Levi, Benjamin; Kooreman, Nigel; Bangs, Charles; Pacharinsak, Cholawat; Ikeno, Fumiaki; Yeung, Alan C.; Gambhir, Sanjiv S.; Robbins, Robert C.; Longaker, Michael T.; Wu, Joseph C.

2011-01-01

Derivation of patient-specific induced pluripotent stem cells (iPSCs) opens a new avenue for future applications of regenerative medicine. However, before iPSCs can be used in a clinical setting, it is critical to validate their in vivo fate following autologous transplantation. Thus far, preclinical studies have been limited to small animals and have yet to be conducted in large animals that are physiologically more similar to humans. In this study, we report the first autologous transplantation of iPSCs in a large animal model through the generation of canine iPSCs (ciPSCs) from the canine adipose stromal cells and canine fibroblasts of adult mongrel dogs. We confirmed pluripotency of ciPSCs using the following techniques: (i) immunostaining and quantitative PCR for the presence of pluripotent and germ layer-specific markers in differentiated ciPSCs; (ii) microarray analysis that demonstrates similar gene expression profiles between ciPSCs and canine embryonic stem cells; (iii) teratoma formation assays; and (iv) karyotyping for genomic stability. Fate of ciPSCs autologously transplanted to the canine heart was tracked in vivo using clinical positron emission tomography, computed tomography, and magnetic resonance imaging. To demonstrate clinical potential of ciPSCs to treat models of injury, we generated endothelial cells (ciPSC-ECs) and used these cells to treat immunodeficient murine models of myocardial infarction and hindlimb ischemia. PMID:21719696

Clinical Evaluation of Decellularized Nerve Allograft with Autologous Bone Marrow Stem Cells to Improve Peripheral Nerve Repair and Functional Outcomes

DTIC Science & Technology

2017-07-01

AWARD NUMBER: W81XWH-15-2-0026 TITLE: Clinical Evaluation of Decellularized Nerve Allograft with Autologous Bone Marrow Stem Cells to Improve...of Decellularized Nerve Allograft with 5a. CONTRACT NUMBER Autologous Bone Marrow Stem Cells to Improve Peripheral Nerve 5b. GRANT NUMBER W81XWH...commercially available decellularized processed peripheral nerve allograft scaffold (Avance® Nerve Graft, AxoGen, Alachua FL) with autologous bone marrow

Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen.

PubMed

Smith, S D; Bolwell, B J; Rybicki, L A; Brown, S; Dean, R; Kalaycio, M; Sobecks, R; Andresen, S; Hsi, E D; Pohlman, B; Sweetenham, J W

2007-08-01

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin's lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan-Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed.

Outcomes of autologous or allogeneic stem cell transplantation for non-Hodgkin lymphoma.

PubMed

Reddy, Nishitha M; Oluwole, Olalekan; Greer, John P; Engelhardt, Brian G; Jagasia, Madan H; Savani, Bipin N

2014-01-01

Transplant outcomes of autologous or allogeneic stem cell transplantation (SCT) have not been elucidated as a single cohort in non-Hodgkin lymphoma (NHL). We analyzed the outcomes of 270 adult recipients receiving autologous (auto) SCT (n = 198) or allogeneic (allo) SCT (n = 72) for NHL between the years 2000 and 2010. Five-year overall survival rates for B and T cell NHL were 58% and 50%, respectively (allo-SCT 51% vs. 54% for B and T-cell NHL, and auto-SCT 60% vs. 47% for B and T cell lymphoma, respectively). In multivariate analysis, the number of chemotherapy regimens and disease status pre-SCT were independently associated with long-term outcome after SCT (for both auto- and allo-SCT). We conclude that the type of transplantation offered to patients, based on patient selection and disease-related factors, can achieve long-term survival, highlighting the importance of further improvement in disease control and reducing procedure-related mortality. The role of transplantation needs to be reevaluated in the era of targeted therapy. Copyright © 2014 ISEH - Society for Hematology and Stem Cells. All rights reserved.

Cellular Therapy With Human Autologous Adipose-Derived Adult Stem Cells for Advanced Keratoconus.

PubMed

Alió Del Barrio, Jorge L; El Zarif, Mona; de Miguel, María P; Azaar, Albert; Makdissy, Norman; Harb, Walid; El Achkar, Ibrahim; Arnalich-Montiel, Francisco; Alió, Jorge L

2017-08-01

The aim of this phase 1 study was to preliminarily evaluate the safety and efficacy of autologous adipose-derived adult stem cell (ADASC) implantation within the corneal stroma of patients with advanced keratoconus. Five consecutive patients were selected. Autologous ADASCs were obtained by elective liposuction. ADASCs (3 × 10) contained in 1 mL saline were injected into the corneal stroma through a femtosecond-assisted 9.5-mm diameter lamellar pocket under topical anesthesia. Patients were reviewed at 1 day, 1 week, 1, 3, and 6 months postoperatively. Visual function, manifest refraction, slit-lamp biomicroscopy, intraocular pressure, endothelial cell density, corneal topography, corneal optical coherence tomography, and corneal confocal biomicroscopy were recorded. No intraoperative or postoperative complications were recorded, with full corneal transparency recovery within 24 hours. Four patients completed the full follow-up. All patients improved their visual function (mean: 1 line of unaided and spectacle-corrected distance vision and 2 lines of rigid contact lens distance vision). Manifest refraction and topographic keratometry remained stable. Corneal optical coherence tomography showed a mean improvement of 16.5 μm in the central corneal thickness, and new collagen production was observed as patchy hyperreflective areas at the level of the stromal pocket. Confocal biomicroscopy confirmed the survival of the implanted stem cells at the surgical plane. Intraocular pressure and endothelial cell density remained stable. Cellular therapy of the human corneal stroma in vivo with autologous ADASCs appears to be safe. Stem cells survive in vivo with intrastromal new collagen production. Future studies with larger samples are required to confirm these preliminary results.

Early Prognostic Value of Monitoring Serum Free Light Chain in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.

PubMed

Özkurt, Zübeyde Nur; Sucak, Gülsan Türköz; Akı, Şahika Zeynep; Yağcı, Münci; Haznedar, Rauf

2017-03-16

We hypothesized the levels of free light chains obtained before and after autologous stem cell transplantation can be useful in predicting transplantation outcome. We analyzed 70 multiple myeloma patients. Abnormal free light chain ratios before stem cell transplantation were found to be associated early progression, although without any impact on overall survival. At day +30, the normalization of levels of involved free light chain related with early progression. According to these results almost one-third reduction of free light chain levels can predict favorable prognosis after autologous stem cell transplantation.

Autologous dental pulp stem cells in periodontal regeneration: a case report.

PubMed

Aimetti, Mario; Ferrarotti, Francesco; Cricenti, Luca; Mariani, Giulia Maria; Romano, Federica

2014-01-01

Histologic findings in animal models suggest that the application of dental pulp stem cells (DPSCs) may promote periodontal regeneration in infrabony defects. This case report describes the clinical and radiographic regenerative potential of autologous DPSCs in the treatment of human noncontained intraosseous defects. A chronic periodontitis patient with one vital third molar requiring extraction was surgically treated. The third molar was extracted and used as an autologous DPSCs source to regenerate the infrabony defect on the mandibular right second premolar. At the 1-year examination, the defect was completely filled with bonelike tissue as confirmed through the reentry procedure.

Impact of autologous and allogeneic stem cell transplantation in peripheral T-cell lymphomas.

PubMed

Reimer, Peter

2010-01-01

Peripheral T/NK-cell lymphomas (PTCLs) are rare malignancies characterized by poor prognosis. So far, no standard therapy has been established, due to the lack of randomised studies. High-dose therapy and autologous stem cell transplantation (HDT-autoSCT) have shown good feasibility with low toxicity in retrospective studies. In relapsing and refractory PTCL several comparison analyses suggest similar efficacy for PTCL when compared with aggressive B-cell lymphoma. In the upfront setting, prospective data show promising results with a long-lasting overall survival in a relevant subset of patients. Achieving a complete remission at transplantation seems to be the most important prognostic factor. Allogeneic stem cell transplantation (alloSCT) has been investigated only as salvage treatment. Especially when using reduced intensity conditioning regimen, eligible patients seem to benefit from this approach. To define the role for upfront stem cell transplantation a randomised trial by the German High-Grade Non-Hodgkin Lymphoma Study Group comparing HDT-autoSCT and alloSCT will be initiated this year.

Development of autologous blood cell therapies

PubMed Central

Kim, Ah Ram; Sankaran, Vijay G.

2016-01-01

Allogeneic hematopoietic stem cell transplantation and blood cell transfusions are commonly performed in patients with a variety of blood disorders. Unfortunately, these donor-derived cell therapies are constrained due to limited supplies, infectious risk factors, a lack of appropriately matched donors, and the risk of immunologic complications from such products. The use of autologous cell therapies has been proposed to overcome these shortcomings. One can derive such therapies directly from hematopoietic stem and progenitor cells of individuals, which can then be manipulated ex vivo to produce desired modifications or differentiated to produce a particular target population. Alternatively, pluripotent stem cells, which have a theoretically unlimited self-renewal capacity and an ability to differentiate into any desired cell type, can be used as an autologous starting source for such manipulation and differentiation approaches. In addition, such cell products can also be used as a delivery vehicle for therapeutics. In this review, we highlight recent advances and discuss ongoing challenges for the in vitro generation of autologous hematopoietic cells that can be used for cell therapy. PMID:27345108

Cytokine-primed bone marrow stem cells vs. peripheral blood stem cells for autologous transplantation: a randomized comparison of GM-CSF vs. G-CSF.

PubMed

Weisdorf, D; Miller, J; Verfaillie, C; Burns, L; Wagner, J; Blazar, B; Davies, S; Miller, W; Hannan, P; Steinbuch, M; Ramsay, N; McGlave, P

1997-10-01

Autologous transplantation for non-Hodgkins lymphoma and Hodgkin's disease is widely used as standard therapy for those with high-risk or relapsed tumor. Peripheral blood stem cell (PBSC) collections have nearly completely replaced bone marrow stem cell (BMSC) harvests because of the perceived advantages of more rapid engraftment, less tumor contamination in the inoculum, and better survival after therapy. The advantage of PBSC, however, may derive from the hematopoietic stimulating cytokines used for PBSC mobilization. Therefore, we tested a randomized comparison of GM-CSF vs. G-CSF used to prime either BMSC or PBSC before collection for use in autologous transplantation. Sixty-two patients receiving transplants (31 PBSC; 31 BMSC) for non-Hodgkin's lymphoma (n = 51) or Hodgkin's disease (n = 11) were treated. All patients received 6 days of randomly assigned cytokine. Those with cellular marrow in morphologic remission underwent BMSC harvest, while those with hypocellular marrow or microscopic marrow tumor involvement had PBSC collected. Neutrophil recovery was similarly rapid in all groups (median 14 days; range 10-23 days), though two patients had delayed neutrophil recovery using GM-CSF primed PBSC (p = 0.01). Red cell and platelet recovery were significantly quicker after BMSC mobilized with GM-CSF or PBSC mobilized with G-CSF. This speedier hematologic recovery resulted in earlier hospital discharge as well. However, in multivariate analysis, neither the stem cell source nor randomly assigned G-CSF vs. GM-CSF was independently associated with earlier multilineage hematologic recovery or shorter hospital stay. Relapse-free survival was not independently affected by either the assigned stem cell source or the randomly assigned priming cytokine, though malignant relapse was more frequent in those assigned to PBSC (RR of relapse 3.15, p = 0.03). These data document that BMSC, when collected following cytokine priming, can yield a similarly rapid hematologic

Pure Red Cell Aplasia due to B19 Parvovirus Infection after Autologous Stem Cell Transplantation

PubMed Central

Tsirigotis, Panagiotis; Girkas, Konstantinos; Economopoulou, Christina; Bouchla, Anthoula; Papanicolaou, Nikolaos; Economopoulou, Panagiota; Papageorgiou, Sotirios; Pappa, Vassiliki; Dervenoulas, John

2011-01-01

Parvovirus B19 is recognized as a rare cause of pure red cell aplasia (PRCA) in allogeneic stem cell (SCT) and solid organ transplant patients. We report a patient with Hodgkin's disease who developed PRCA due to parvovirus B19 after autologous SCT and who had an excellent response after treatment with gamma-globulin. PMID:23198254

Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for Development of Autologous Stem Cell Therapy.

PubMed

Gao, Yuanzheng; Guo, Xiuming; Santostefano, Katherine; Wang, Yanlin; Reid, Tammy; Zeng, Desmond; Terada, Naohiro; Ashizawa, Tetsuo; Xia, Guangbin

2016-08-01

Myotonic dystrophy type 1 (DM1) is caused by expanded Cytosine-Thymine-Guanine (CTG) repeats in the 3'-untranslated region (3' UTR) of the Dystrophia myotonica protein kinase (DMPK) gene, for which there is no effective therapy. The objective of this study is to develop genome therapy in human DM1 induced pluripotent stem (iPS) cells to eliminate mutant transcripts and reverse the phenotypes for developing autologous stem cell therapy. The general approach involves targeted insertion of polyA signals (PASs) upstream of DMPK CTG repeats, which will lead to premature termination of transcription and elimination of toxic mutant transcripts. Insertion of PASs was mediated by homologous recombination triggered by site-specific transcription activator-like effector nuclease (TALEN)-induced double-strand break. We found genome-treated DM1 iPS cells continue to maintain pluripotency. The insertion of PASs led to elimination of mutant transcripts and complete disappearance of nuclear RNA foci and reversal of aberrant splicing in linear-differentiated neural stem cells, cardiomyocytes, and teratoma tissues. In conclusion, genome therapy by insertion of PASs upstream of the expanded DMPK CTG repeats prevented the production of toxic mutant transcripts and reversal of phenotypes in DM1 iPS cells and their progeny. These genetically-treated iPS cells will have broad clinical application in developing autologous stem cell therapy for DM1.

Development of autologous blood cell therapies.

PubMed

Kim, Ah Ram; Sankaran, Vijay G

2016-10-01

Allogeneic hematopoietic stem cell transplantation and blood cell transfusions are performed commonly in patients with a variety of blood disorders. Unfortunately, these donor-derived cell therapies are constrained due to limited supplies, infectious risk factors, a lack of appropriately matched donors, and the risk of immunologic complications from such products. The use of autologous cell therapies has been proposed to overcome these shortcomings. One can derive such therapies directly from hematopoietic stem and progenitor cells of individuals, which can then be manipulated ex vivo to produce the desired modifications or differentiated to produce a particular target population. Alternatively, pluripotent stem cells, which have a theoretically unlimited self-renewal capacity and an ability to differentiate into any desired cell type, can be used as an autologous starting source for such manipulation and differentiation approaches. Such cell products can also be used as a delivery vehicle for therapeutics. In this review, we highlight recent advances and discuss ongoing challenges for the in vitro generation of autologous hematopoietic cells that can be used for cell therapy. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

High-dose therapy and autologous hematopoietic stem cell transplant in T-cell lymphoma: a single center experience.

PubMed

Cairoli, Anne; Ketterer, Nicolas; Barelli, Stefano; Duchosal, Michel A

2014-08-01

We report here the long-term outcome of autologous stem cell transplant in peripheral T-cell lymphoma (PTCL). Forty-three consecutive patients with PTCL diagnosed between 2000 and 2011 were treated with high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) in our center. Diagnoses included PTCL-not otherwise specified (n = 19), anaplastic large cell lymphoma (n = 11), angioimmunoblastic T-cell lymphoma (n = 5), enteropathy-associated T-cell lymphoma (n = 5) and other rare subtypes (n = 3). Thirty-six patients with a median age of 50 years (range 22-65) were transplanted in first response and seven after relapse. After a median follow-up of 63 months, estimated overall survival at 12 years was 40%, progression-free survival at 12 years was 34% and event-free survival at 12 years was 30%. On univariate analysis, age less than 50 years and no B symptoms at diagnosis were significantly associated with prolonged overall and progression-free-survival. HDCT/ASCT for peripheral T-cell lymphoma can lead to long-term survival for patients responding to induction chemotherapy.

[Sarcoidosis flare after autologous stem cell transplantation: An immune paradox?

PubMed

Marchal, A; Charlotte, F; Maksud, P; Haroche, J; Lifferman, F; Miyara, M; Choquet, S; Amoura, Z; Cohen Aubart, F

2017-09-01

Sarcoidosis is a systemic granulomatous disorder of unknown cause. Apparition or flare of previously diagnosed sarcoidosis following hematopoietic stem cell transplantation (HSCT) has rarely been reported. We report a 62-year-old woman who presented a radiological flare of sarcoidosis post-autologous stem cell transplantation for a POEMS syndrome. Imaging findings and lymph node histology, which revealed non-caseating granuloma, were consistent with the sarcoidosis diagnosis. The patient was asymptomatic and was kept free of treatment. Sarcoidosis must be considered ahead of compatible clinicoradiological presentation occurring after HSCT. Sarcoidosis can mimic metastatic cancer or lymphatic relapse. Tissue biopsies and exclusion of differential diagnosis of granuloma diseases are warranted to confirm sarcoidosis diagnosis. Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Clinical Evaluation of Decellularized Nerve Allograft with Autologous Bone Marrow Stem Cells to Improve Peripheral Nerve Repair and Functional Outcomes

DTIC Science & Technology

2016-07-01

AWARD NUMBER: W81XWH-15-2-0026 TITLE: Clinical Evaluation of Decellularized Nerve Allograft With Autologous Bone Marrow Stem Cells To Improve...5b. GRANT NUMBER W81XWH-15-2-0026 CClinical Evaluation of Decellularized Nerve Allograft With Autologous Bone Marrow Stem Cells To Improve...co- treatments of a commercially available decellularized processed peripheral nerve allograft scaffold (Avance® Nerve Graft, AxoGen, Alachua FL) with

Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis

PubMed Central

Abrahamsson, Sofia V.; Angelini, Daniela F.; Dubinsky, Amy N.; Morel, Esther; Oh, Unsong; Jones, Joanne L.; Carassiti, Daniele; Reynolds, Richard; Salvetti, Marco; Calabresi, Peter A.; Coles, Alasdair J.; Battistini, Luca; Martin, Roland; Burt, Richard K.

2013-01-01

Autologous haematopoietic stem cell transplantation has been tried as one experimental strategy for the treatment of patients with aggressive multiple sclerosis refractory to other immunotherapies. The procedure is aimed at ablating and repopulating the immune repertoire by sequentially mobilizing and harvesting haematopoietic stem cells, administering an immunosuppressive conditioning regimen, and re-infusing the autologous haematopoietic cell product. ‘Non-myeloablative’ conditioning regimens to achieve lymphocytic ablation without marrow suppression have been proposed to improve safety and tolerability. One trial with non-myeloablative autologous haematopoietic stem cell transplantation reported clinical improvement and inflammatory stabilization in treated patients with highly active multiple sclerosis. The aim of the present study was to understand the changes in the reconstituted immune repertoire bearing potential relevance to its mode of action. Peripheral blood was obtained from 12 patients with multiple sclerosis participating in the aforementioned trial and longitudinally followed for 2 years. We examined the phenotype and function of peripheral blood lymphocytes by cell surface or intracellular staining and multi-colour fluorescence activated cell sorting alone or in combination with proliferation assays. During immune reconstitution post-transplantation we observed significant though transient increases in the proportion of CD4+FoxP3+ T cells and CD56high natural killer cell subsets, which are cell subsets associated with immunoregulatory function. CD8+CD57+ cytotoxic T cells were persistently increased after therapy and were able to suppress CD4+ T cell proliferation with variable potency. In contrast, a CD161high proinflammatory CD8+ T cell subset was depleted at all time-points post-transplantation. Phenotypic characterization revealed that the CD161highCD8+ T cells were mucosal-associated invariant T cells, a novel cell population originating

[Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction].

PubMed

Strauer, B E; Brehm, M; Zeus, T; Gattermann, N; Hernandez, A; Sorg, R V; Kögler, G; Wernet, P

2001-08-24

The regenerative potential of human autologous adult stem cells on myocardial regeneration and neovascularisation after myocardial infarction may contribute to healing of the infarction area. But no clinical application has previously been reported. We here describe for the first time the results of this method applied in a patient who had sustained an acute myocardial infarction. 14 hours after the onset of left precordial pain a 46-year-old man was admitted to our hospital for interventional diagnosis and treatment. Coronary angiography demonstrated occlusion of the anterior descending branch of the left coronary artery with transmural infarction. This was treated by percutaneous transluminal catheter angioplasty and stent placement. Mononuclear bone marrow cells of the patient were prepared and 6 days after infaction 1,2 infinity 107 cells were transplanted at low pressure via a percutaneous transluminal catheter placed in the infarct-related artery. Before and 10 weeks after this procedure left ventricular function, infarct size, ventricular geometry and myocardial perfusion were measured by (201)thallium SPECT both at rest and on exercise, together with bull's-eye analysis, dobutamine stress echocardiography, right heart catheterisation and radionuclide ventriculography. At 10 weeks after the stem cell transplantation the transmural infarct area had been reduced from 24.6 % to 15.7 % of left ventricular circumference, while ejection fraction, cardiac index and stroke volume had increased by 20-30 %. On exercise the end diastolic volume had decreased by 30 % and there was a comparable fall in left ventricular filling pressure (mean pulmonary capillary pressure). These results for the first time demonstrate that selective intracoronary transplantation of human autologous adult stem cells is possible under clinical conditions and that it can lead to regeneration of the myocardial scar after transmural infarction. The therapeutic effects may be ascribed to stem

Nanofat-derived stem cells with platelet-rich fibrin improve facial contour remodeling and skin rejuvenation after autologous structural fat transplantation

PubMed Central

Liang, Zhi-Jie; Chen, Hai; Zhu, Mao-Guang; Xu, Fang-Tian; He, Ning; Wei, Xiao-Juan; Li, Hong-Mian

2017-01-01

Traditional autologous fat transplantation is a common surgical procedure for treating facial soft tissue depression and skin aging. However, the transplanted fat is easily absorbed, reducing the long-term efficacy of the procedure. Here, we examined the efficacy of nanofat-assisted autologous fat structural transplantation. Nanofat-derived stem cells (NFSCs) were isolated, mechanically emulsified, cultured, and characterized. Platelet-rich fibrin (PRF) enhanced proliferation and adipogenic differentiation of NFSCs in vitro. We then compared 62 test group patients with soft tissue depression or signs of aging who underwent combined nanofat, PRF, and autologous fat structural transplantation to control patients (77 cases) who underwent traditional autologous fat transplantation. Facial soft tissue depression symptoms and skin texture were improved to a greater extent after nanofat transplants than after traditional transplants, and the nanofat group had an overall satisfaction rate above 90%. These data suggest that NFSCs function similarly to mesenchymal stem cells and share many of the biological characteristics of traditional fat stem cell cultures. Transplants that combine newly-isolated nanofat, which has a rich stromal vascular fraction (SVF), with PRF and autologous structural fat granules may therefore be a safe, highly-effective, and long-lasting method for remodeling facial contours and rejuvenating the skin. PMID:28978136

Patients' health beliefs and coping prior to autologous peripheral stem cell transplantation.

PubMed

Frick, E; Fegg, M J; Tyroller, M; Fischer, N; Bumeder, I

2007-03-01

The aim of this study was to determine the associations between health locus of control (LoC), causal attributions and coping in tumour patients prior to autologous peripheral blood stem cell transplantation. Patients completed the Questionnaire of Health Related Control Expectancies, the Questionnaire of Personal Illness Causes (QPIC), and the Freiburg Questionnaire of Coping with Illness. A total of 126 patients (45% women; 54% suffering from a multiple myeloma, 29% from non-Hodgkin lymphomas, and 17% from other malignancies) participated in the study. Cluster analysis yielded four LoC clusters: 'fatalistic external', 'powerful others', 'yeah-sayer' and 'double external'. Self-blaming QPIC items were positively correlated with depressive coping, and 'fate or destiny' attributions with religious coping (P<0.001). The highest scores were found for 'active coping' in the LoC clusters 'powerful others' and 'yeah-sayer'. External LoC and an active coping style prevail before undergoing autologous peripheral blood stem cell transplantation, whereas the depressive coping is less frequent, associated with self-blaming causal attributions. Health beliefs include causal and control attributions, which can improve or impair the patient's adjustment. A mixture between internal and external attributions seems to be most adaptive.

Combined transplantation of autologous hematopoietic stem cells and allogenic mesenchymal stem cells increases T regulatory cells in systemic lupus erythematosus with refractory lupus nephritis and leukopenia.

PubMed

Wang, Q; Qian, S; Li, J; Che, N; Gu, L; Wang, Q; Liu, Y; Mei, H

2015-10-01

Autologous hematopoietic stem cell (HSC) and mesenchymal stem cell (MSC) transplantation is currently being evaluated as a novel treatment for autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we report a case of autologous HSC transplantation combined with MSCs in a 25-year-old severe SLE patient with multiple life-threatening complications and refractory to conventional cyclophosphamide (CYC) therapy. After being pretreated with CYC, fludarabine and antithymocyte globulin, the patient was transplanted with autologous CD34+HSCs and MSCs by intravenous infusion. Hematopoietic regeneration was observed on day 12 thereafter. After HSC and MSC transplantation, the patient's clinical symptoms caused by SLE were remitted, and the SLEDAI score decreased. Moreover, CD4+CD25+FoxP3+Treg cells increased in peripheral blood mononuclear cells (PBMCs) after transplantation. This result suggests that the combined transplantation of HSCs and MSCs may reset the adaptive immune system to re-establish self-tolerance in SLE. A 36-month follow-up showed that the clinical symptoms remained in remission. Although a longer follow-up is required for assessing the long-term efficacy, our present results suggest that the combined transplantation of HSCs and MSCs may be a novel and effective therapy for refractory SLE. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

DHAP plus filgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory lymphoma: A single center experience.

PubMed

Berber, Ilhami; Erkurt, Mehmet Ali; Kuku, Irfan; Kaya, Emin; Bag, Harika Gozukara; Nizam, Ilknur; Koroglu, Mustafa; Ozgul, Mustafa

2016-02-01

This study aimed to evaluate the efficiency of DHAP regimen plus filgrastim for mobilization of stem cells in patients with recurrent and/or refractory lymphoma. Thirty-four patients who took DHAP as salvage therapy prior to autologous stem cell transplantation were included. After chemotherapies, 2 cycles of DHAP plus filgrastim were administered to the patients. Stem cells from 32 patients (94%) were collected on median 11th day (8-12), and the median collected CD34(+) cell dose was 9.7 × 10(6)/kg (range 3.8-41.6). DHAP plus filgrastim was found to be an effective chemotherapy regimen in mobilizing CD34(+) stem cells into the peripheral. Copyright © 2016 Elsevier Ltd. All rights reserved.

Open for business: a comparative study of websites selling autologous stem cells in Australia and Japan.

PubMed

Munsie, Megan; Lysaght, Tamra; Hendl, Tereza; Tan, Hui-Yin Lynn; Kerridge, Ian; Stewart, Cameron

2017-11-10

This article examines online marketing practices of Japanese and Australian clinics offering putative autologous stem cell treatments. We conducted google searches for keywords related to stem cell therapy and stem cell clinics in English and Japanese. We identified websites promoting 88 point-of-sale clinics in Japan and 70 in Australia. Our findings provide further evidence of the rapid global growth in clinics offering unproven stem cell interventions. We also show that these clinics adopt strategies to promote their services as though they are consistent with evidentiary and ethical standards of science, research and medicine. Unless addressed, these practices risk harming not only vulnerable patients but also undermining public trust in science and medicine.

Perivascular Mesenchymal Stem Cells in Sheep: Characterization and Autologous Transplantation in a Model of Articular Cartilage Repair.

PubMed

Hindle, Paul; Baily, James; Khan, Nusrat; Biant, Leela C; Simpson, A Hamish R; Péault, Bruno

2016-11-01

Previous research has indicated that purified perivascular stem cells (PSCs) have increased chondrogenic potential compared to conventional mesenchymal stem cells (MSCs) derived in culture. This study aimed to develop an autologous large animal model for PSC transplantation and to specifically determine if implanted cells are retained in articular cartilage defects. Immunohistochemistry and fluorescence-activated cell sorting were used to ascertain the reactivity of anti-human and anti-ovine antibodies, which were combined and used to identify and isolate pericytes (CD34 - CD45 - CD146 + ) and adventitial cells (CD34 + CD45 - CD146 - ). The purified cells demonstrated osteogenic, adipogenic, and chondrogenic potential in culture. Autologous ovine PSCs (oPSCs) were isolated, cultured, and efficiently transfected using a green fluorescence protein (GFP) encoding lentivirus. The cells were implanted into articular cartilage defects on the medial femoral condyle using hydrogel and collagen membranes. Four weeks following implantation, the condyle was explanted and confocal laser scanning microscopy demonstrated the presence of oPSCs in the defect repaired with the hydrogel. These data suggest the testability in a large animal of native MSC autologous grafting, thus avoiding possible biases associated with xenotransplantation. Such a setting will be used in priority for indications in orthopedics, at first to model articular cartilage repair.

Scaffold-Based Delivery of Autologous Mesenchymal Stem Cells for Mandibular Distraction Osteogenesis: Preliminary Studies in a Porcine Model

PubMed Central

Sun, Zongyang; Tee, Boon Ching; Kennedy, Kelly S.; Kennedy, Patrick M.; Kim, Do-Gyoon; Mallery, Susan R.; Fields, Henry W.

2013-01-01

Purpose Bone regeneration through distraction osteogenesis (DO) is promising but remarkably slow. To accelerate it, autologous mesenchymal stem cells have been directly injected to the distraction site in a few recent studies. Compared to direct injection, a scaffold-based method can provide earlier cell delivery with potentially better controlled cell distribution and retention. This pilot project investigated a scaffold-based cell-delivery approach in a porcine mandibular DO model. Materials and Methods Eleven adolescent domestic pigs were used for two major sets of studies. The in-vitro set established methodologies to: aspirate bone marrow from the tibia; isolate, characterize and expand bone marrow-derived mesenchymal stem cells (BM-MSCs); enhance BM-MSC osteogenic differentiation using FGF-2; and confirm cell integration with a gelatin-based Gelfoam scaffold. The in-vivo set transplanted autologous stem cells into the mandibular distraction sites using Gelfoam scaffolds; completed a standard DO-course and assessed bone regeneration by macroscopic, radiographic and histological methods. Repeated-measure ANOVAs and t-tests were used for statistical analyses. Results From aspirated bone marrow, multi-potent, heterogeneous BM-MSCs purified from hematopoietic stem cell contamination were obtained. FGF-2 significantly enhanced pig BM-MSC osteogenic differentiation and proliferation, with 5 ng/ml determined as the optimal dosage. Pig BM-MSCs integrated readily with Gelfoam and maintained viability and proliferative ability. After integration with Gelfoam scaffolds, 2.4–5.8×107 autologous BM-MSCs (undifferentiated or differentiated) were transplanted to each experimental DO site. Among 8 evaluable DO sites included in the final analyses, the experimental DO sites demonstrated less interfragmentary mobility, more advanced gap obliteration, higher mineral content and faster mineral apposition than the control sites, and all transplanted scaffolds were completely

Septicemia from Lactobacillus rhamnosus GG, from a Probiotic Enriched Yogurt, in a Patient with Autologous Stem Cell Transplantation.

PubMed

Koyama, Satoshi; Fujita, Hiroyuki; Shimosato, Takeshi; Kamijo, Aki; Ishiyama, Yasufumi; Yamamoto, Eri; Ishii, Yoshimi; Hattori, Yukako; Hagihara, Maki; Yamazaki, Etsuko; Tomita, Naoto; Nakajima, Hideaki

2018-02-17

Probiotic-rich foods are consumed without much restriction. We report here, a case of septic shock caused by yogurt derived Lactobacillus species in a 54-year-old male patient with acute promyelocytic leukemia, in second complete remission, and who was an autologous stem cell transplantation recipient. He received high dose chemotherapy and autologous peripheral blood stem cell transplantation. He ingested commercially available probiotic-enriched yogurt because of severe diarrhea. One week later, he developed septic shock, and the pathogen was determined by strain-specific PCR analysis as Lactobacillus rhamnosus GG (ATCC 53103), which was found to be identical with the strain in the yogurt he consumed. Thus, because even low virulent Lactobacilli in the probiotic products can be pathogenic in the compromised hosts, ingestion of such products should be considered with caution in neutropenic patients with severe diarrhea, such as stem cell transplantation recipients.

Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma.

PubMed

Le Gouill, Steven; Thieblemont, Catherine; Oberic, Lucie; Moreau, Anne; Bouabdallah, Krimo; Dartigeas, Caroline; Damaj, Gandhi; Gastinne, Thomas; Ribrag, Vincent; Feugier, Pierre; Casasnovas, Olivier; Zerazhi, Hacène; Haioun, Corinne; Maisonneuve, Hervé; Houot, Roch; Jardin, Fabrice; Van Den Neste, Eric; Tournilhac, Olivier; Le Dû, Katell; Morschhauser, Franck; Cartron, Guillaume; Fornecker, Luc-Matthieu; Canioni, Danielle; Callanan, Mary; Béné, Marie C; Salles, Gilles; Tilly, Hervé; Lamy, Thierry; Gressin, Remy; Hermine, Olivier

2017-09-28

Mantle-cell lymphoma is generally incurable. Despite high rates of complete response after initial immunochemotherapy followed by autologous stem-cell transplantation, patients have relapses. We investigated whether rituximab maintenance therapy at a dose of 375 mg per square meter of body-surface area administered every 2 months for 3 years after transplantation would prolong the duration of response. In a phase 3 trial involving 299 patients who were younger than 66 years of age at diagnosis, we randomly assigned 240 patients to receive rituximab maintenance therapy or to undergo observation after autologous stem-cell transplantation (120 patients per group); 59 patients did not undergo randomization. The primary end point was event-free survival (with an event defined as disease progression, relapse, death, allergy to rituximab, or severe infection) after transplantation among patients who underwent randomization. After four courses of immunochemotherapy induction (rituximab, dexamethasone, cytarabine, and a platinum derivative [R-DHAP]), the overall response rate was 89%, and the complete response rate 77%. Transplantation was performed in 257 patients. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Starting from randomization, the rate of event-free survival at 4 years was 79% (95% confidence interval [CI], 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P=0.001). The rate of progression-free survival at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001). The rate of overall survival was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). According to a Cox regression unadjusted analysis, the rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0

Enhancement of the repair of dog alveolar cleft by an autologous iliac bone, bone marrow-derived mesenchymal stem cell, and platelet-rich fibrin mixture.

PubMed

Yuanzheng, Chen; Yan, Gao; Ting, Li; Yanjie, Fu; Peng, Wu; Nan, Bai

2015-05-01

Autologous bone graft has been regarded as the criterion standard for the repair of alveolar cleft. However, the most prominent issue in alveolar cleft treatment is the high absorption rate of the bone graft. The authors' objective was to investigate the effects of an autologous iliac bone, bone marrow-derived mesenchymal stem cell, and platelet-rich fibrin mixture on the repair of dog alveolar cleft. Twenty beagle dogs with unilateral alveolar clefts created by surgery were divided randomly into four groups: group A underwent repair with an autologous iliac bone, bone marrow-derived mesenchymal stem cell, and platelet-rich fibrin mixture; group B underwent repair with autologous iliac bone and bone marrow-derived mesenchymal stem cells; group C underwent repair with autologous iliac bone and platelet-rich fibrin; and group D underwent repair with autologous iliac bone as the control. One day and 6 months after transplantation, the transplant volumes and bone mineral density were assessed by quantitative computed tomography. All of the transplants were harvested for hematoxylin and eosin staining 6 months later. Bone marrow-derived mesenchymal stem cells and platelet-rich fibrin transplants formed the greatest amounts of new bone among the four groups. The new bone formed an extensive union with the underlying maxilla in groups A, B, and C. Transplants with the bone marrow-derived mesenchymal stem cells, platelet-rich fibrin, and their mixture retained the majority of their initial volume, whereas the transplants in the control group showed the highest absorption rate. Bone mineral density of transplants with the bone marrow-derived mesenchymal stem cells, platelet-rich fibrin, and their mixture 6 months later was significantly higher than in the control group (p < 0.05), and was the highest in bone marrow-derived mesenchymal stem cells and platelet-rich fibrin mixed transplants. Hematoxylin and eosin staining showed that the structure of new bones formed the best

How we manage autologous stem cell transplantation for patients with multiple myeloma

PubMed Central

Dingli, David

2014-01-01

An estimated 22 350 patients had multiple myeloma diagnosed in 2013, representing 1.3% of all new cancers; 10 710 deaths are projected, representing 1.8% of cancer deaths. Approximately 0.7% of US men and women will have a myeloma diagnosis in their lifetime, and with advances in therapy, 77 600 US patients are living with myeloma. The 5-year survival rate was 25.6% in 1989 and was 44.9% in 2005. The median age at diagnosis is 69 years, with 62.4% of patients aged 65 or older at diagnosis. Median age at death is 75 years. The rate of new myeloma cases has been rising 0.7% per year during the past decade. The most common indication for autologous stem cell transplantation in the United States is multiple myeloma, and this article is designed to provide the specifics of organizing a transplant program for multiple myeloma. We review the data justifying use of stem cell transplantation as initial management in myeloma patients. We provide selection criteria that minimize the risks of transplantation. Specific guidelines on mobilization and supportive care through the transplant course, as done at Mayo Clinic, are given. A review of the data on tandem vs sequential autologous transplants is provided. PMID:24973360

Treatment of AVN Using Autologous BM Stem Cells and Activated Platelet-Derived Growth Factor Concentrates.

PubMed

Nandeesh, Nagaraj H; Janardhan, Kiranmayee; Subramanian, Vignesh; Ashtekar, Abhishek Bhushan; Srikruthi, Nandagiri; Koka, Prasad S; Deb, Kaushik

Avascular Necrosis (AVN) of hip is a devastating condition seen in younger individuals. It is the ischemic death of the constituents of the bone cartilage of the hip. The femoral head (FH) is the most common site for AVN. It results from interruption of the normal blood flow to the FH that fits into the hip socket. Earlier studies using autologous bone marrow stem cell concentrate injections have shown encouraging results with average success rates. The current study was designed to improve significantly the cartilage regeneration and clinical outcome. Total of 48 patients underwent autologous bone marrow stem cell and activated platelet-rich plasma derived growth factor concentrate (PRP-GFC) therapy for early and advanced stages AVN of femoral head in a single multi-specialty center. The total treatment was divided into three phases. In the phase I, all the clinical diagnostic measurements such as magnetic resonance imaging (MRI), computed tomography (CT) etc. with respect to the AVN patients and bone marrow aspiration from posterior iliac spine from the patients were carried out. In the phase II, isolation of stem cells and preparation from the patients were performed. Subsequently, in phase III, the stem cells and PRP- GFCs were transplanted in the enrolled patients. Ninety three percent of the enrolled AVN patients showed marked enhancement in the hip bone joint space (more than 3mm) after combined stem cells and PRP-GFC treatment as evidenced by comparison of the pre- and post-treatment MRI data thus indicative of regeneration of cartilage. The treated patients showed significant improvement in their motor function, cartilage regrowth (3 to 10mm), and high satisfaction in the two-year follow-up. Combination of stem cell and PRP-GFC therapy has shown promising cartilage regeneration in 45 out of 48 patients of AVN. This study clearly demonstrates the safety and efficacy of this treatment. Larger numbers of patients need to be evaluated to better understand the

TOOTH (The Open study Of dental pulp stem cell Therapy in Humans): Study protocol for evaluating safety and feasibility of autologous human adult dental pulp stem cell therapy in patients with chronic disability after stroke.

PubMed

Nagpal, Anjali; Kremer, Karlea L; Hamilton-Bruce, Monica A; Kaidonis, Xenia; Milton, Austin G; Levi, Christopher; Shi, Songtao; Carey, Leeanne; Hillier, Susan; Rose, Miranda; Zacest, Andrew; Takhar, Parabjit; Koblar, Simon A

2016-07-01

Stroke represents a significant global disease burden. As of 2015, there is no chemical or biological therapy proven to actively enhance neurological recovery during the chronic phase post-stroke. Globally, cell-based therapy in stroke is at the stage of clinical translation and may improve neurological function through various mechanisms such as neural replacement, neuroprotection, angiogenesis, immuno-modulation, and neuroplasticity. Preclinical evidence in a rodent model of middle cerebral artery ischemic stroke as reported in four independent studies indicates improvement in neurobehavioral function with adult human dental pulp stem cell therapy. Human adult dental pulp stem cells present an exciting potential therapeutic option for improving post-stroke disability. TOOTH (The Open study Of dental pulp stem cell Therapy in Humans) will investigate the use of autologous stem cell therapy for stroke survivors with chronic disability, with the following objectives: (a) determine the maximum tolerable dose of autologous dental pulp stem cell therapy; (b) define that dental pulp stem cell therapy at the maximum tolerable dose is safe and feasible in chronic stroke; and (c) estimate the parameters of efficacy required to design a future Phase 2/3 clinical trial. TOOTH is a Phase 1, open-label, single-blinded clinical trial with a pragmatic design that comprises three stages: Stage 1 will involve the selection of 27 participants with middle cerebral artery ischemic stroke and the commencement of autologous dental pulp stem cell isolation, growth, and testing in sequential cohorts (n = 3). Stage 2 will involve the transplantation of dental pulp stem cell in each cohort of participants with an ascending dose and subsequent observation for a 6-month period for any dental pulp stem cell-related adverse events. Stage 3 will investigate the neurosurgical intervention of the maximum tolerable dose of autologous dental pulp stem cell followed by 9 weeks of intensive task

Gingival Fibroblasts as Autologous Feeders for Induced Pluripotent Stem Cells.

PubMed

Yu, G; Okawa, H; Okita, K; Kamano, Y; Wang, F; Saeki, M; Yatani, H; Egusa, H

2016-01-01

Human gingival fibroblasts (hGFs) present an attractive source of induced pluripotent stem cells (iPSCs), which are expected to be a powerful tool for regenerative dentistry. However, problems to be addressed prior to clinical application include the use of animal-derived feeder cells for cultures. The aim of this study was to establish an autologous hGF-derived iPSC (hGF-iPSC) culture system by evaluating the feeder ability of hGFs. In both serum-containing and serum-free media, hGFs showed higher proliferation than human dermal fibroblasts (hDFs). Three hGF strains were isolated under serum-free conditions, although 2 showed impaired proliferation. When hGF-iPSCs were transferred onto mitomycin C-inactivated hGFs, hDFs, or mouse-derived SNL feeders, hGF and SNL feeders were clearly hGF-iPSC supportive for more than 50 passages, whereas hDF feeders were only able to maintain undifferentiated hGF-iPSC growth for a few passages. After 20 passages on hGF feeders, embryonic stem cell marker expression and CpG methylation at the NANOG and OCT3/4 promoters were similar for hGF-iPSCs cultured on hGF and SNL feeder cells. Long-term cultures of hGF-iPSCs on hGF feeders sustained their normal karyotype and pluripotency. On hGF feeders, hGF-iPSC colonies were surrounded by many colony-derived fibroblast-like cells, and the size of intact colonies at 7 d after passage was significantly larger than that on SNL feeders. Allogeneic hGF strains also maintained hGF-iPSCs for 10 passages. Compared with hDFs, hGFs showed a higher production of laminin-332, laminin α5 chain, and insulin-like growth factor-II, which have been reported to sustain the long-term self-renewal of pluripotent stem cells. These results suggest that hGFs possess an excellent feeder capability and thus can be used as alternatives to conventional mouse-derived SNL and hDF feeders. In addition, our findings suggest that hGF feeders are promising candidates for animal component-free ex vivo expansion of

Autologous bone marrow stem cell transplantation for the treatment of postoperative hand infection with a skin defect in diabetes mellitus: A case report.

PubMed

Liu, Yihong; Liu, Yuchen; Wang, Pujie; Tian, Haoming; Ai, Jianzhong; Liu, Yangbo; Zhou, Yi; Liu, Zhongwen; Guo, Wenjun; Yang, Shenke

2014-06-01

Among stem cells, autologous mesenchymal stem cells (MSCs) are ideal for transplantation by virtue of limited rejection reactions and marked proliferative ability. This study presents a novel method by which MSCs were harvested from the bone marrow of a patient who presented with severe post-traumatic infection and a non-healing skin defect in the hand, secondary to uncontrolled diabetes mellitus (DM). An autologous MSC suspension was injected into the persistent skin defect after stabilizing the blood glucose level and appropriate infection control. During the course of a regular 18-month postoperative follow-up, the patient exhibited immediate recovery with no transplant-associated complications, as well as no evidence of tumorigenicity. Thus, transplantation of autologous MSCs may play a role in the clinical application of stem cells, particularly for treatment of skin defects following surgery in cases of DM and for those caused by various other traumas.

Peripheral blood stem cell mobilization and engraftment after autologous stem cell transplantation with biosimilar rhG-CSF.

PubMed

Reményi, Péter; Gopcsa, László; Marton, Imelda; Réti, Marienn; Mikala, Gábor; Pető, Mónika; Barta, Anikó; Bátai, Arpád; Farkas, Zita; Borbényi, Zita; Csukly, Zoltán; Bodó, Imre; Fábián, János; Király, Agnes; Lengyel, Lilla; Piukovics, Klára; Torbágyi, Eva; Masszi, Tamás

2014-04-01

Biosimilar versions of filgrastim [recombinant human granulocyte colony-stimulating factor (rhG-CSF)] are now widely available. To date, biosimilar rhG-CSF has demonstrated a comparable quality, safety and efficacy profile to the originator product (filgrastim [Neupogen(®)], Amgen Inc., CA, USA) in the prevention and management of neutropenia. Biosimilar rhG-CSFs have also been used to induce peripheral blood stem cell (PBSC) mobilization in patients undergoing autologous stem cell transplantation (AHSCT). The authors have examined the effectiveness of a biosimilar rhG-CSF (Zarzio(®), Sandoz Biopharmaceuticals, Holzkirchen, Germany) in two retrospective studies across two medical centers in Hungary. In Study 1, 70 patients with hematological malignancies scheduled to undergo AHSCT received chemotherapy followed by biosimilar rhG-CSF (2 × 5 μg) for facilitating neutrophil, leukocyte, and platelet engraftment. In study 2, 40 additional patients with lymphoid malignancies and planned AHSCT received chemotherapy followed by biosimilar rhG-CSF for PBSC mobilization. The effectiveness of treatment was assessed by the average yield of cluster of differentiation (CD) 34+ cells and the number of leukaphereses required. In Study 1 (patients undergoing AHSCT), the median age was 56 years and most patients were male (60%). The conditioning regimens were mainly high-dose melphalan (n = 41) and carmustine (BiCNU(®), Bristol-Myers Squibb, NJ, USA), etoposide, cytarabine and melphalan BEAM (n = 21). Median times to absolute neutrophil and leukocyte engraftment were 9 (range 8-11 days) and 10 (8-12) days, respectively. Median time to platelet engraftment was 10.5 days (7-19 days). In Study 2, the patients' median age was 54 years and the majority (57.5%) were female. The median time interval between day 1 of mobilizing chemotherapy and first leukapheresis was 12 (9-27) days. In the autologous PBSC grafts, the median number of CD34+ cells harvested was 5.2 × 10(6)/kg (2

Derivation of Neural Stem Cells from Human Adult Peripheral CD34+ Cells for an Autologous Model of Neuroinflammation

PubMed Central

Wang, Tongguang; Choi, Elliot; Monaco, Maria Chiara G.; Campanac, Emilie; Medynets, Marie; Do, Thao; Rao, Prashant; Johnson, Kory R.; Elkahloun, Abdel G.; Von Geldern, Gloria; Johnson, Tory; Subramaniam, Sriram; Hoffman, Dax; Major, Eugene; Nath, Avindra

2013-01-01

Proinflammatory factors from activated T cells inhibit neurogenesis in adult animal brain and cultured human fetal neural stem cells (NSC). However, the role of inhibition of neurogenesis in human neuroinflammatory diseases is still uncertain because of the difficulty in obtaining adult NSC from patients. Recent developments in cell reprogramming suggest that NSC may be derived directly from adult fibroblasts. We generated NSC from adult human peripheral CD34+ cells by transfecting the cells with Sendai virus constructs containing Sox2, Oct3/4, c-Myc and Klf4. The derived NSC could be differentiated to glial cells and action potential firing neurons. Co-culturing NSC with activated autologous T cells or treatment with recombinant granzyme B caused inhibition of neurogenesis as indicated by decreased NSC proliferation and neuronal differentiation. Thus, we have established a unique autologous in vitro model to study the pathophysiology of neuroinflammatory diseases that has potential for usage in personalized medicine. PMID:24303066

High-dose chemotherapy with autologous hematopoietic stem cell support for solid tumors in adults.

PubMed

Pedrazzoli, Paolo; Rosti, Giovanni; Secondino, Simona; Carminati, Ornella; Demirer, Taner

2007-10-01

Supported by experimental evidence and convincing results of early phase II studies, since the 1980s high-dose chemotherapy (HDC) with autologous hematopoietic stem cell support (AHSCT) has been uncritically adopted by many oncologists as a potentially curative option for several solid tumors. As a result, the number (and size) of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) in this setting was limited and the benefit of a greater escalation of dose of chemotherapy with stem cell transplantation in solid tumors remains, with the possible exception of breast carcinoma (BC) and germ cell tumors (GCT), largely unsettled. In this article, we review and comment on the data from studies to date of HDC for solid tumors in adults.

Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: a randomized clinical trial.

PubMed

Chen, Fa-Ming; Gao, Li-Na; Tian, Bei-Min; Zhang, Xi-Yu; Zhang, Yong-Jie; Dong, Guang-Ying; Lu, Hong; Chu, Qing; Xu, Jie; Yu, Yang; Wu, Rui-Xin; Yin, Yuan; Shi, Songtao; Jin, Yan

2016-02-19

Periodontitis, which progressively destroys tooth-supporting structures, is one of the most widespread infectious diseases and the leading cause of tooth loss in adults. Evidence from preclinical trials and small-scale pilot clinical studies indicates that stem cells derived from periodontal ligament tissues are a promising therapy for the regeneration of lost/damaged periodontal tissue. This study assessed the safety and feasibility of using autologous periodontal ligament stem cells (PDLSCs) as an adjuvant to grafting materials in guided tissue regeneration (GTR) to treat periodontal intrabony defects. Our data provide primary clinical evidence for the efficacy of cell transplantation in regenerative dentistry. We conducted a single-center, randomized trial that used autologous PDLSCs in combination with bovine-derived bone mineral materials to treat periodontal intrabony defects. Enrolled patients were randomly assigned to either the Cell group (treatment with GTR and PDLSC sheets in combination with Bio-oss(®)) or the Control group (treatment with GTR and Bio-oss(®) without stem cells). During a 12-month follow-up study, we evaluated the frequency and extent of adverse events. For the assessment of treatment efficacy, the primary outcome was based on the magnitude of alveolar bone regeneration following the surgical procedure. A total of 30 periodontitis patients aged 18 to 65 years (48 testing teeth with periodontal intrabony defects) who satisfied our inclusion and exclusion criteria were enrolled in the study and randomly assigned to the Cell group or the Control group. A total of 21 teeth were treated in the Control group and 20 teeth were treated in the Cell group. All patients received surgery and a clinical evaluation. No clinical safety problems that could be attributed to the investigational PDLSCs were identified. Each group showed a significant increase in the alveolar bone height (decrease in the bone-defect depth) over time (p < 0.001). However

Aging of bone marrow mesenchymal stromal/stem cells: Implications on autologous regenerative medicine.

PubMed

Charif, N; Li, Y Y; Targa, L; Zhang, L; Ye, J S; Li, Y P; Stoltz, J F; Han, H Z; de Isla, N

2017-01-01

With their proliferation, differentiation into specific cell types, and secretion properties, mesenchymal stromal/stem cells (MSC) are very interesting tools to be used in regenerative medicine. Bone marrow (BM) was the first MSC source characterized. In the frame of autologous MSC therapy, it is important to detect donor's parameters affecting MSC potency. Age of the donors appears as one parameter that could greatly affect MSC properties. Moreover, in vitro cell expansion is needed to obtain the number of cells necessary for clinical developments. It will lead to in vitro cell aging that could modify cell properties. This review recapitulates several studies evaluating the effect of in vitro and in vivo MSC aging on cell properties.

Comparative Efficacy of Autologous Stromal Vascular Fraction and Autologous Adipose-Derived Mesenchymal Stem Cells Combined With Hyaluronic Acid for the Treatment of Sheep Osteoarthritis.

PubMed

Lv, Xiaoteng; He, Jiyin; Zhang, Xue; Luo, Xuan; He, Na; Sun, Zhongwei; Xia, Huitang; Liu, Victor; Zhang, Li; Lin, Xiangming; Lin, Liping; Yin, Huabin; Jiang, Dong; Cao, Wei; Wang, Richard; Zhou, Guangdong; Wang, Wen

2018-01-01

The current study explored whether intra-articular (IA) injection of autologous adipose mesenchymal stem cells (ASCs) combined with hyaluronic acid (HA) achieved better therapeutic efficacy than autologous stromal vascular fraction (SVF) combined with HA to prevent osteoarthritis (OA) progression and determined how long autologous ASCs combined with HA must remain in the joint to observe efficacy. OA models were established by performing anterior cruciate ligament transection (ACLT) and medial meniscectomy (MM). Autologous SVF (1×10 7 mononuclear cells), autologous low-dose ASCs (1×10 7 ), and autologous high-dose ASCs (5×10 7 ) combined with HA, and HA alone, or saline alone were injected into the OA model animals at 12 and 15 weeks after surgery, respectively. Compared with SVF+HA treatment, low-dose ASC+HA treatment yielded better magnetic resonance imaging (MRI) scores and macroscopic results, while the cartilage thickness of the tibial plateau did not differ between low, high ASC+HA and SVF+HA treatments detected by micro-computed tomography (µCT). Immunohistochemistry revealed that high-dose ASC+HA treatment rescued hypertrophic chondrocytes expressing collagen X in the deep area of articular cartilage. Western blotting analysis indicated the high- and low-dose ASC+HA groups expressed more collagen X than did the SVF+HA group. Enzyme-linked immunosorbent assay showed treatment with both ASC+HA and SVF+HA resulted in differing anti-inflammatory and trophic effects. Moreover, superparamagnetic iron oxide particle (SPIO)-labeled autologous ASC signals were detected by MRI at 2 and 18 weeks post-injection and were found in the lateral meniscus at 2 weeks and in the marrow cavity of the femoral condyle at 18 weeks post-injection. Thus, IA injection of autologous ASC+HA may demonstrate better efficacy than autologous SVF+HA in blocking OA progression and promoting cartilage regeneration, and autologous ASCs (5×10 7 cells) combined with HA potentially survive

Safety and efficacy of high-dose chemotherapy with autologous stem cell transplantation for patients with malignant astrocytomas.

PubMed

Chen, Benjamin; Ahmed, Tauseef; Mannancheril, Anney; Gruber, Michael; Benzil, Deborah L

2004-05-15

Malignant astrocytomas are among the most resistant tumors to curative treatments. Mean survival without treatment is measured in weeks, and even with maximal surgery and radiation, the mean reported survival is < 1 year. The advent of supportive treatments and newer agents has resulted in benefits for many patients with cancer. The authors investigated the safety and effect on survival of a high-dose thiotepa and carboplatin regimen with autologous stem cell transplantation (ASCT) in patients with malignant astrocytomas who were enrolled in a prospective trial approved by an institutional review board (IRB). Twenty-one patients were enrolled in an IRB-approved, prospective trial. After baseline testing was completed, patients underwent peripheral stem cell mobilization with cyclophosphamide (4 g/m2) and etoposide (450 mg/m2) followed by granulocyte-colony-stimulating factor (10 microg/kg). Peripheral stem cells were harvested when leukocyte counts recovered. Patients received 2 cycles of thiotepa (750 mg/m2) and carboplatin (1600 mg/m2) followed by infusion of the preserved stem cells. The cycles were administered 6-10 weeks apart. Primary outcome measures were patient survival (Kaplan-Meier analysis) and treatment toxicity (using National Cancer Institute common toxicity criteria). Autologous stem cells were harvested effectively and transfused in all patients. Kaplan-Meier survival analysis demonstrated a survival time of 34.3 +/- 5.5 months (range, 9-94 months). Despite significant myelosuppression, only three patients experienced Grade 4 complications and eight experienced Grade 3 complications. High-dose chemotherapy with thiotepa and carboplatin with concomitant ASCT was used safely to treat patients with malignant astrocytomas and may provide a survival advantage. Copyright 2004 American Cancer Society.

Regenerative Repair of Damaged Meniscus with Autologous Adipose Tissue-Derived Stem Cells

PubMed Central

Pak, Jaewoo; Lee, Jung Hun; Lee, Sang Hee

2014-01-01

Mesenchymal stem cells (MSCs) are defined as pluripotent cells found in numerous human tissues, including bone marrow and adipose tissue. Such MSCs, isolated from bone marrow and adipose tissue, have been shown to differentiate into bone and cartilage, along with other types of tissues. Therefore, MSCs represent a promising new therapy in regenerative medicine. The initial treatment of meniscus tear of the knee is managed conservatively with nonsteroidal anti-inflammatory drugs and physical therapy. When such conservative treatment fails, an arthroscopic resection of the meniscus is necessary. However, the major drawback of the meniscectomy is an early onset of osteoarthritis. Therefore, an effective and noninvasive treatment for patients with continuous knee pain due to damaged meniscus has been sought. Here, we present a review, highlighting the possible regenerative mechanisms of damaged meniscus with MSCs (especially adipose tissue-derived stem cells (ASCs)), along with a case of successful repair of torn meniscus with significant reduction of knee pain by percutaneous injection of autologous ASCs into an adult human knee. PMID:24592390

Autologous stem cell transplantation for the treatment of neuroblastoma in Korea.

PubMed Central

Ryu, Kyung Ha; Ahn, Hyo Seop; Koo, Hong Hoe; Kook, Hoon; Kim, Moon Kyu; Kim, Hack Ki; Ghim, Thad; Moon, Hyung Nam; Seo, Jong Jin; Sung, Ki Woong; Shin, Hee Young; Yoo, Eun Sun; Lyu, Chuhl Joo; Lee, Young Ho; Lee, Hahng; Cho, Bin; Cho, Hyun Sang; Choi, Hyung Soo; Hah, Jeong Ok; Hwang, Tai Ju

2003-01-01

Autologous stem cell transplantation (ASCT) for the treatment of high-risk neuroblastoma (NBL) is an accepted method for restoring bone marrow depression after high dose chemotherapy. We retrospectively analyzed eighty eight cases of NBL that underwent ASCT following marrow ablative therapy at 12 transplant centers of the Korean Society of Pediatric Hematology-Oncology between January 1996 and September 2000. Seventy nine children were of stage IV NBL and 9 were of stage III with N-myc amplification. Various cytoreductive regimens were used. However, the main regimen was 'CEM' consisting of carboplatin, etoposide and melphalan, and this was used in 66 patients. Total body irradiation was also added in 36 patients for myeloablation. To reduce tumor cell contamination, stem cell infusions after CD34+ cell selection were performed in 16 patients. Post-transplantation therapies included the second transplantation in 18 patients, interleukin2 therapy in 45, 13-cis retinoic acid in 40, 131-meta-iodobenzylguanidine in 4, conventional chemotherapy in 11, and local radiotherapy in 8. Twenty two patients died, sixty six patients are surviving 1 to 46 months after ASCT (median followup duration, 14.5 months). Although the follow-up period was short and the number of patients small, we believe that ASCT might improve the survival rate in high-risk NBL. PMID:12692423

EXERCISE in pediatric autologous stem cell transplant patients: a randomized controlled trial protocol

PubMed Central

2012-01-01

Background Hematopoietic stem cell transplantation is an intensive therapy used to improve survivorship and cure various oncologic diseases. However, this therapy is associated with high mortality rates and numerous negative side-effects. The recovery of the immune system is a special concern and plays a key role in the success of this treatment. In healthy populations it is known that exercise plays an important role in immune system regulation, but little is known about the role of exercise in the hematological and immunological recovery of children undergoing hematopoietic stem cell transplant. The primary objective of this randomized-controlled trial (RCT) is to study the effect of an exercise program (in- and outpatient) on immune cell recovery in patients undergoing an autologous stem cell transplantation. The secondary objective is to determine if an exercise intervention diminishes the usual deterioration in quality of life, physical fitness, and the acquisition of a sedentary lifestyle. Methods This RCT has received approval from The Conjoint Health Research Ethics Board (CHREB) of the University of Calgary (Ethics ID # E-24476). Twenty-four participants treated for a malignancy with autologous stem cell transplant (5 to 18 years) in the Alberta Children’s Hospital will be randomly assigned to an exercise or control group. The exercise group will participate in a two-phase exercise intervention (in- and outpatient) from hospitalization until 10 weeks after discharge. The exercise program includes strength, flexibility and aerobic exercise. During the inpatient phase this program will be performed 5 times/week and will be supervised. The outpatient phase will combine a supervised session with two home-based exercise sessions with the use of the Wii device. The control group will follow the standard protocol without any specific exercise program. A range of outcomes, including quantitative and functional recovery of immune system, cytokine levels in

Concise Review: Human Dermis as an Autologous Source of Stem Cells for Tissue Engineering and Regenerative Medicine.

PubMed

Vapniarsky, Natalia; Arzi, Boaz; Hu, Jerry C; Nolta, Jan A; Athanasiou, Kyriacos A

2015-10-01

The exciting potential for regenerating organs from autologous stem cells is on the near horizon, and adult dermis stem cells (DSCs) are particularly appealing because of the ease and relative minimal invasiveness of skin collection. A substantial number of reports have described DSCs and their potential for regenerating tissues from mesenchymal, ectodermal, and endodermal lineages; however, the exact niches of these stem cells in various skin types and their antigenic surface makeup are not yet clearly defined. The multilineage potential of DSCs appears to be similar, despite great variability in isolation and in vitro propagation methods. Despite this great potential, only limited amounts of tissues and clinical applications for organ regeneration have been developed from DSCs. This review summarizes the literature on DSCs regarding their niches and the specific markers they express. The concept of the niches and the differentiation capacity of cells residing in them along particular lineages is discussed. Furthermore, the advantages and disadvantages of widely used methods to demonstrate lineage differentiation are considered. In addition, safety considerations and the most recent advancements in the field of tissue engineering and regeneration using DSCs are discussed. This review concludes with thoughts on how to prospectively approach engineering of tissues and organ regeneration using DSCs. Our expectation is that implementation of the major points highlighted in this review will lead to major advancements in the fields of regenerative medicine and tissue engineering. Autologous dermis-derived stem cells are generating great excitement and efforts in the field of regenerative medicine and tissue engineering. The substantial impact of this review lies in its critical coverage of the available literature and in providing insight regarding niches, characteristics, and isolation methods of stem cells derived from the human dermis. Furthermore, it provides

Concise Review: Human Dermis as an Autologous Source of Stem Cells for Tissue Engineering and Regenerative Medicine

PubMed Central

Vapniarsky, Natalia; Arzi, Boaz; Hu, Jerry C.; Nolta, Jan A.

2015-01-01

The exciting potential for regenerating organs from autologous stem cells is on the near horizon, and adult dermis stem cells (DSCs) are particularly appealing because of the ease and relative minimal invasiveness of skin collection. A substantial number of reports have described DSCs and their potential for regenerating tissues from mesenchymal, ectodermal, and endodermal lineages; however, the exact niches of these stem cells in various skin types and their antigenic surface makeup are not yet clearly defined. The multilineage potential of DSCs appears to be similar, despite great variability in isolation and in vitro propagation methods. Despite this great potential, only limited amounts of tissues and clinical applications for organ regeneration have been developed from DSCs. This review summarizes the literature on DSCs regarding their niches and the specific markers they express. The concept of the niches and the differentiation capacity of cells residing in them along particular lineages is discussed. Furthermore, the advantages and disadvantages of widely used methods to demonstrate lineage differentiation are considered. In addition, safety considerations and the most recent advancements in the field of tissue engineering and regeneration using DSCs are discussed. This review concludes with thoughts on how to prospectively approach engineering of tissues and organ regeneration using DSCs. Our expectation is that implementation of the major points highlighted in this review will lead to major advancements in the fields of regenerative medicine and tissue engineering. Significance Autologous dermis-derived stem cells are generating great excitement and efforts in the field of regenerative medicine and tissue engineering. The substantial impact of this review lies in its critical coverage of the available literature and in providing insight regarding niches, characteristics, and isolation methods of stem cells derived from the human dermis. Furthermore, it

Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia

PubMed Central

Gribben, John G.; Zahrieh, David; Stephans, Katherine; Bartlett-Pandite, Lini; Alyea, Edwin P.; Fisher, David C.; Freedman, Arnold S.; Mauch, Peter; Schlossman, Robert; Sequist, Lecia V.; Soiffer, Robert J.; Marshall, Blossom; Neuberg, Donna; Ritz, Jerome; Nadler, Lee M.

2005-01-01

We report here on the long-term follow-up on 162 patients with high-risk chronic lymphocytic leukemia (CLL) who have undergone hematopoietic stem cell transplantation (SCT) at a single center from 1989 to 1999. Twenty-five patients with human leukocyte antigen (HLA)-matched sibling donors underwent T-cell-depleted allogeneic SCT, and 137 patients without HLA-matched sibling donors underwent autologous SCT. The 100-day mortality was 4% for both groups, but later morbidity and mortality were negatively affected on outcome. Progression-free survival was significantly longer following autologous than allogeneic SCT, but there was no difference in overall survival and no difference in the cumulative incidence of disease recurrence or deaths without recurrence between the 2 groups. At a median follow-up of 6.5 years there is no evidence of a plateau of progression-free survival. The majority of patients treated with donor lymphocyte infusions after relapse responded, demonstrating a significant graft-versus-leukemia effect in CLL. From these findings we have altered our approach for patients with high-risk CLL and are currently exploring the role of related and unrelated allogeneic SCT following reduced-intensity conditioning regimens. PMID:16131571

Autologous mesenchymal stem cells or meniscal cells: what is the best cell source for regenerative meniscus treatment in an early osteoarthritis situation?

PubMed

Zellner, Johannes; Pattappa, Girish; Koch, Matthias; Lang, Siegmund; Weber, Johannes; Pfeifer, Christian G; Mueller, Michael B; Kujat, Richard; Nerlich, Michael; Angele, Peter

2017-10-10

Treatment of meniscus tears within the avascular region represents a significant challenge, particularly in a situation of early osteoarthritis. Cell-based tissue engineering approaches have shown promising results. However, studies have not found a consensus on the appropriate autologous cell source in a clinical situation, specifically in a challenging degenerative environment. The present study sought to evaluate the appropriate cell source for autologous meniscal repair in a demanding setting of early osteoarthritis. A rabbit model was used to test autologous meniscal repair. Bone marrow and medial menisci were harvested 4 weeks prior to surgery. Bone marrow-derived mesenchymal stem cells (MSCs) and meniscal cells were isolated, expanded, and seeded onto collagen-hyaluronan scaffolds before implantation. A punch defect model was performed on the lateral meniscus and then a cell-seeded scaffold was press-fit into the defect. Following 6 or 12 weeks, gross joint morphology and OARSI grade were assessed, and menisci were harvested for macroscopic, histological, and immunohistochemical evaluation using a validated meniscus scoring system. In conjunction, human meniscal cells isolated from non-repairable bucket handle tears and human MSCs were expanded and, using the pellet culture model, assessed for their meniscus-like potential in a translational setting through collagen type I and II immunostaining, collagen type II enzyme-linked immunosorbent assay (ELISA), and gene expression analysis. After resections of the medial menisci, all knees showed early osteoarthritic changes (average OARSI grade 3.1). However, successful repair of meniscus punch defects was performed using either meniscal cells or MSCs. Gross joint assessment demonstrated donor site morbidity for meniscal cell treatment. Furthermore, human MSCs had significantly increased collagen type II gene expression and production compared to meniscal cells (p < 0.05). The regenerative potential of the

Use of peripherally inserted central venous catheters (PICCs) in children receiving autologous or allogeneic stem-cell transplantation.

PubMed

Benvenuti, Stefano; Ceresoli, Rosanna; Boroni, Giovanni; Parolini, Filippo; Porta, Fulvio; Alberti, Daniele

2018-03-01

The aim of our study was to present our experience with the use of peripherally inserted central catheters (PICCs) in pediatric patients receiving autologous or allogenic blood stem-cell transplantation. The insertion of the device in older children does not require general anesthesia and does not require a surgical procedure. From January 2014 to January 2017, 13 PICCs were inserted as a central venous device in 11 pediatric patients submitted to 14 autologous or allogeneic stem-cell transplantation, at the Bone Marrow Transplant Unit of the Children's Hospital of Brescia. The mean age of patients at the time of the procedure was 11.3 years (range 3-18 years). PICCs remained in place for an overall period of 4104 days. All PICCs were positioned by the same specifically trained physician and utilized by nurses of our stem-cell transplant unit. No insertion-related complications were observed. Late complications were catheter ruptures and line occlusions (1.2 per 1000 PICC days). No rupture or occlusion required removal of the device. No catheter-related venous thrombosis, catheter-related bloodstream infection (CRBSI), accidental removal or permanent lumen occlusion were observed. Indications for catheter removal were completion of therapy (8 patients) and death (2 patients). Three PICCs are currently being used for blood sampling in follow-up patients after transplantation. Our data suggest that PICCs are a safe and effective alternative to conventional central venous catheters even in pediatric patients with high risk of infectious and hemorrhagic complications such as patients receiving stem-cell transplantation.

Long-term survival following autologous and allogeneic stem cell transplantation for blastic plasmacytoid dendritic cell neoplasm.

PubMed

Aoki, Tomohiro; Suzuki, Ritsuro; Kuwatsuka, Yachiyo; Kako, Shinichi; Fujimoto, Katsuya; Taguchi, Jun; Kondo, Tadakazu; Ohata, Kinya; Ito, Toshiro; Kamoda, Yoshimasa; Fukuda, Takahiro; Ichinohe, Tatsuo; Takeuchi, Kengo; Izutsu, Koji; Suzumiya, Junji

2015-06-04

We sought to clarify the role of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN). We retrospectively identified 25 BPDCN patients (allo-HSCT, n = 14; auto-HSCT, n = 11) from registry data of the Japan Society for Hematopoietic Cell Transplantation and analyzed clinicopathologic data and clinical outcomes after transplantation. The median age at HSCT was 58 years (range, 17-67 years). All 11 patients who underwent auto-HSCT were in the first complete remission (CR1). With a median follow-up of 53.5 months, the overall survival rates at 4 years for patients who underwent auto-HSCT and allo-HSCT were 82% and 53% (P = .11), respectively, and progression-free survival rates were 73% and 48% (P = .14), respectively. Auto-HSCT for BPDCN in CR1 appears to provide promising results and deserves further evaluation in the setting of prospective trials. © 2015 by The American Society of Hematology.

Impaired Therapeutic Capacity of Autologous Stem Cells in a Model of Type 2 Diabetes

PubMed Central

Shin, Laura

2012-01-01

Endogenous stem cells in the bone marrow respond to environmental cues and contribute to tissue maintenance and repair. In type 2 diabetes, a multifaceted metabolic disease characterized by insulin resistance and hyperglycemia, major complications are seen in multiple organ systems. To evaluate the effects of this disease on the endogenous stem cell population, we used a type 2 diabetic mouse model (db/db), which recapitulates these diabetic phenotypes. Bone marrow-derived mesenchymal stem cells (MSCs) from db/db mice were characterized in vitro using flow cytometric cell population analysis, differentiation, gene expression, and proliferation assays. Diabetic MSCs were evaluated for their therapeutic potential in vivo using an excisional splint wound model in both nondiabetic wild-type and diabetic mice. Diabetic animals possessed fewer MSCs, which were proliferation and survival impaired in vitro. Examination of the recruitment response of stem and progenitor cells after wounding revealed that significantly fewer endogenous MSCs homed to the site of injury in diabetic subjects. Although direct engraftment of healthy MSCs accelerated wound closure in both healthy and diabetic subjects, diabetic MSC engraftment produced limited improvement in the diabetic subjects and could not produce the same therapeutic outcomes as in their nondiabetic counterparts in vivo. Our data reveal stem cell impairment as a major complication of type 2 diabetes in mice and suggest that the disease may stably alter endogenous MSCs. These results have implications for the efficiency of autologous therapies in diabetic patients and identify endogenous MSCs as a potential therapeutic target. PMID:23197759

Use of biosimilar filgrastim compared with lenograstim in autologous haematopoietic stem-cell transplant and in sibling allogeneic transplant

PubMed Central

Uddin, Shab; Russell, Pippa; Farrell, Maresa; Davy, Barbara; Taylor, Joe

2015-01-01

Objectives: Biosimilar filgrastim was compared with lenograstim for autologous haematopoietic stem-cell transplant (HSCT) in patients with haematological malignancies. Data from a separate group of sibling donors who underwent allogeneic HSCT are also reported. Methods: Patients with lymphoma or multiple myeloma (MM) who underwent autologous HSCT with biosimilar filgrastim were compared with a historical control group of patients who received lenograstim. Peripheral blood (PB) cells counts were monitored after 7–8 consecutive days of granulocyte-colony stimulating factor (G-CSF) injection and apheresis was performed on day 8 if PB CD34+ cell count was ⩾10 cells/µl. The target PB CD34+ cell doses were ⩾2.0 × 106/kg (lymphoma), ⩾4.0 × 106/kg (MM ⩾60 years old) or ⩾8.0 × 106/kg (MM <60 years old). Results: A total of 259 patients were included in the autologous HSCT comparison (biosimilar filgrastim, n = 104; lenograstim, n = 155). In patients with lymphoma and older MM patients (⩾60 years old), no significant differences were observed between groups with regard to stem-cell mobilization parameters. However, in MM patients <60 years old, all parameters were significantly superior in the biosimilar filgrastim group, including the need for 1 rather than 2 apheresis procedures. No significant differences were observed between groups in median number of days to absolute neutrophil count (ANC) or platelet recovery. In the allogeneic setting, 47 sibling donors received biosimilar filgrastim. Mean CD34+ count at the first apheresis was 6.1 × 106/kg. A total of 13 donors needed a second apheresis and 4 required a third. Among recipients, median days to ANC recovery was 16 (10–28) and to platelet recovery was 13 (9–54). Conclusions: Biosimilar filgrastim is as effective as lenograstim for autologous HSCT in patients with lymphoma or MM patients ⩾60 years old. However, mobilization with biosimilar filgrastim appeared to be

The Chondrogenic Induction Potential for Bone Marrow-Derived Stem Cells between Autologous Platelet-Rich Plasma and Common Chondrogenic Induction Agents: A Preliminary Comparative Study.

PubMed

Wang, Shan-Zheng; Chang, Qing; Kong, Xiang-Fei; Wang, Chen

2015-01-01

The interests in platelet-rich plasma (PRP) and their application in stem cell therapy have contributed to a better understanding of the basic biology of the prochondrogenesis effect on bone marrow-derived stem cells (BMSCs). We aimed at comparing the effect of autologous PRP with common chondrogenic induction agents (CCIAs) on the chondrogenic differentiation of BMSCs. Rabbit BMSCs were isolated and characterized by flow cytometry and differentiated towards adipocytes and osteoblasts. The chondrogenic response of BMSCs to autologous PRP and CCIAs which included transforming growth factor-β1 (TGF-β1), dexamethasone (DEX), and vitamin C (Vc) was examined by cell pellet culture. The isolated BMSCs after two passages highly expressed CD29 and CD44 but minimally expressed CD45. The osteogenic and adipogenic differentiation potentials of the isolated BMSCs were also confirmed. Compared with common CCIAs, autologous PRP significantly upregulated the chondrogenic related gene expression, including Col-2, AGC, and Sox-9. Osteogenic related gene expression, including Col-1 and OCN, was not of statistical significance between these two groups. Thus, our data shows that, compared with common chondrogenic induction agents, autologous PRP can be more effective in promoting the chondrogenesis of BMSCs.

Potential feasibility of dental stem cells for regenerative therapies: stem cell transplantation and whole-tooth engineering.

PubMed

Nakahara, Taka

2011-07-01

Multipotent mesenchymal stem cells from bone marrow are expected to be a somatic stem cell source for the development of new cell-based therapy in regenerative medicine. However, dental clinicians are unlikely to carry out autologous cell/tissue collection from patients (i.e., marrow aspiration) as a routine procedure in their clinics; hence, the utilization of bone marrow stem cells seems impractical in the dental field. Dental tissues harvested from extracted human teeth are well known to contain highly proliferative and multipotent stem cell compartments and are considered to be an alternative autologous cell source in cell-based medicine. This article provides a short overview of the ongoing studies for the potential application of dental stem cells and suggests the utilization of 2 concepts in future regenerative medicine: (1) dental stem cell-based therapy for hepatic and other systemic diseases and (2) tooth replacement therapy using the bioengineered human whole tooth, called the "test-tube dental implant." Regenerative therapies will bring new insights and benefits to the fields of clinical medicine and dentistry.

Treatment of aggressive multiple myeloma by high-dose chemotherapy and total body irradiation followed by blood stem cells autologous graft

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fermand, J.P.; Levy, Y.; Gerota, J.

1989-01-01

Eight patients with stage III aggressive multiple myeloma, refractory to current chemotherapy in six cases, were treated by high-dose chemotherapy (nitrosourea, etoposide, and melphalan) (HDC) and total body irradiation (TBI), followed by autografting with blood stem cells. These cells were previously collected by leukapheresis performed during hematologic recovery following cytotoxic drug-induced bone marrow aplasia. Seven patients were alive 9 to 17 months after HDC-TBI and graft. One died at day 40 from cerebral bleeding. All living patients achieved a 90% or greater reduction in tumor mass. In two cases, a complete remission (CR) has persisted at a follow-up of 15more » and 16 months. Three patients have been well and off therapy with stable minimal residual disease (RD) since 10, 11, and 17 months, respectively. A patient in apparent CR and another with RD have relapsed 9 to 12 months posttreatment. Autologous blood-derived hematopoietic stem cells induced successful and sustained engraftment in all living patients. These results, although still preliminary, indicate that HDC and TBI, followed by blood stem cells autograft, which has both practical and theoretical interest over allogeneic or autologous bone marrow transplantation, deserve consideration in selected patients with multiple myeloma.« less

Autologous Mesenchymal Stem Cells, Applied in a Bioabsorbable Matrix, for Treatment of Perianal Fistulas in Patients With Crohn's Disease.

PubMed

Dietz, Allan B; Dozois, Eric J; Fletcher, Joel G; Butler, Greg W; Radel, Darcie; Lightner, Amy L; Dave, Maneesh; Friton, Jessica; Nair, Asha; Camilleri, Emily T; Dudakovic, Amel; van Wijnen, Andre J; Faubion, William A

2017-07-01

In patients with Crohn's disease, perianal fistulas recur frequently, causing substantial morbidity. We performed a 12-patient, 6-month, phase 1 trial to determine whether autologous mesenchymal stem cells, applied in a bioabsorbable matrix, can heal the fistula. Fistula repair was not associated with any serious adverse events related to mesenchymal stem cells or plug placement. At 6 months, 10 of 12 patients (83%) had complete clinical healing and radiographic markers of response. We found placement of mesenchymal stem cell-coated matrix fistula plugs in 12 patients with chronic perianal fistulas to be safe and lead to clinical healing and radiographic response in 10 patients. ClinicalTrials.gov Identifier: NCT01915927. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

[Immunology in the medical practice.XXXII. Transplantation of autologous hematopoietic stem cells for treatment of refractory auto-immune diseases; preliminary favorable results with 35 patients].

PubMed

Vlieger, A M; van den Hoogen, F H; Brinkman, D M; van Laar, J M; Schipperus, M; Kruize, A A; Wulffraat, N M

2000-08-12

The objective of this study was to document the experiences in the first Dutch pilot studies of the effect of transplantation of autologous haematopoietic stem cells in patients with therapy-resistant autoimmune disease. The first results in 21 adults and 14 children are promising: remission of the disease was achieved in 13 patients, while in the others a significant reduction of disease activity was seen with a corresponding improvement of the quality of life. Infectious complications were frequently observed. Two children with systemic juvenile idiopathic arthritis developed a fatal infection-associated macrophage activation syndrome. Multicentre randomised studies are necessary to study the effects of autologous stem cell transplantation and modifications such as T-cell depletion.

Cartilage Repair With Autologous Bone Marrow Mesenchymal Stem Cell Transplantation: Review of Preclinical and Clinical Studies.

PubMed

Yamasaki, Shinya; Mera, Hisashi; Itokazu, Maki; Hashimoto, Yusuke; Wakitani, Shigeyuki

2014-10-01

Clinical trials of various procedures, including bone marrow stimulation, mosaicplasty, and autologous chondrocyte implantation, have been explored to treat articular cartilage defects. However, all of them have some demerits. We focused on autologous culture-expanded bone marrow mesenchymal stem cells (BMSC), which can proliferate without losing their capacity for differentiation. First, we transplanted BMSC into the defective articular cartilage of rabbit and succeeded in regenerating osteochondral tissue. We then applied this transplantation in humans. Our previous reports showed that treatment with BMSC relieves the clinical symptoms of chondral defects in the knee and elbow joint. We investigated the efficacy of BMSC for osteoarthritic knee treated with high tibial osteotomy, by comparing 12 BMSC-transplanted patients with 12 cell-free patients. At 16-month follow-up, although the difference in clinical improvement between both groups was not significant, the arthroscopic and histological grading score was better in the cell-transplanted group. At the over 10-year follow-up, Hospital for Special Surgery knee scores improved to 76 and 73 in the BMSC-transplanted and cell-free groups, respectively, which were better than preoperative scores. Additionally, neither tumors nor infections were observed in all patients, and in the clinical study, we have never observed hypertrophy of repaired tissue, thereby guaranteeing the clinical safety of this therapy. Although we have never observed calcification above the tidemark in rabbit model and human histologically, the repair cartilage was not completely hyaline cartilage. To elucidate the optimum conditions for cell therapy, other stem cells, culture conditions, growth factors, and gene transfection methods should be explored.

Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques

PubMed Central

Hayashi, Takuya; Wakao, Shohei; Kitada, Masaaki; Ose, Takayuki; Watabe, Hiroshi; Kuroda, Yasumasa; Mitsunaga, Kanae; Matsuse, Dai; Shigemoto, Taeko; Ito, Akihito; Ikeda, Hironobu; Fukuyama, Hidenao; Onoe, Hirotaka; Tabata, Yasuhiko; Dezawa, Mari

2012-01-01

A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson’s disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [11C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson’s disease. PMID:23202734

Early immunotherapy using autologous adult stem cells reversed the effect of anti-pancreatic islets in recently diagnosed type 1 diabetes mellitus: preliminary results.

PubMed

Mesples, Alejandro; Majeed, Nasir; Zhang, Yun; Hu, Xiang

2013-10-14

Bone marrow stem cell treatment has been proven a promising therapeutic strategy and showed significant results given the strong immune modulating properties. We have investigated the safety and efficacy of autologous bone marrow stem cell transplantation through liver puncture in two patients with recently diagnosed type 1 diabetes mellitus. The procedure was approved by the Institutional Ethics Committee. In 2011, in three young patients, type 1 diabetes mellitus diagnosis was confirmed, with the presence of positive antibodies and ketoacidosis. Two patients was treated with autologous bone marrow stem cell stimulated with filgrastim and transplantation, through liver puncture, as immune modulators. One patients was treated with conventional treatment and participate in this experiment as a control group. The families of the patients signed the informed consent. No specific statistical analysis was performed. The patients had less than 8 years old, diagnosis of type 1 diabetes for less than 60 days, body mass index less than 22 kg/m2, normal complete blood count, coagulation and renal function, no lesions in target organs, glycosylated hemoglobin (HbA1c) level less than 13.70%, c-peptide level less than 0.67 ng/ml, positive results of Islets Cells Antibody (ICA), Glutamic Acid Decarboxylase (GAD) and insulin antibody. In two patients treated, the follow up at 12 months showed negative value in ICA, GAD and anti insulin antibody levels, with an increased levels of c peptide and decreased levels of blood glucose and HbA1c. Treatment with autologous bone marrow stem cells is easy and effective as it reversed the production and effect of anti pancreatic islet antibody and significantly resulted in an increased c-peptide concentration.

A Novel Biopsy Method for Isolating Neural Stem Cells from the Subventricular Zone of the Adult Rat Brain for Autologous Transplantation in CNS Injuries.

PubMed

Aligholi, Hadi; Hassanzadeh, Gholamreza; Gorji, Ali; Azari, Hassan

2016-01-01

Despite all attempts the problem of regeneration in damaged central nervous system (CNS) has remained challenging due to its cellular complexity and highly organized and sophisticated connections. In this regard, stem cell therapy might serve as a viable therapeutic approach aiming either to support the damaged tissue and hence to reduce the subsequent neurological dysfunctions and impairments or to replace the lost cells and re-establish damaged circuitries. Adult neural stem/progenitor cells (NS/PCs) are one of the outstanding cell sources that can be isolated from the subventricular zone (SVZ) of the lateral ventricles. These cells can differentiate into neurons, astrocytes, and oligodendrocytes. Implanting autologous NS/PCs will greatly benefit the patients by avoiding immune rejection after implantation, better survival, and integration with the host tissue. Developing safe and efficient methods in small animal models will provide us with the opportunity to optimize procedures required to achieve successful human autologous NS/PC transplantation in near future. In this chapter, a highly controlled and safe biopsy method for harvesting stem cell containing tissue from the SVZ of adult rat brain is introduced. Then, isolation and expansion of NS/PCs from harvested specimen as well as the techniques to verify proliferation and differentiation capacity of the resulting NS/PCs are discussed. Finally, a method for assessing the biopsy lesion volume in the brain is described. This safe biopsy method in rat provides a unique tool to study autologous NS/PC transplantation in different CNS injury models.

Stem-cell Based Therapies for Epidermolysis Bullosa

DTIC Science & Technology

2013-10-01

This application addresses the FY11 PRMRP Topic Area, Epidermolysis Bullosa, and proposes to develop stem - cell based therapies for junctional...accomplish this goal, we are proposing to develop stem - cell based therapies for EB using autologous induced pluripotent stem cells (iPSCs) derived from

Stem-Cell Based Therapies for Epidermolysis Bullosa

DTIC Science & Technology

2014-10-01

This application addresses the FY11 PRMRP Topic Area, Epidermolysis Bullosa, and proposes to develop stem - cell based therapies for junctional...accomplish this goal, we are proposing to develop stem - cell based therapies for EB using autologous induced pluripotent stem cells (iPSCs) derived from

Beneficial Effects of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Naturally Occurring Tendinopathy

PubMed Central

Smith, Roger Kenneth Whealands; Werling, Natalie Jayne; Dakin, Stephanie Georgina; Alam, Rafiqul; Goodship, Allen E.; Dudhia, Jayesh

2013-01-01

Tendon injuries are a common age-related degenerative condition where current treatment strategies fail to restore functionality and normal quality of life. This disease also occurs naturally in horses, with many similarities to human tendinopathy making it an ideal large animal model for human disease. Regenerative approaches are increasingly used to improve outcome involving mesenchymal stem cells (MSCs), supported by clinical data where injection of autologous bone marrow derived MSCs (BM-MSCs) suspended in marrow supernatant into injured tendons has halved the re-injury rate in racehorses. We hypothesized that stem cell therapy induces a matrix more closely resembling normal tendon than the fibrous scar tissue formed by natural repair. Twelve horses with career-ending naturally-occurring superficial digital flexor tendon injury were allocated randomly to treatment and control groups. 1X107 autologous BM-MSCs suspended in 2 ml of marrow supernatant were implanted into the damaged tendon of the treated group. The control group received the same volume of saline. Following a 6 month exercise programme horses were euthanized and tendons assessed for structural stiffness by non-destructive mechanical testing and for morphological and molecular composition. BM-MSC treated tendons exhibited statistically significant improvements in key parameters compared to saline-injected control tendons towards that of normal tendons and those in the contralateral limbs. Specifically, treated tendons had lower structural stiffness (p<0.05) although no significant difference in calculated modulus of elasticity, lower (improved) histological scoring of organisation (p<0.003) and crimp pattern (p<0.05), lower cellularity (p<0.007), DNA content (p<0.05), vascularity (p<0.03), water content (p<0.05), GAG content (p<0.05), and MMP-13 activity (p<0.02). Treatment with autologous MSCs in marrow supernatant therefore provides significant benefits compared to untreated tendon repair in

Low Connexin Channel-Dependent Intercellular Communication in Human Adult Hematopoietic Progenitor/Stem Cells: Probing Mechanisms of Autologous Stem Cell Therapy

PubMed Central

Yang, Jian; Darley, Richard L; Hallett, Maurice; Evans, W Howard

2009-01-01

Human bone marrow is a clinical source of autologous progenitor stem cells showing promise for cardiac repair following ischemic insult. Functional improvements following delivery of adult bone marrow CD34+ cells into heart tissue may require metabolic/electrical communication between participating cells. Since connexin43 (Cx43) channels are implicated in cardiogenesis and provide intercellular connectivity in the heart, the authors analyzed the expression of 20 connexins (Cx) in CD34+ cells and in monocytes and granulocytes in bone marrow and spinal cord. Reverse transcriptase-polymerase chain reaction (RT-PCR) detected only low expression of Cx43 and Cx37. Very low level dye coupling was detected by flow cytometry between CD34+ cells and other Cx43 expressing cells, including HL-1 cardiac cells, and was not inhibited by specific gap junction inhibitors. The results indicate that CD34+ cells are unlikely to communicate via gap junctions and the authors conclude that use of CD34+ cells to repair damaged hearts is unlikely to involve gap junctions. The results concur with the hypothesis that bone marrow cells elicit improved cardiac function through release of undefined paracrine mediators. PMID:20298144

Hematopoietic stem cell transplantation in Europe 1998.

PubMed

Gratwohl, A; Passweg, J; Baldomero, H; Hermans, J; Urbano-Ispizua, A

2000-01-01

Transplantation of hematopoietic stem cells from blood or bone marrow has become accepted therapy for many diseases. Numbers of transplants have increased significantly and stem cell source, donor type and indications have changed during this decade. Information on these changes is essential for interpretation of current data, patient counseling and health care planning. Since 1990, members of the European Group for Blood and Marrow Transplantation and teams known to perform blood or marrow transplants have been invited annually to report their transplant numbers by indication, donor type and stem cell source. Data from these surveys have been used to present data for 1998, to assess current status and to give numbers of transplants per participating country, coefficients of variation between countries for individual indications and changes in indication, stem cell source and donor type over the past decade. In 1998, a total of 20 892 transplants were performed by 528 teams in 31 European countries. Of these transplants 18 400 were first transplants, 5308 (29%) were allogenic, and 13 092 (71%) were autologous. Of the autologous transplants, 809 (6%) were bone marrow derived, and 12 283 (94%) were from peripheral blood stems cells. Of the allogeneic transplants, 3372 (64%) were bone marrow derived, and 1936 (36%) were peripheral blood stem cell transplants. In 1990, the respective figures were 2137 allogeneic (50%) and 2097 (50%) autologous transplants, all exclusively bone marrow derived. Main indications in 1998 were leukemias with 6015 transplants (33%), 68% thereof allogeneic transplants; lymphomas with 7492 transplants (41%), 94% thereof autologous transplants; solid tumors with 4025 transplants (22%), 99% thereof autologous transplants; non-malignant disorders with 868 transplants (5%), 80% thereof allogeneic transplants. Absolute numbers of transplants per year did increase from 4234 in 1990 to 20 892 in 1998. Increase is higher for autologous, than for

Characterizing differences between MSCs and TM cells: Toward autologous stem cell therapies for the glaucomatous trabecular meshwork.

PubMed

Snider, Eric J; Vannatta, R Taylor; Schildmeyer, Lisa; Stamer, W Daniel; Ethier, C Ross

2018-03-01

Glaucoma, a leading cause of blindness, is characterized by an increase in intraocular pressure, which is largely determined by resistance to aqueous humour outflow through the trabecular meshwork (TM). In glaucoma, the cellularity of the TM is decreased, and, as a result, stem cell therapies for the TM represent a potential therapeutic option for restoring TM function and treating glaucoma patients. We here focus on adipose derived mesenchymal stem cells (MSCs) as a potential autologous cell source for TM regenerative medicine applications and describe characterization techniques at the messenger (reverse transcription-quantitative polymerase chain reaction), protein (western blotting, flow cytometry), and functional (contractility, phagocytosis) levels to distinguish MSCs from TM cells. We present a panel of 12 transcripts to allow: (a) suitable normalization of reverse transcription-quantitative polymerase chain reaction results across cell types and after exposure to potential differentiation stimuli; (b) distinguishing MSCs from TM cells; (c) distinguishing subtypes of TM cells; and (d) distinguishing TM cells from those in neighbouring tissue. At the protein level, dexamethasone induction of myocilin was a robust discriminating factor between MSCs and TM cells and was complemented by other protein markers. Finally, we show that contractility and phagocytosis differ between MSCs and TM cells. These methods are recommended for use in future differentiation studies to fully define if a functional TM-like phenotype is being achieved. Copyright © 2017 John Wiley & Sons, Ltd.

Effect of autologous adipose-derived mesenchymal stem cell therapy in the treatment of a post-traumatic chondral defect of the knee

PubMed Central

Freitag, Julien; Li, Douglas; Wickham, James; Shah, Kiran; Tenen, Abi

2017-01-01

Isolated chondral defects have a limited capacity to heal and predispose to the development of osteoarthritis. Current surgical management can be unpredictable in outcome. Improved understanding of the action of mesenchymal stem cells (MSCs) has seen renewed interest in their role in cartilage repair. A 26-year-old athlete presented with a post-traumatic, isolated patella chondral defect. The patient underwent an arthroscopy with removal of a chondral loose body. After failure to symptomatically improve 12 months following surgery, the patient received intra-articular autologous adipose-derived mesenchymal stem cell (ADMSC) therapy. PMID:29038190

Effect of autologous platelet-rich plasma on the chondrogenic differentiation of rabbit adipose-derived stem cells in vitro

PubMed Central

TANG, XIAO-BO; DONG, PEI-LONG; WANG, JIAN; ZHOU, HAI-YANG; ZHANG, HAI-XIANG; WANG, SHAN-ZHENG

2015-01-01

This study aimed to isolate rabbit adipose-derived stem cells (ADSCs) and explore the potential of platelet-rich plasma (PRP) in the chondrogenic differentiation of ADSCs, thereby potentially providing a new approach for the repair and regeneration of cartilage injury. Rabbit ADSCs were isolated and characterized by induction towards adipogenic, osteogenic and chondrogenic lineages in vitro. The isolated ADSCs were also cultured with or without 10% PRP. Immunofluorescence staining, toluidine blue staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to detect type II collagen (Col II) and aggrecan (AGC) expression. Col II immunofluorescence staining and toluidine blue staining indicated that following induction by autologous PRP, ADSCs manifested Col II and AGC expression. The expression of Col II and AGC mRNA was significantly upregulated in the PRP-treated cells when compared with that in control cells. Autologous PRP produced by laboratory centrifugation was able to promote the chondrogenic differentiation of rabbit ADSCs in vitro. PMID:26622340

Development of an oral care guide for patients undergoing autologous stem cell transplantation.

PubMed

Salvador, Prisco T

2006-01-01

Nurses identified oral mucositis as a recurring issue in clinical practice. To meet this challenge, a group of nurses took a leadership role in developing an oral care guide. The University Health Network Nursing Research Utilization Model and the Neuman Systems Model served as conceptual frameworks. A flowchart was developed to ensure a coordinated and continuous provision of oral care. Educational presentations were conducted to familiarize nurses and members of the multidisciplinary team of the practice changes. The introduction of the oral care regimen as primary prevention, plus systematic oral assessment and monitoring had the potential to reduce the occurrence and severity of oral mucositis in patients undergoing autologous stem cell transplantation.

Restoring the quantity and quality of elderly human mesenchymal stem cells for autologous cell-based therapies.

PubMed

Block, Travis J; Marinkovic, Milos; Tran, Olivia N; Gonzalez, Aaron O; Marshall, Amanda; Dean, David D; Chen, Xiao-Dong

2017-10-27

Degenerative diseases are a major public health concern for the aging population and mesenchymal stem cells (MSCs) have great potential for treating many of these diseases. However, the quantity and quality of MSCs declines with aging, limiting the potential efficacy of autologous MSCs for treating the elderly population. Human bone marrow (BM)-derived MSCs from young and elderly donors were obtained and characterized using standard cell surface marker criteria (CD73, CD90, CD105) as recommended by the International Society for Cellular Therapy (ISCT). The elderly MSC population was isolated into four subpopulations based on size and stage-specific embryonic antigen-4 (SSEA-4) expression using fluorescence-activated cell sorting (FACS), and subpopulations were compared to the unfractionated young and elderly MSCs using assays that evaluate MSC proliferation, quality, morphology, intracellular reactive oxygen species, β-galactosidase expression, and adenosine triphosphate (ATP) content. The ISCT-recommended cell surface markers failed to detect any differences between young and elderly MSCs. Here, we report that elderly MSCs were larger in size and displayed substantially higher concentrations of intracellular reactive oxygen species and β-galactosidase expression and lower amounts of ATP and SSEA-4 expression. Based on these findings, cell size and SSEA-4 expression were used to separate the elderly MSCs into four subpopulations by FACS. The original populations (young and elderly MSCs), as well as the four subpopulations, were then characterized before and after culture on tissue culture plastic and BM-derived extracellular matrix (BM-ECM). The small SSEA-4-positive subpopulation representing ~ 8% of the original elderly MSC population exhibited a "youthful" phenotype that was similar to that of young MSCs. The biological activity of this elderly subpopulation was inhibited by senescence-associated factors produced by the unfractionated parent population

Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis.

PubMed

Cohen, Jeffrey A; Imrey, Peter B; Planchon, Sarah M; Bermel, Robert A; Fisher, Elizabeth; Fox, Robert J; Bar-Or, Amit; Sharp, Susan L; Skaramagas, Thomai T; Jagodnik, Patricia; Karafa, Matt; Morrison, Shannon; Reese Koc, Jane; Gerson, Stanton L; Lazarus, Hillard M

2018-04-01

Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest. To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS. Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0-6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1-2 × 10 6 MSCs/kg were thawed and administered IV. In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1-3 passages) was 1.9 × 10 6 MSCs/kg (range, 1.5-2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation. Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.

Optimizing autologous cell grafts to improve stem cell gene therapy.

PubMed

Psatha, Nikoletta; Karponi, Garyfalia; Yannaki, Evangelia

2016-07-01

Over the past decade, stem cell gene therapy has achieved unprecedented curative outcomes for several genetic disorders. Despite the unequivocal success, clinical gene therapy still faces challenges. Genetically engineered hematopoietic stem cells are particularly vulnerable to attenuation of their repopulating capacity once exposed to culture conditions, ultimately leading to low engraftment levels posttransplant. This becomes of particular importance when transduction rates are low or/and competitive transplant conditions are generated by reduced-intensity conditioning in the absence of a selective advantage of the transduced over the unmodified cells. These limitations could partially be overcome by introducing megadoses of genetically modified CD34(+) cells into conditioned patients or by transplanting hematopoietic stem cells hematopoietic stem cells with high engrafting and repopulating potential. On the basis of the lessons gained from cord blood transplantation, we summarize the most promising approaches to date of increasing either the numbers of hematopoietic stem cells for transplantation or/and their engraftability, as a platform toward the optimization of engineered stem cell grafts. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Intra-discal injection of autologous, hypoxic cultured bone marrow-derived mesenchymal stem cells in five patients with chronic lower back pain: a long-term safety and feasibility study.

PubMed

Elabd, Christian; Centeno, Christopher J; Schultz, John R; Lutz, Gregory; Ichim, Thomas; Silva, Francisco J

2016-09-01

Chronic low back pain due to disc degeneration represents a major social and economic burden worldwide. The current standard of care is limited to symptomatic relief and no current approved therapy promotes disc regeneration. Bone marrow-derived mesenchymal stem cells (MSCs) are easily accessible and well characterized. These MSCs are multipotent and exhibit great tissue regenerative potential including bone, cartilage, and fibrous tissue regeneration. The use of this cell-based biologic for treating protruding disc herniation and/or intervertebral disc degeneration is a promising therapeutic strategy, due to their known regenerative, immuno-modulatory and anti-inflammatory properties. Five patients diagnosed with degenerative disc disease received an intra-discal injection of autologous, hypoxic cultured, bone marrow-derived mesenchymal stem cells (15.1-51.6 million cells) as part of a previous study. These patients were re-consented to participate in this study in order to assess long-term safety and feasibility of intra-discal injection of autologous, hypoxic cultured, bone marrow-derived mesenchymal stem cells 4-6 years post mesenchymal stem cell infusion. The follow-up study consisted of a physical examination, a low back MRI, and a quality of life questionnaire. Patients' lower back MRI showed absence of neoplasms or abnormalities surrounding the treated region. Based on the physical examination and the quality of life questionnaire, no adverse events were reported due to the procedure or to the stem cell treatment 4-6 years post autologous, hypoxic cultured mesenchymal stem cell infusion. All patients self-reported overall improvement, as well as improvement in strength, post stem cell treatment, and four out of five patients reported improvement in mobility. This early human clinical data suggests the safety and feasibility of the clinical use of hypoxic cultured bone marrow-derived mesenchymal stem cells for the treatment of lower back pain due to

Stem cells in cardiac repair.

PubMed

Henning, Robert J

2011-01-01

Myocardial infarction is the leading cause of death among people in industrialized nations. Although the heart has some ability to regenerate after infarction, myocardial restoration is inadequate. Consequently, investigators are currently exploring the use of human embryonic stem cells (hESCs), skeletal myoblasts and adult bone marrow stem cells to limit infarct size. hESCs are pluripotent cells that can regenerate myocardium in infarcted hearts, attenuate heart remodeling and contribute to left ventricle (LV) systolic force development. Since hESCs can form heart teratomas, investigators are differentiating hESCs toward cardiac progenitor cells prior to transplantation into hearts. Large quantities of hESCs cardiac progenitor cells, however, must be generated, immune rejection must be prevented and grafts must survive over the long term to significantly improve myocardial performance. Transplanted autologous skeletal myoblasts can survive in infarcted myocardium in small numbers, proliferate, differentiate into skeletal myofibers and increase the LV ejection fraction. These cells, however, do not form electromechanical connections with host cardiomyocytes. Consequently, electrical re-entry can occur and cause cardiac arrhythmias. Autologous bone marrow mononuclear cells contain hematopoietic and mesenchymal stem cells. In several meta-analyses, patients with coronary disease who received autologous bone marrow cells by intracoronary injection show significant 3.7% (range: 1.9-5.4%) increases in LV ejection fraction, decreases in LV end-systolic volume of -4.8 ml (range: -1.4 to -8.2 ml) and reductions in infarct size of 5.5% (-1.9 to -9.1%), without experiencing arrhythmias. Bone marrow cells appear to release biologically active factors that limit myocardial damage. Unfortunately, bone marrow cells from patients with chronic diseases propagate poorly and can die prematurely. Substantial challenges must be addressed and resolved to advance the use of stem cells

Autologous serum improves bone formation in a primary stable silica-embedded nanohydroxyapatite bone substitute in combination with mesenchymal stem cells and rhBMP-2 in the sheep model

PubMed Central

Boos, Anja M; Weigand, Annika; Deschler, Gloria; Gerber, Thomas; Arkudas, Andreas; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

2014-01-01

New therapeutic strategies are required for critical size bone defects, because the gold standard of transplanting autologous bone from an unharmed area of the body often leads to several severe side effects and disadvantages for the patient. For years, tissue engineering approaches have been seeking a stable, axially vascularized transplantable bone replacement suitable for transplantation into the recipient bed with pre-existing insufficient conditions. For this reason, the arteriovenous loop model was developed and various bone substitutes have been vascularized. However, it has not been possible thus far to engineer a primary stable and axially vascularized transplantable bone substitute. For that purpose, a primary stable silica-embedded nanohydroxyapatite (HA) bone substitute in combination with blood, bone marrow, expanded, or directly retransplanted mesenchymal stem cells, recombinant human bone morphogenetic protein 2 (rhBMP-2), and different carrier materials (fibrin, cell culture medium, autologous serum) was tested subcutaneously for 4 or 12 weeks in the sheep model. Autologous serum lead to an early matrix change during degradation of the bone substitute and formation of new bone tissue. The best results were achieved in the group combining mesenchymal stem cells expanded with 60 μg/mL rhBMP-2 in autologous serum. Better ingrowth of fibrovascular tissue could be detected in the autologous serum group compared with the control (fibrin). Osteoclastic activity indicating an active bone remodeling process was observed after 4 weeks, particularly in the group with autologous serum and after 12 weeks in every experimental group. This study clearly demonstrates the positive effects of autologous serum in combination with mesenchymal stem cells and rhBMP-2 on bone formation in a primary stable silica-embedded nano-HA bone grafting material in the sheep model. In further experiments, the results will be transferred to the sheep arteriovenous loop model in

Application of adipocyte-derived stem cells in treatment of cutaneous radiation syndrome.

PubMed

Riccobono, Diane; Agay, Diane; Scherthan, Harry; Forcheron, Fabien; Vivier, Mylène; Ballester, Bruno; Meineke, Viktor; Drouet, Michel

2012-08-01

Cutaneous radiation syndrome caused by local high dose irradiation is characterized by delayed outcome and incomplete healing. Recent therapeutic management of accidentally irradiated burn patients has suggested the benefit of local cellular therapy using mesenchymal stem cell grafting. According to the proposed strategy of early treatment, large amounts of stem cells would be necessary in the days following exposure and hospitalization, which would require allogeneic stem cells banking. In this context, the authors compared the benefit of local autologous and allogeneic adipocyte-derived stem cell injection in a large animal model. Minipigs were locally irradiated using a 60Co gamma source at a dose of 50 Gy and divided into three groups. Two groups were grafted with autologous (n = 5) or allogeneic (n = 5) adipocyte-derived stem cells four times after the radiation exposure, whereas the control group received the vehicle without cells (n = 8). A clinical score was elaborated to compare the efficiency of the three treatments. All controls exhibited local inflammatory injuries leading to a persistent painful necrosis, thus mimicking the clinical evolution in human victims. In the autologous adipocyte-derived stem cells group, skin healing without necrosis or uncontrollable pain was observed. In contrast, the clinical outcome was not significantly different in the adipocyte-derived stem cell allogeneic group when compared with controls. This study suggests that autologous adipocyte-derived stem cell grafting improves cutaneous radiation syndrome wound healing, whereas allogeneic adipocyte derived stem cells do not. Further studies will establish whether manipulation of allogeneic stem cells will improve their therapeutic potential.

Impact of the use of autologous stem cell transplantation at first relapse both in naïve and previously rituximab exposed follicular lymphoma patients treated in the GELA/GOELAMS FL2000 study

PubMed Central

Le Gouill, Steven; De Guibert, Sophie; Planche, Lucie; Brice, Pauline; Dupuis, Jehan; Cartron, Guillaume; Van Hoof, Achiel; Casasnovas, Olivier; Gyan, Emmanuel; Tilly, Hervé; Fruchart, Christophe; Deconinck, Eric; Fitoussi, Olivier; Gastaud, Lauris; Delwail, Vincent; Gabarre, Jean; Gressin, Rémy; Blanc, Michel; Foussard, Charles; Salles, Gilles

2011-01-01

Background We analyzed detailed characteristics and salvage treatment in 175 follicular lymphoma patients from the FL2000 study who were in progression after first-line therapy with or without addition of rituximab to chemotherapy and interferon. Design and Methods The impact of using autologous stem cell transplantation and/or rituximab administration at first progression was investigated, taking into account initial therapy. With a median follow up of 31 months, 3-year event free and overall survival rates after progression were 50% (95%CI 42–58%) and 72% (95%CI 64–78%), respectively. Results The 3-year event free rate of rituximab re-treated patients (n=112) was 52% (95%CI 41–62%) versus 40% (95%CI 24–55%) for those not receiving rituximab second line (n=53) (P=0.075). There was a significant difference in 3-year overall survival between patients receiving autologous stem cell transplantation and those not: 92% (95%CI 78–97%) versus 63% (95%CI 51–72%) (P=0.0003), respectively. In multivariate analysis, both autologous stem cell transplantation and period of progression/relapse affected event free and overall survival. Conclusions Regardless of front-line rituximab exposure, this study supports incorporating autologous stem cell transplantation in the therapeutic approach at first relapse for follicular lymphoma patients. PMID:21486862

Clinical-scale laser-based scanning and processing of live cells: selective photothermal killing of fluorescent tumor targets for autologous stem cell transplantation

NASA Astrophysics Data System (ADS)

Koller, Manfred R.; Hanania, Elie G.; Eisfeld, Timothy; O'Neal, Robert A.; Khovananth, Kevin M.; Palsson, Bernhard O.

2001-04-01

High-dose chemotherapy, followed by autologous hematopoietic stem cell (HSC) transplantation, is widely used for the treatment of cancer. However, contaminating tumor cells within HSC harvests continue to be of major concern since re-infused tumor cells have proven to contribute to disease relapse. Many tumor purging methods have been evaluated, but all leave detectable tumor cells in the transplant and result in significant loss of HSCs. These shortcomings cause engraftment delays and compromise the therapeutic value of purging. A novel approach integrating automated scanning cytometry, image analysis, and selective laser-induced killing of labeled cells within a cell mixture is described here. Non-Hodgkin's lymphoma (NHL) cells were spiked into cell mixtures, and fluorochrome-conjugated antibodies were used to label tumor cells within the mixture. Cells were then allowed to settle on a surface, and as the surface was scanned with a fluorescence excitation source, a laser pulse was fired at every detected tumor cell using high-speed beam steering mirrors. Tumor cells were selectively killed with little effect on adjacent non-target cells, demonstrating the feasibility of this automated cell processing approach. This technology has many potential research and clinical applications, one example of which is tumor cell purging for autologous HSC transplantation.

Long-term sequelae of autologous bone marrow or peripheral stem cell transplantation for lymphoid malignancies.

PubMed

Vose, J M; Kennedy, B C; Bierman, P J; Kessinger, A; Armitage, J O

1992-02-01

The study was made to evaluate the long-term physical and psychosocial changes after high-dose therapy and autologous bone marrow or peripheral stem transplantation for recurrent lymphoid malignancies. Patients who had undergone high dose therapy and autologous bone marrow or peripheral stem cell transplantation for recurrent lymphoid malignancies at least 1 year previously were contacted by phone interview regarding their status after the transplant. The patients' comments were confirmed by checking medical records when possible. Fifty patients who had undergone transplantation at the University of Nebraska Medical Center at least 1 year before the interview were available for interview and willing to answer questions. After transplant, many patients noticed temporary changes in their appearance, which usually returned to normal within 1 year. Few patients reported remarkable cardiovascular, gastrointestinal, or pulmonary changes after transplantation. However, up to one-third of the patients reported changes in sexual function or desire. The most common infectious problem after transplant was Herpes zoster, which occurred in 25% of the patients. Overall, the patients had a positive outlook after high-dose therapy and transplantation, with most being able to return to work and enjoy a normal life style. Ninety-six percent of the patients stated that they would be willing to undergo high-dose therapy and transplantation again under the same circumstances.

[Treatment outcome and prognosis of autologous hematopoietic stem cell transplantation combined with high dose radiotherapy/chemotherapy in 22 patients with nasal NK/T cell lymphoma].

PubMed

Cui, Xiu-Zhen; Wang, Hua-Qing; Liu, Xian-Ming; Zhang, Hui-Lai; Li, Wei

2007-09-01

To analyze the outcome and prognosis of autologous hematopoietic stem cell transplantation (AHSCT) combined with high dose radiotherapy/chemotherapy in 22 patients with nasal NK/T cell lymphoma. From July 1992 to December 2005, 22 patients with nasal NK/T cell lymphoma were diagnosed pathologically. Immunophenotyping was performed in 13 cases. The patients were classified by Ann Arbor staging system and international prognosis index (IPI). The patients received cycles of chemotherapy every other two weeks or combined with radiotherapy for remission induction, followed high dose radiotherapy/chemotherapy, combined with autologous peripheral blood stem cell transplantation (APBSCT), or autologous bone-marrow transplantation (ABMT). Patients were given complementary radiotherapy after transplantation if they did not have it before. Twelve patients of IPI 3 -4 received consolidation chemotherapy, and one of them received the second transplantation. The median follow-up duration was 64 (12 - 168) months. The 5 and 8-year overall survivals (OS) were 79.3% and 64.1%, and disease free survivals (DFS) were 36.4% and 27.3%, respectively. The 5-year OS were as follows: for stage I - II and III - IV disease were 90.0% and 70.0% (P = 0. 041); for patients without and with B symptom were 100.0% and 70.7% (P = 0.045); and for IPI 1 - 2 and 3 - 4 were 100.0% and 60.0% (P = 0.035), respectively. Multivariate analysis by COX regression revealed that disease stage, B symptom and IPI were independent prognostic factors. AHSCT combined with high dose radiotherapy/chemotherapy is an effective treatment for patients with poor prognosis nasal NK/T cell lymphoma.

[Hematopoietic reconstitution after transplantation of uncontrolled-rate cryopreservation autologous peripheral blood hematopoietic stem cells using -80 °C mechanical freezer].

PubMed

Liu, Mo; Zhao, Yu; Sun, Jing-Fen; Zhao, Wei; Wang, Li-Li; Yu, Li

2015-02-01

This study was to identify the efficacy of -80°C cryopreservated peripheral blood hemato-poietic stem cell (PBHSC) transplantation for hematopoietic reanstitution in patients. The efficacy of 104 patients underwent autologous peripheral blood hematopoietic stem cell transplantation using uncontrolled-rate freezing and storage at -80°C was evaluated. This cryopreservation method could effectively cryopreserve peripheral blood stem cells. Out of 104 patients only 2 patients died, other patients got hematologic reconstition satisfactorily, the median engrafement times of neutrophils and platelet were 12 and 14 days respectively, the activity of cells after rehabilitation was 94%, the mean recovery rates of CD34(+) cells and mononuclear cells (MNC) were 86% and 80.3% respectively. There were no significant influences on engrafement time in sex, chemotherapy circles and radiotherapy. The engrafement of leukocytes associated with amount of CD34(+) cells. This simple uncontrolled-rate freezing PBHSC at -80°C is safe, effective and economic, and can meet clinical needs. As compared with the classical cryopreservation, there were no significant differences in hematopoietic reconstitution. Therefore, this method worth to popularize and apply in clinic.

Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation

PubMed Central

Ho, Vincent T.; Vanneman, Matthew; Kim, Haesook; Sasada, Tetsuro; Kang, Yoon Joong; Pasek, Mildred; Cutler, Corey; Koreth, John; Alyea, Edwin; Sarantopoulos, Stefanie; Antin, Joseph H.; Ritz, Jerome; Canning, Christine; Kutok, Jeffery; Mihm, Martin C.; Dranoff, Glenn; Soiffer, Robert

2009-01-01

Through an immune-mediated graft-versus-leukemia effect, allogeneic hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with hematologic malignancies. Nonetheless, subjects with high-risk acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated tumor cells engineered to secrete GM-CSF generates a potent antitumor effect without exacerbating the toxicities of graft-versus-host disease (GVHD). To test whether this strategy might be similarly active in humans, we conducted a Phase I clinical trial in which high-risk acute myeloid leukemia or myelodysplasia patients were immunized with irradiated, autologous, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT. Despite the administration of a calcineurin inhibitor as prophylaxis against GVHD, vaccination elicited local and systemic reactions that were qualitatively similar to those previously observed in nontransplanted, immunized solid-tumor patients. While the frequencies of acute and chronic GVHD were not increased, 9 of 10 subjects who completed vaccination achieved durable complete remissions, with a median follow-up of 26 months (range 12–43 months). Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment. Together, these results establish the safety and immunogenicity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic HSCT, and raise the possibility that this combinatorial immunotherapy might potentiate graft-versus-leukemia in patients. PMID:19717467

Generating autologous hematopoietic cells from human-induced pluripotent stem cells through ectopic expression of transcription factors.

PubMed

Hwang, Yongsung; Broxmeyer, Hal E; Lee, Man Ryul

2017-07-01

Hematopoietic cell transplantation (HCT) is a successful treatment modality for patients with malignant and nonmalignant disorders, usually when no other treatment option is available. The cells supporting long-term reconstitution after HCT are the hematopoietic stem cells (HSCs), which can be limited in numbers. Moreover, finding an appropriate human leukocyte antigen-matched donor can be problematic. If HSCs can be stably produced in large numbers from autologous or allogeneic cell sources, it would benefit HCT. Induced pluripotent stem cells (iPSCs) established from patients' own somatic cells can be differentiated into hematopoietic cells in vitro. This review will highlight recent methods for regulating human (h) iPSC production of HSCs and more mature blood cells. Advancements in transcription factor-mediated regulation of the developmental stages of in-vivo hematopoietic lineage commitment have begun to provide an understanding of the molecular mechanism of hematopoiesis. Such studies involve not only directed differentiation in which transcription factors, specifically expressed in hematopoietic lineage-specific cells, are overexpressed in iPSCs, but also direct conversion in which transcription factors are introduced into patient-derived somatic cells which are dedifferentiated to hematopoietic cells. As iPSCs derived from patients suffering from genetically mutated diseases would express the same mutated genetic information, CRISPR-Cas9 gene editing has been utilized to differentiate genetically corrected iPSCs into normal hematopoietic cells. IPSCs provide a model for molecular understanding of disease, and also may function as a cell population for therapy. Efficient differentiation of patient-specific iPSCs into HSCs and progenitor cells is a potential means to overcome limitations of such cells for HCT, as well as for providing in-vitro drug screening templates as tissue-on-a-chip models.

Peripheral Motor and Sensory Nerve Conduction following Transplantation of Undifferentiated Autologous Adipose Tissue-Derived Stem Cells in a Biodegradable U.S. Food and Drug Administration-Approved Nerve Conduit.

PubMed

Klein, Silvan M; Vykoukal, Jody; Li, De-Pei; Pan, Hui-Lin; Zeitler, Katharina; Alt, Eckhard; Geis, Sebastian; Felthaus, Oliver; Prantl, Lukas

2016-07-01

Conduits preseeded with either Schwann cells or stem cells differentiated into Schwann cells demonstrated promising results for the outcome of nerve regeneration in nerve defects. The concept of this trial combines nerve repair by means of a commercially available nerve guidance conduit and preseeding with autologous, undifferentiated, adipose tissue-derived stem cells. Adipose tissue-derived stem cells were harvested from rats and subsequently seeded onto a U.S. Food and Drug Administration-approved type I collagen conduit. Sciatic nerve gaps 10 mm in length were created, and nerve repair was performed by the transplantation of either conduits preseeded with autologous adipose tissue-derived stem cells or acellular (control group) conduits. After 6 months, the motor and sensory nerve conduction velocity were assessed. Nerves were removed and examined by hematoxylin and eosin, van Gieson, and immunohistochemistry (S100 protein) staining for the quality of axonal regeneration. Nerve gaps treated with adipose tissue-derived stem cells showed superior nerve regeneration, reflected by higher motor and sensory nerve conduction velocity values. The motor and sensory nerve conduction velocity were significantly greater in nerves treated with conduits preseeded with adipose tissue-derived stem cells than in nerves treated with conduits alone (p < 0.05). Increased S100 immunoreactivity was detected for the adipose tissue-derived stem cell group. In this group, axon arrangement inside the conduits was more organized. Transplantation of adipose tissue-derived stem cells significantly improves motor and sensory nerve conduction velocity in peripheral nerve gaps. Preseeded conduits showed a more organized axon arrangement inside the conduit in comparison with nerve conduits alone. The approach used here could readily be translated into a clinical therapy. Therapeutic, V.

Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high-dose melphalan in patients with multiple myeloma.

PubMed

Talamo, Giampaolo; Rakszawski, Kevin L; Rybka, Witold B; Dolloff, Nathan G; Malysz, Jozef; Berno, Tamara; Zangari, Maurizio

2012-08-01

High-dose melphalan (HD-Mel) is considered the current standard of care among the preparative regimens used in autologous peripheral blood stem cell transplantation (SCT) for multiple myeloma (MM), but optimal time and schedule of administration is not defined. We retrospectively analyzed outcomes and toxicities of HD-Mel administered on day -2 vs. day -1 before autologous stem cells infusion. A total of 138 consecutive MM patients treated at Penn State Hershey Cancer Institute between 2007 and 2010 were included in this study. No difference in time to hematopoietic recovery, common SCT-related toxicities, and clinical outcomes was seen between patients who received HD-Mel on day -2 (group A, n = 47), and those who received it on day -1 (group B, n = 91). Prompt and full hematopoietic recovery occurred even when stem cells were infused between 8 and 24 h after completion of chemotherapy. In the absence of prospective and randomized data, we conclude that a single I.V. infusion of HD-Mel on day -1 is a safe and effective practice, and the so-called 'day of rest' before the transplant appears not to be necessary. © 2012 John Wiley & Sons A/S.

Stem Cell Ophthalmology Treatment Study (SCOTS): bone marrow-derived stem cells in the treatment of Leber's hereditary optic neuropathy

PubMed Central

Weiss, Jeffrey N.; Levy, Steven; Benes, Susan C.

2016-01-01

The Stem Cell Ophthalmology Treatment Study (SCOTS) is currently the largest-scale stem cell ophthalmology trial registered at ClinicalTrials.gov (identifier: NCT01920867). SCOTS utilizes autologous bone marrow-derived stem cells (BMSCs) to treat optic nerve and retinal diseases. Treatment approaches include a combination of retrobulbar, subtenon, intravitreal, intra-optic nerve, subretinal, and intravenous injection of autologous BMSCs according to the nature of the disease, the degree of visual loss, and any risk factors related to the treatments. Patients with Leber's hereditary optic neuropathy had visual acuity gains on the Early Treatment Diabetic Retinopathy Study (ETDRS) of up to 35 letters and Snellen acuity improvements from hand motion to 20/200 and from counting fingers to 20/100. Visual field improvements were noted. Macular and optic nerve head nerve fiber layer typically thickened. No serious complications were seen. The increases in visual acuity obtained in our study were encouraging and suggest that the use of autologous BMSCs as provided in SCOTS for ophthalmologic mitochondrial diseases including Leber's hereditary optic neuropathy may be a viable treatment option. PMID:27904503

Differences of isolated dental stem cells dependent on donor age and consequences for autologous tooth replacement.

PubMed

Kellner, Manuela; Steindorff, Marina M; Strempel, Jürgen F; Winkel, Andreas; Kühnel, Mark P; Stiesch, Meike

2014-06-01

Autologous therapy via stem cell-based tissue regeneration is an aim to rebuild natural teeth. One option is the use of adult stem cells from the dental pulp (DPSCs), which have been shown to differentiate into several types of tissue in vitro and in vivo, especially into tooth-like structures. DPSCs are mainly isolated from the dental pulp of third molars routinely extracted for orthodontic reasons. Due to the extraction of third molars at various phases of life, DPSCs are isolated at different developmental stages of the tooth. The present study addressed the question whether DPSCs from patients of different ages were similar in their growth characteristics with respect to the stage of tooth development. Therefore DPSCs from third molars of 12-30 year-old patients were extracted, and growth characteristics, e.g. doubling time and maximal cell division potential were analysed. In addition, pulp and hard dental material weight were recorded. Irrespective of the age of patients almost all isolated cells reached 40-60 generations with no correlation between maximal cell division potential and patient age. Cells from patients <22 years showed a significantly faster doubling time than the cells from patients ≥22 years. The age of patients at the time of stem cell isolation is not a crucial factor concerning maximal cell division potential, but does have an impact on the doubling time. However, differences in individuals regarding growth characteristics were more pronounced than age-dependent differences. Copyright © 2014 Elsevier Ltd. All rights reserved.

Potential benefits of allogeneic bone marrow mesenchymal stem cells for wound healing

PubMed Central

Badiavas, Alexander R.; Badiavas, Evangelos V.

2011-01-01

Introduction It is becoming increasingly evident that select adult stem cells have the capacity to participate in repair and regeneration of damaged and/or diseased tissues. Mesenchymal stem cells have been among the most studied adult stem cells for the treatment of a variety of conditions including wound healing. Areas covered Mesenchymal stem cell features potentially beneficial to cutaneous wound healing applications are reviewed. Expert opinion Given their potential for in vitro expansion and immune modulatory effects, both autologous and allogeneic mesenchymal stem cells appear to be well suited as wound healing therapies. Allogeneic mesenchymal stem cells derived from young healthy donors could have particular advantage over autologous sources where age and systemic disease can be significant factors. PMID:21854302

Ten-year follow-up of pediatric patients with non-Hodgkin lymphoma treated with allogeneic or autologous stem cell transplantation.

PubMed

Giulino-Roth, Lisa; Ricafort, Rosanna; Kernan, Nancy A; Small, Trudy N; Trippett, Tanya M; Steinherz, Peter G; Prockop, Susan E; Scaradavou, Andromachi; Chiu, Michelle; O'Reilly, Richard J; Boulad, Farid

2013-12-01

Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting. To evaluate the role of SCT for children with NHL, we reviewed 36 consecutive pediatric patients with NHL who underwent an allogeneic (n = 21) or autologous (n = 15) SCT at our institution between 1982 and 2004. Pathologic classification included: lymphoblastic lymphoma (n = 12), Burkitt lymphoma (BL) (n = 5), diffuse large B-cell lymphoma (n = 4), anaplastic large cell lymphoma (ALCL) (n = 13), peripheral T cell lymphoma (n = 1), and undifferentiated NHL (n = 1). Donor source for allogeneic-SCT recipients was an HLA-matched related donor (n = 15), a matched unrelated donor (n = 4), or a mismatched donor (related n = 1; unrelated n = 1). Twenty-eight patients (78%) had chemotherapy responsive disease at the time of transplant (either CR or PR). Overall survival (OS) and disease-free survival (DFS) were 55% and 53% with a median follow-up of 9.75 years. Outcomes were similar in patients receiving autologous and allogeneic-SCT (DFS 53% in both groups). Patients with ALCL had a DFS of 76.9%. In contrast, of five patients transplanted for BL, none survived. DFS among patients with chemotherapy sensitive disease was 61%, compared with 25% among patients with relapsed/refractory disease (P = 0.019). Allogeneic and autologous SCT offer the prospect of durable, disease-free survival for a significant proportion of pediatric patients with relapsed or refractory NHL. Survival is superior among patients with chemotherapy sensitive disease. © 2013 Wiley Periodicals, Inc.

Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study

PubMed Central

2014-01-01

Background Progressive Supranuclear Palsy (PSP) is a sporadic and progressive neurodegenerative disease which belongs to the family of tauopathies and involves both cortical and subcortical structures. No effective therapy is to date available. Methods/design Autologous bone marrow (BM) mesenchymal stem cells (MSC) from patients affected by different type of parkinsonisms have shown their ability to improve the dopaminergic function in preclinical and clinical models. It is also possible to isolate and expand MSC from the BM of PSP patients with the same proliferation rate and immuphenotypic profile as MSC from healthy donors. BM MSC can be efficiently delivered to the affected brain regions of PSP patients where they can exert their beneficial effects through different mechanisms including the secretion of neurotrophic factors. Here we propose a randomized, placebo-controlled, double-blind phase I clinical trial in patients affected by PSP with MSC delivered via intra-arterial injection. Discussion To our knowledge, this is the first clinical trial to be applied in a no-option parkinsonism that aims to test the safety and to exploit the properties of autologous mesenchymal stem cells in reducing disease progression. The study has been designed to test the safety of this “first-in-man” approach and to preliminarily explore its efficacy by excluding the placebo effect. Trial registration NCT01824121 PMID:24438512

Autologous Stem Cells in Achilles Tendinopathy (ASCAT): protocol for a phase IIA, single-centre, proof-of-concept study

PubMed Central

Goldberg, Andrew J; Zaidi, Razi; Brooking, Deirdre; Kim, Louise; Korda, Michelle; Masci, Lorenzo; Green, Ruth; O’Donnell, Paul; Smith, Roger

2018-01-01

Introduction Achilles tendinopathy (AT) is a cause of pain and disability affecting both athletes and sedentary individuals. More than 150 000 people in the UK every year suffer from AT. While there is much preclinical work on the use of stem cells in tendon pathology, there is a scarcity of clinical data looking at the use of mesenchymal stem cells to treat tendon disease and there does not appear to be any studies of the use of autologous cultured mesenchymal stem cells (MSCs) for AT. Our hypothesis is that autologous culture expanded MSCs implanted into an area of mid-portion AT will lead to improved pain-free mechanical function. The current paper presents the protocol for a phase IIa clinical study. Methods and analysis The presented protocol is for a non-commercial, single-arm, open-label, phase IIa proof-of-concept study. The study will recruit 10 participants and will follow them up for 6 months. Included will be patients aged 18–70 years with chronic mid-portion AT who have failed at least 6 months of non-operative management. Participants will have a bone marrow aspirate collected from the posterior iliac crest under either local or general anaesthetic. MSCs will be isolated and expanded from the bone marrow. Four to 6 weeks after the harvest, participants will undergo implantation of the culture expanded MSCs under local anaesthetic and ultrasound guidance. The primary outcome will be safety as defined by the incidence rate of serious adverse reaction. The secondary outcomes will be efficacy as measured by patient-reported outcome measures and radiological outcome using ultrasound techniques. Ethics and dissemination The protocol has been approved by the National Research Ethics Service Committee (London, Harrow; reference 13/LO/1670). Trial findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration number NCT02064062. PMID:29764889

Predictive factors for long-term engraftment of autologous blood stem cells.

PubMed

Duggan, P R; Guo, D; Luider, J; Auer, I; Klassen, J; Chaudhry, A; Morris, D; Glück, S; Brown, C B; Russell, J A; Stewart, D A

2000-12-01

Data from 170 consecutive patients aged 19-66 years (median age 46 years) who underwent unmanipulated autologous blood stem cell transplant (ASCT) were analyzed to determine if total CD34+ cells/kg infused, CD34+ subsets (CD34+41+, CD34+90+, CD34+33-, CD34+38-, CD34+38-DR-), peripheral blood CD34+ cell (PBCD34+) count on first apheresis day, or various clinical factors were associated with low blood counts 6 months post ASCT. Thirty-four patients were excluded from analysis either because of death (n = 17) or re-induction chemotherapy prior to 6 months post ASCT (n = 13), or because of lack of follow-up data (n = 4). Of the remaining 136 patients, 46% had low WBC ( < 4 x 10(9)/l), 41% low platelets (<150 x 10(9)/l), and 34% low hemoglobin ( < 120 g/l) at a median of 6 months following ASCT. By Spearman's rank correlation, both the total CD34+ cell dose/kg and the PBCD34+ count correlated with 6 month blood counts better than any subset of CD34+ cells or any clinical factor. The PBCD34+ count was overall a stronger predictor of 6 month blood counts than was the total CD34+ cells/kg infused. Both factors retained their significance in multivariate analysis, controlling for clinical factors. In conclusion, subsets of CD34+ cells and clinical factors are inferior to the total CD34+ cell dose/kg and PBCD34+ count in predicting 6 month blood counts following ASCT.

[High dosage therapy and autologous peripheral stem cell transplantation in breast carcinoma].

PubMed

Kier, P; Ruckser, R; Buxhofer, V; Habertheuer, K H; Zelenka, P; Tatzreiter, G; Hübl, G; Kittl, E; Hauser, A; Sebesta, C; Hinterberger, W

2000-01-01

42 breast cancer patients were treated by high-dose chemotherapy (HDC) and autologous peripheral stem-cell transplantation (ASTx) in the Donauspital between 1992 and 1999. 24 patients had stage II/III breast cancer with high risk for relapse. The other 18 patients underwent HDC and ASTx in chemosensitive stage IV. After previous conventional chemotherapy peripheral stem-cells were harvested by one cycle of mobilisation chemotherapy (epirubicin/taxol, FEC 120 or cyclophosphamide) followed by cytokine stimulation. 16 patients were treated by a tandem transplantation (conditioning protocol for 1st ASTx was melphalan 200 mg/m2 and for 2nd transplant it was CTC: cyclophosphamide 6 g/m2; thiotepa 500 mg/m2; carboplatin 800 mg/m2). The other 26 patients received one HDC with CTC as conditioning protocol. The HDC was well tolerated by all patients, there was no transplant-related mortality. The median survival and the progression-free survival (PFS) after HDC and ASTx in stage IV breast cancer patients were 28 and 11 months, respectively. The median survival and PFS were not yet reached in stage II/III patients after 55 months. The actuarial survival and PFS in that patient group were 70% after 55 months. Our data confirm the low risk and good efficacy of HDC and ASTx in breast cancer patients. Nevertheless randomised studies are necessary to evaluate the importance of HDC compared to intensified conventional protocols without ASTx.

Defibrotide prevents the activation of macrovascular and microvascular endothelia caused by soluble factors released to blood by autologous hematopoietic stem cell transplantation.

PubMed

Palomo, Marta; Diaz-Ricart, Maribel; Rovira, Montserrat; Escolar, Ginés; Carreras, Enric

2011-04-01

Endothelial activation and damage occur in association with autologous hematopoietic stem cell transplantation (HSCT). Several of the early complications associated with HSCT seem to have a microvascular location. Through the present study, we have characterized the activation and damage of endothelial cells of both macro (HUVEC) and microvascular (HMEC) origin, occurring early after autologous HSCT, and the potential protective effect of defibrotide (DF). Sera samples from patients were collected before conditioning (Pre), at the time of transplantation (day 0), and at days 7, 14, and 21 after autologous HSCT. Changes in the expression of endothelial cell receptors at the surface, presence and reactivity of extracellular adhesive proteins, and the signaling pathways involved were analyzed. The expression of ICAM-1 at the cell surface increased progressively in both HUVEC and HMEC. However, a more prothrombotic profile was denoted for HMEC, in particular at the time of transplantation (day 0), reflecting the deleterious effect of the conditioning treatment on the endothelium, especially at a microvascular location. Interestingly, this observation correlated with a higher increase in the expression of both tissue factor and von Willebrand factor on the extracellular matrix, together with activation of intracellular p38 MAPK and Akt. Previous exposure and continuous incubation of cells with DF prevented the signs of activation and damage induced by the autologous sera. These observations corroborate that conditioning treatment in autologous HSCT induces a proinflammatory and a prothrombotic phenotype, especially at a microvascular location, and indicate that DF has protective antiinflammatory and antithrombotic effects in this setting. Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

False-Positive [18F]fluorodeoxyglucose-avid lymph nodes on positron emission tomography-computed tomography after allogeneic but not autologous stem-cell transplantation in patients with lymphoma.

PubMed

Ulaner, Gary A; Lilienstein, Joshua; Gönen, Mithat; Maragulia, Jocelyn; Moskowitz, Craig H; Zelenetz, Andrew D

2014-01-01

Determine the clinical significance of [(18)F]fluorodeoxyglucose (FDG)-avid lesions in patients with lymphoma treated with stem-cell transplantation. All patients who underwent stem-cell transplantation for lymphoma at Memorial Sloan-Kettering Cancer Center between January 2005 and December 2009 and had post-transplantation FDG positron emission tomography/computed tomography (PET/CT) examinations were included. PET/CT examinations were evaluated for FDG-avid lesions suggestive of disease. Clinical records, biopsy results, and subsequent imaging examinations were evaluated for malignancy. Two hundred fifty-one patients were identified, 107 with allogeneic and 144 with autologous stem-cell transplantation. Of allogeneic stem-cell transplantation recipients, 50 had FDG-avid lesions suggestive of lymphoma, defined as FDG-avidity greater than liver background. However, only 29 of these 50 demonstrated lymphoma on biopsy, whereas biopsy attempts were benign in the other 21 patients. Sensitivity analysis determined that a 1.5-cm short axis nodal measurement distinguished patients with malignant from nonmalignant biopsies. In 21 of 22 patients with FDG-avid lymph nodes ≤ 1.5 cm, biopsy attempts were benign. In the absence of treatment, these nodes either resolved or were stable on repeat imaging. Disease-free survival of patients with FDG-avid ≤ 1.5 cm lymph nodes was comparable with patients without FDG-avid lesions. In comparison, autologous stem-cell transplantation patients rarely demonstrated FDG-avid lesions suggestive of disease without malignant pathology. Twenty percent (21 of 107) of patients with an allogeneic stem-cell transplantation demonstrated FDG-avid lymph nodes up to 1.5 cm in short axis on PET/CT, which did not represent active lymphoma. After allogeneic stem-cell transplantation of patients with lymphoma, benign FDG-avid ≤ 1.5 cm lymph nodes can mimic malignancy.

Stem cells for the treatment of neurodegenerative diseases

PubMed Central

2010-01-01

Stem cells offer an enormous pool of resources for the understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and although great care will need to be taken when moving forward with prospective treatments, the application of stem cells is highly promising. PMID:21144012

The Use Of Laser Irradiation To Stimulate Adipose Derived Stem Cell Proliferation And Differentiation For Use In Autologous Grafts

NASA Astrophysics Data System (ADS)

Abrahamse, Heidi

2009-09-01

Stem cells are characterized by the qualities of self-renewal, long term viability, and the ability to differentiate into various cell types. Historically, stem cells have been isolated from the inner cell mass of blastocysts and harvesting these cells resulted in the death of the embryo leading to religious, political and ethical issues. The identification and subsequent isolation of adult stem cells from bone marrow stroma have been welcomed as an alternate source for stem cells. The clinical use of Mesenchymal Stem Cells (MSCs) presented problems such as limited cell number, pain and morbidity upon isolation. Adipose tissue is derived from the mesenchyme, is easily isolated, a reliable source of stem cells and able to differentiate into different cell types including smooth muscle. Over the past few years, the identification and characterization of stem cells has led the potential use of these cells as a promising alternative to cell replacement therapy. Smooth muscle is a major component of human tissues and is essential for the normal functioning of many different organs. Low intensity laser irradiation has been shown to increase viability, protein expression and migration of stem cells in vitro, and to stimulate proliferation of various types of stem cells. In addition, the use of laser irradiation to stimulate differentiation in the absence of growth factors has also been demonstrated in normal human neural progenitor cells (NHNPCs) in vitro where NHNPCs are not only capable of being sustained by light in the absence of growth factors, but that they are also able to differentiate normally as assessed by neurite formation. Our work has focused on the ability of laser irradiation to proliferate adipose derived stem cells (ADSCs), maintain ADSC character and increase the rate and maintenance of differentiation of ADSCs into smooth muscle and skin fibroblast cells. Current studies are also investigating the effect of different irradiation wavelengths and

Adeno-Associated Virus Vectors and Stem Cells: Friends or Foes?

PubMed

Brown, Nolan; Song, Liujiang; Kollu, Nageswara R; Hirsch, Matthew L

2017-06-01

The infusion of healthy stem cells into a patient-termed "stem-cell therapy"-has shown great promise for the treatment of genetic and non-genetic diseases, including mucopolysaccharidosis type 1, Parkinson's disease, multiple sclerosis, numerous immunodeficiency disorders, and aplastic anemia. Stem cells for cell therapy can be collected from the patient (autologous) or collected from another "healthy" individual (allogeneic). The use of allogenic stem cells is accompanied with the potentially fatal risk that the transplanted donor T cells will reject the patient's cells-a process termed "graft-versus-host disease." Therefore, the use of autologous stem cells is preferred, at least from the immunological perspective. However, an obvious drawback is that inherently as "self," they contain the disease mutation. As such, autologous cells for use in cell therapies often require genetic "correction" (i.e., gene addition or editing) prior to cell infusion and therefore the requirement for some form of nucleic acid delivery, which sets the stage for the AAV controversy discussed herein. Despite being the most clinically applied gene delivery context to date, unlike other more concerning integrating and non-integrating vectors such as retroviruses and adenovirus, those based on adeno-associated virus (AAV) have not been employed in the clinic. Furthermore, published data regarding AAV vector transduction of stem cells are inconsistent in regards to vector transduction efficiency, while the pendulum swings far in the other direction with demonstrations of AAV vector-induced toxicity in undifferentiated cells. The variation present in the literature examining the transduction efficiency of AAV vectors in stem cells may be due to numerous factors, including inconsistencies in stem-cell collection, cell culture, vector preparation, and/or transduction conditions. This review summarizes the controversy surrounding AAV vector transduction of stem cells, hopefully setting the

Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies.

PubMed

Kebriaei, Partow; Huls, Helen; Jena, Bipulendu; Munsell, Mark; Jackson, Rineka; Lee, Dean A; Hackett, Perry B; Rondon, Gabriela; Shpall, Elizabeth; Champlin, Richard E; Cooper, Laurence J N

2012-05-01

Limited curative treatment options exist for patients with advanced B-lymphoid malignancies, and new therapeutic approaches are needed to augment the efficacy of hematopoietic stem-cell transplantation (HSCT). Cellular therapies, such as adoptive transfer of T cells that are being evaluated to target malignant disease, use mechanisms independent of chemo- and radiotherapy with nonoverlapping toxicities. Gene therapy is employed to generate tumor-specific T cells, as specificity can be redirected through enforced expression of a chimeric antigen receptor (CAR) to achieve antigen recognition based on the specificity of a monoclonal antibody. By combining cell and gene therapies, we have opened a new Phase I protocol at the MD Anderson Cancer Center (Houston, TX) to examine the safety and feasibility of administering autologous genetically modified T cells expressing a CD19-specific CAR (capable of signaling through chimeric CD28 and CD3-ζ) into patients with high-risk B-lymphoid malignancies undergoing autologous HSCT. The T cells are genetically modified by nonviral gene transfer of the Sleeping Beauty system and CAR(+) T cells selectively propagated in a CAR-dependent manner on designer artificial antigen-presenting cells. The results of this study will lay the foundation for future protocols including CAR(+) T-cell infusions derived from allogeneic sources.

Comparison of culture media indicates a role for autologous serum in enhancing phenotypic preservation of rabbit limbal stem cells in explant culture.

PubMed

Gürdal, Mehmet; Barut Selver, Özlem; Baysal, Kemal; Durak, İsmet

2018-04-01

In this study, we aimed to compare the effects of six different cell culture media and autologous serum (AS) on the phenotypic characteristics of rabbit limbal epithelial stem cells (LESC) cultivated on porous polyethylene terephthalate (PET) membranes. Limbal explants from rabbit corneas were grown on PET membrane inserts in five different media: DMEM-F12 with fetal bovine serum (FBS) (DMEM-F12-FBS), with pluripotin (DMEM-F12-pluripotin) and with autologous serum (DMEM-F12-AS), Epilife, Keratinocyte Serum Free Medium (KSFM) and Defined-Keratinocyte Serum Free Medium. The effects of different media were evaluated by total cell yield from explants, measuring the expression of proteins by immunofluorescence and gene expression by Real Time PCR. In all five media tested, most of the limbal epithelial cells (LEC) which proliferated from explants were positive for cytokeratin (CK) 14 (85-90%), indicating that all five media support the growth of LESC from explants. The expression of differentiation markers; CK 3 and 12 was highest in DMEM-F12-FBS (56%), was lower in Epilife and KSFM (26 and 19%, respectively), with the lowest values (13%) obtained in DMEM-F12-AS. Gene expression of limbal cultures on PET membrane inserts was compared to fresh limbal tissue. In DMEM-F12-FBS, DMEM-F12-pluripotin, and DMEM-F12-AS, expression of potential LESC markers CXCR4 and polycomb complex protein BMI-1 were similar to limbal tissue. DMEM-F12 with 10% AS maintained a higher percentage of potential stem cell marker genes and lower expression of genes involved in differentiation compared to Epilife or KSFM. Our study shows that rabbit LEC can be cultivated on PET inserts using DMEM-F12 with autologous serum without a requirement for amniotic membrane or feeder cells.

Preclinical studies for a phase 1 clinical trial of autologous hematopoietic stem cell gene therapy for sickle cell disease.

PubMed

Urbinati, Fabrizia; Wherley, Jennifer; Geiger, Sabine; Fernandez, Beatriz Campo; Kaufman, Michael L; Cooper, Aaron; Romero, Zulema; Marchioni, Filippo; Reeves, Lilith; Read, Elizabeth; Nowicki, Barbara; Grassman, Elke; Viswanathan, Shivkumar; Wang, Xiaoyan; Hollis, Roger P; Kohn, Donald B

2017-09-01

Gene therapy by autologous hematopoietic stem cell transplantation (HSCT) represents a new approach to treat sickle cell disease (SCD). Optimization of the manufacture, characterization and testing of the transduced hematopoietic stem cell final cell product (FCP), as well as an in depth in vivo toxicology study, are critical for advancing this approach to clinical trials. Data are shown to evaluate and establish the feasibility of isolating, transducing with the Lenti/β AS3 -FB vector and cryopreserving CD34 + cells from human bone marrow (BM) at clinical scale. In vitro and in vivo characterization of the FCP was performed, showing that all the release criteria were successfully met. In vivo toxicology studies were conducted to evaluate potential toxicity of the Lenti/β AS3 -FB LV in the context of a murine BM transplant. Primary and secondary transplantation did not reveal any toxicity from the lentiviral vector. Additionally, vector integration site analysis of murine and human BM cells did not show any clonal skewing caused by insertion of the Lenti/β AS3 -FB vector in cells from primary and secondary transplanted mice. We present here a complete protocol, thoroughly optimized to manufacture, characterize and establish safety of a FCP for gene therapy of SCD. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Clinicopathologic findings following intra-articular injection of autologous and allogeneic placentally derived equine mesenchymal stem cells in horses.

PubMed

Carrade, Danielle D; Owens, Sean D; Galuppo, Larry D; Vidal, Martin A; Ferraro, Gregory L; Librach, Fred; Buerchler, Sabine; Friedman, Michael S; Walker, Naomi J; Borjesson, Dori L

2011-04-01

The development of an allogeneic mesenchymal stem cell (MSC) product to treat equine disorders would be useful; however, there are limited in vivo safety data for horses. We hypothesized that the injection of self (autologous) and non-self (related allogeneic or allogeneic) MSC would not elicit significant alterations in physical examination, gait or synovial fluid parameters when injected into the joints of healthy horses. Sixteen healthy horses were used in this study. Group 1 consisted of foals (n = 6), group 2 consisted of their dams (n = 5) and group 3 consisted of half-siblings (n = 5) to group 1 foals. Prior to injection, MSC were phenotyped. Placentally derived MSC were injected into contralateral joints and MSC diluent was injected into a separate joint (control). An examination, including lameness evaluation and synovial fluid analysis, was performed at 0, 24, 48 and 72 h post-injection. MSC were major histocompatibility complex (MHC) I positive, MHC II negative and CD86 negative. Injection of allogeneic MSC did not elicit a systemic response. Local responses such as joint swelling or lameness were minimal and variable. Intra-articular MSC injection elicited marked inflammation within the synovial fluid (as measured by nucleated cell count, neutrophil number and total protein concentration). However, there were no significant differences between the degree and type of inflammation elicited by self and non-self-MSC. The healthy equine joint responds similarly to a single intra-articular injection of autologous and allogeneic MSC. This pre-clinical safety study is an important first step in the development of equine allogeneic stem cell therapies.

Acquired von Willebrand Syndrome Associated to Secondary IgM MGUS Emerging after Autologous Stem Cell Transplantation for AL Amyloidosis

PubMed Central

Qamar, Hina; Lee, Adrienne; Valentine, Karen; Skeith, Leslie; Jimenez-Zepeda, Victor H

2017-01-01

Acquired von Willebrand syndrome (AVWS) is a rare hemorrhagic disorder that occurs in patients with no prior personal or family history of bleeding. Here, we describe a case of AVWS occurring after autologous stem cell transplantation (ASCT). Interestingly, AVWS developed after bortezomib-based induction and conditioning regimens. Recent evidence suggests that the proximity of the bortezomib therapy to the collection of stem cells with consequent depletion of regulatory T cells after the conditioning regimen could explain some of the unusual autoimmune complications reported in patients receiving bortezomib prior to ASCT. In addition, this patient developed a secondary MGUS post-ASCT, which may have also contributed to the AVWS. To the best of our knowledge, this is the first case of post-ASCT AVWS reported. Prospective data is needed to better elucidate the mechanisms by which these unusual complications occur in patients receiving bortezomib prior to ASCT. PMID:28512563

Acquired von Willebrand Syndrome Associated to Secondary IgM MGUS Emerging after Autologous Stem Cell Transplantation for AL Amyloidosis.

PubMed

Qamar, Hina; Lee, Adrienne; Valentine, Karen; Skeith, Leslie; Jimenez-Zepeda, Victor H

2017-01-01

Acquired von Willebrand syndrome (AVWS) is a rare hemorrhagic disorder that occurs in patients with no prior personal or family history of bleeding. Here, we describe a case of AVWS occurring after autologous stem cell transplantation (ASCT). Interestingly, AVWS developed after bortezomib-based induction and conditioning regimens. Recent evidence suggests that the proximity of the bortezomib therapy to the collection of stem cells with consequent depletion of regulatory T cells after the conditioning regimen could explain some of the unusual autoimmune complications reported in patients receiving bortezomib prior to ASCT. In addition, this patient developed a secondary MGUS post-ASCT, which may have also contributed to the AVWS. To the best of our knowledge, this is the first case of post-ASCT AVWS reported. Prospective data is needed to better elucidate the mechanisms by which these unusual complications occur in patients receiving bortezomib prior to ASCT.

A population-based cohort study of late mortality in adult autologous hematopoietic stem cell transplant recipients in Australia.

PubMed

Ashton, Lesley J; Le Marsney, Renate E; Dodds, Anthony J; Nivison-Smith, Ian; Wilcox, Leonie; O'Brien, Tracey A; Vajdic, Claire M

2014-07-01

We assessed overall and cause-specific mortality and risk factors for late mortality in a nation-wide population-based cohort of 4547 adult cancer patients who survived 2 or more years after receiving an autologous hematopoietic stem cell transplantation (HSCT) in Australia between 1992 and 2005. Deaths after HSCT were identified from the Australasian Bone Marrow Transplant Recipient Registry and through data linkage with the National Death Index. Overall, the survival probability was 56% at 10 years from HSCT, ranging from 34% for patients with multiple myeloma to 90% for patients with testicular cancer. Mortality rates moved closer to rates observed in the age- and sex-matched Australian general population over time but remained significantly increased 11 or more years from HSCT (standardized mortality ratio, 5.9). Although the proportion of deaths from nonrelapse causes increased over time, relapse remained the most frequent cause of death for all diagnoses, 10 or more years after autologous HSCT. Our findings show that prevention of disease recurrence remains 1 of the greatest challenges for autologous HSCT recipients, while the increasing rates of nonrelapse deaths due to the emergence of second cancers, circulatory diseases, and respiratory diseases highlight the long-term health issues faced by adult survivors of autologous HSCT. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma.

PubMed

Baertsch, Marc-Andrea; Schlenzka, Jana; Mai, Elias K; Merz, Maximilian; Hillengaß, Jens; Raab, Marc S; Hose, Dirk; Wuchter, Patrick; Ho, Anthony D; Jauch, Anna; Hielscher, Thomas; Kunz, Christina; Luntz, Steffen; Klein, Stefan; Schmidt-Wolf, Ingo G H; Goerner, Martin; Schmidt-Hieber, Martin; Reimer, Peter; Graeven, Ullrich; Fenk, Roland; Salwender, Hans; Scheid, Christof; Nogai, Axel; Haenel, Mathias; Lindemann, Hans W; Martin, Hans; Noppeney, Richard; Weisel, Katja; Goldschmidt, Hartmut

2016-04-25

Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary

Effect of activated autologous platelet-rich plasma on proliferation and osteogenic differentiation of human adipose-derived stem cells in vitro

PubMed Central

Xu, Fang-Tian; Li, Hong-Mian; Yin, Qing-Shui; Liang, Zhi-Jie; Huang, Min-Hong; Chi, Guang-Yi; Huang, Lu; Liu, Da-Lie; Nan, Hua

2015-01-01

To investigate whether activated autologous platelet-rich plasma (PRP) can promote proliferation and osteogenic differentiation of human adipose-derived stem cells (hASCs) in vitro. hASCs were isolated from lipo-aspirates, and characterized by specific cell markers and multilineage differentiation capacity after culturing to the 3rd passage. PRP was collected and activated from human peripheral blood of the same patient. Cultured hASCs were treated with normal osteogenic inductive media alone (group A, control) or osteogenic inductive media plus 5%, 10%, 20%, 40%PRP (group B, C, D, E, respectively). Cell proliferation was assessed by CCK-8 assay. mRNA expression of osteogenic marker genes including alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OCN) and core binding factor alpha 1 (Cbfa1) were determined by Real-Time Quantitative PCR Analysis (qPCR). Data revealed that different concentrations of activated autologous PRP significantly promoted hASCs growth in the proliferation phase compared to the without PRP group and resulted in a dose-response relationship. At 7-d and 14-d time point of the osteogenic induced stage, ALP activity in PRP groups gradually increased with the increasing of concentrations of PRP and showed that dose-response relationship. At 21-d time point of the osteogenic induced stage, PRP groups make much more mineralization and mRNA relative expression of ALP, OPN, OCN and Cbfa1 than that without PRP groups and show that dose-response relationship. This study indicated that different concentrations of activated autologous PRP can promote cell proliferation at earlier stage and promote osteogenic differentiation at later stage of hASCs in vitro. Moreover, it displayed a dose-dependent effect of activated autologous PRP on cell proliferation and osteogenic differentiation of hASCs in vitro. PMID:25901195

Effect of N-Acetylcysteine on Adipose-Derived Stem Cell and Autologous Fat Graft Survival in a Mouse Model.

PubMed

Gillis, Joshua; Gebremeskel, Simon; Phipps, Kyle D; MacNeil, Lori A; Sinal, Christopher J; Johnston, Brent; Hong, Paul; Bezuhly, Michael

2015-08-01

Autologous fat grafting is a popular reconstructive technique, but is limited by inconsistent graft retention. The authors examined whether a widely available, clinically safe antioxidant, N-acetylcysteine, could improve adipose-derived stem cell survival and graft take when added to tumescent solution during fat harvest. Inguinal fat pads were harvested from C57BL/6 mice using tumescent solution with or without N-acetylcysteine. Flow cytometric, proliferation, and differentiation assays were performed on isolated primary adipose-derived stem cells and 3T3-L1 preadipocytes treated with or without hydrogen peroxide and/or N-acetylcysteine. N-Acetylcysteine-treated or control grafts were injected under recipient mouse scalps and assessed by serial micro-computed tomographic volumetric analysis. Explanted grafts underwent immunohistochemical analysis. In culture, N-acetylcysteine protected adipose-derived stem cells from oxidative stress and improved cell survival following hydrogen peroxide treatment. Combined exposure to both N-acetylcysteine and hydrogen peroxide led to a 200-fold increase in adipose-derived stem cell proliferation, significantly higher than with either agent alone. N-Acetylcysteine decreased differentiation of adipose-derived stem cells into mature adipocytes, as evidenced by decreased transcription of adipocyte differentiation markers and reduced Oil Red-O staining. In vivo, N-acetylcysteine treatment resulted in improved graft retention at 3 months compared with control (46 versus 17 percent; p = 0.027). N-Acetylcysteine-treated grafts demonstrated less fibrosis and inflammation, and a 33 percent increase in adipocyte density compared with controls (p < 0.001) that was not associated with increased vascularity. These findings provide proof of principle for the addition of N-acetylcysteine to tumescent harvest solution in the clinical setting to optimize fat graft yields.

New perspectives in human stem cell therapeutic research.

PubMed

Trounson, Alan

2009-06-11

Human stem cells are in evaluation in clinical stem cell trials, primarily as autologous bone marrow studies, autologous and allogenic mesenchymal stem cell trials, and some allogenic neural stem cell transplantation projects. Safety and efficacy are being addressed for a number of disease state applications. There is considerable data supporting safety of bone marrow and mesenchymal stem cell transplants but the efficacy data are variable and of mixed benefit. Mechanisms of action of many of these cells are unknown and this raises the concern of unpredictable results in the future. Nevertheless there is considerable optimism that immune suppression and anti-inflammatory properties of mesenchymal stem cells will be of benefit for many conditions such as graft versus host disease, solid organ transplants and pulmonary fibrosis. Where bone marrow and mesenchymal stem cells are being studied for heart disease, stroke and other neurodegenerative disorders, again progress is mixed and mostly without significant benefit. However, correction of multiple sclerosis, at least in the short term is encouraging. Clinical trials on the use of embryonic stem cell derivatives for spinal injury and macular degeneration are beginning and a raft of other clinical trials can be expected soon, for example, the use of neural stem cells for killing inoperable glioma and embryonic stem cells for regenerating beta islet cells for diabetes. The change in attitude to embryonic stem cell research with the incoming Obama administration heralds a new co-operative environment for study and evaluation of stem cell therapies. The Californian stem cell initiative (California Institute for Regenerative Medicine) has engendered global collaboration for this new medicine that will now also be supported by the US Federal Government. The active participation of governments, academia, biotechnology, pharmaceutical companies, and private investment is a powerful consortium for advances in health.

Icing oral mucositis: Oral cryotherapy in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant.

PubMed

Chen, Joey; Seabrook, Jamie; Fulford, Adrienne; Rajakumar, Irina

2017-03-01

Background Up to 70% of patients receiving hematopoietic stem cell transplant develop oral mucositis as a side effect of high-dose melphalan conditioning chemotherapy. Oral cryotherapy has been documented to be potentially effective in reducing oral mucositis. The aim of this study was to examine the effectiveness of the cryotherapy protocol implemented within the hematopoietic stem cell transplant program. Methods A retrospective chart review was conducted of adult multiple myeloma patients who received high-dose melphalan conditioning therapy for autologous hematopoietic stem cell transplant. Primary endpoints were incidence and severity of oral mucositis. Secondary endpoints included duration of oral mucositis, duration of hospital stay, parenteral narcotics use and total parenteral nutrition use. Results One hundred and forty patients were included in the study, 70 patients in both no cryotherapy and cryotherapy groups. Both oral mucositis incidence and severity were found to be significantly lower in the cryotherapy group. Fifty (71.4%) experienced mucositis post cryotherapy compared to 67 (95.7%) in the no cryotherapy group (p < 0.001). The median oral mucositis severity, assessed using the WHO oral toxicity scale from grade 0-4, experienced in the no group was 2.5 vs. 2 in the cryotherapy group (p = 0.03). Oral mucositis duration and use of parenteral narcotics were also significantly reduced. Duration of hospital stay and use of parenteral nutrition were similar between the two groups. Conclusion The cryotherapy protocol resulted in a significantly lower incidence and severity of oral mucositis. These results provide evidence for the continued use of oral cryotherapy, an inexpensive and generally well-tolerated practice.

Hematopoietic stem cell transplantation for non-Hodgkin lymphoma.

PubMed

Bhatt, Vijaya Raj; Vose, Julie M

2014-12-01

Up-front rituximab-based chemotherapy has improved outcomes in non-Hodgkin lymphoma (NHL); refractory or relapsed NHL still accounts for approximately 18,000 deaths in the United States. Autologous hematopoietic stem cell transplantation (SCT) can improve survival in primary refractory or relapsed aggressive NHL and mantle cell lymphoma and in relapsed follicular or peripheral T-cell lymphoma. Autologous SCT as a consolidation therapy after first complete or partial remission in high-risk aggressive NHL, mantle cell lymphoma, and peripheral T-cell lymphoma may improve progression-free survival. Allogeneic SCT offers a lower relapse rate but a higher nonrelapse mortality resulting in overall survival similar to autologous SCT. Copyright © 2014 Elsevier Inc. All rights reserved.

Do autologous peripheral blood cell transplants provide more than hematopoietic recovery?

PubMed

Kessinger, A

1995-07-01

Bone marrow damage caused by myeloablative radiation therapy and/or chemotherapy can be repaired by intravenously infusing viable stem/progenitor cells collected from either blood or bone marrow. The hematopoietic graft product contains both stem/progenitor cells and populations of hematopoietic and nonhematopoietic (accessory) cells. The frequency of accessory cell types varies with the source of the graft product; marrow or blood. Reinfusion of these accessory cells causes effects other than the hematopoietic restoration provided by the stem/progenitor cells such as graft versus host disease and graft versus leukemia effect after allogeneic transplants. Effects of infused accessory cells in the autologous setting are less well studied and could provide ancillary advantages and/or disadvantages to the patient. Do these additional effects actually occur, and, if they do, are they more likely to appear following peripheral blood cell transplants (PBCT) or after autologous bone marrow transplants (AMBT)? Preliminary data are beginning to accumulate which suggest that reinfusion of occult tumor cells is less likely with PBCT, that immune reconstitution is different depending on the source of the autograft and that, for certain diseases, patient event-free survival following PBCT rather than ABMT may be better. However, infusion of occult tumor cells may result in re-establishment of the malignancy. If the accessory cells (including potential occult tumor cells) are eliminated from the product before transplant, will the patient have a better clinical outcome, or would benefits provided by infused accessory cells outweigh the risks of infused occult tumor cells? These controversial issues are in the very early stages of investigation.

A Phase III Clinical Trial Showing Limited Efficacy of Autologous Mesenchymal Stem Cell Therapy for Spinal Cord Injury.

PubMed

Oh, Sun Kyu; Choi, Kyoung Hyo; Yoo, Jong Yoon; Kim, Dae Yul; Kim, Sang Joon; Jeon, Sang Ryong

2016-03-01

In our previous report, 3 of 10 patients with spinal cord injury who were injected with autologous mesenchymal stem cells (MSCs) showed motor improvement in the upper extremities and in activities of daily living. To report on the results of a phase III clinical trial of autologous MSCs therapy. Patients were selected based on the following criteria: chronic American Spinal Injury Association B status patients who had more than 12 months of cervical injury, and no neurological changes during the recent 3 months of vigorous rehabilitation. We injected 1.6 × 10 autologous MSCs into the intramedullary area at the injured level and 3.2 × 10 autologous MSCs into the subdural space. Outcome data were collected over 6 months regarding neurological examination, magnetic resonance imaging with diffusion tensor imaging, and electrophysiological analyses. Among the 16 patients, only 2 showed improvement in neurological status (unilateral right C8 segment from grade 1 to grade 3 in 1 patient and bilateral C6 from grade 3 to grade 4 and unilateral right C8 from grade 0 to grade 1 in 1 patient). Both patients with neurological improvement showed the appearance of continuity in the spinal cord tract by diffusion tensor imaging. There were no adverse effects associated with MSCs injection. Single MSCs application to intramedullary and intradural space is safe, but has a very weak therapeutic effect compared with multiple MSCs injection. Further clinical trials to enhance the effect of MSCs injection are necessary.

Advantages of non-cryopreserved autologous hematopoietic stem cell transplantation against a cryopreserved strategy.

PubMed

Sarmiento, M; Ramírez, P; Parody, R; Salas, M Q; Beffermann, N; Jara, V; Bertín, P; Pizarro, I; Lorca, C; Rivera, E; Galleguillos, M; Ocqueteau, M; Sánchez-Ortega, I; Patiño, B; Sureda, A

2018-02-13

Autologous stem cell transplantation (auto-HSCT) is an effective treatment strategy for hematological malignancies. The standard mode of handling hematopoietic progenitors for the autologous procedure (CRYO) consists on its collection and freezing with dimethyl sulfoxide (DMSO) and its subsequent thawing and re-infusion. This process is toxic and expensive. Non-cryopreserved (non-CRYO) is a less expensive mode of auto-HSCT. We designed a comparative study between both strategies performed in two different centers to analyze the short-term complications. In total 111 auto-HSCT were performed from January/2015 to October/2016 (42 non-CRYO and 74 CRYO). There were 74 males and 69 (62%) patients had the underlying diagnosis of multiple myeloma. No differences were seen on the characteristics of the apheresis products and their viability. Engraftment was significantly faster in the non-CRYO group (p = 0.001). Febrile neutropenia and severe mucositis were lower in the non-CRYO group (40% vs 92% p = 0.0001 and 11% vs 64%, p = 0.001, respectively). In addition, length of hospitalization was 5 days shorter in the non-CRYO group (p = 0.0001). Overall responses and transplantation outcomes were similar. Our data demonstrate a clear advantage of the non-CRYO over CRYO auto-HSCT with faster engraftment, lower incidence of febrile neutropenia and shorter hospital stay after the transplantation procedure. These data are especially relevant for centers with high transplant activity or with limited resources.

Adipose-derived mesenchymal stem cells and regenerative medicine.

PubMed

Konno, Masamitsu; Hamabe, Atsushi; Hasegawa, Shinichiro; Ogawa, Hisataka; Fukusumi, Takahito; Nishikawa, Shimpei; Ohta, Katsuya; Kano, Yoshihiro; Ozaki, Miyuki; Noguchi, Yuko; Sakai, Daisuke; Kudoh, Toshihiro; Kawamoto, Koichi; Eguchi, Hidetoshi; Satoh, Taroh; Tanemura, Masahiro; Nagano, Hiroaki; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi

2013-04-01

Adipose tissue-derived mesenchymal stem cells (ADSCs) are multipotent and can differentiate into various cell types, including osteocytes, adipocytes, neural cells, vascular endothelial cells, cardiomyocytes, pancreatic β-cells, and hepatocytes. Compared with the extraction of other stem cells such as bone marrow-derived mesenchymal stem cells (BMSCs), that of ADSCs requires minimally invasive techniques. In the field of regenerative medicine, the use of autologous cells is preferable to embryonic stem cells or induced pluripotent stem cells. Therefore, ADSCs are a useful resource for drug screening and regenerative medicine. Here we present the methods and mechanisms underlying the induction of multilineage cells from ADSCs. © 2013 The Authors Development, Growth & Differentiation © 2013 Japanese Society of Developmental Biologists.

Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia.

PubMed

Reeves, Daniel B; Peterson, Christopher W; Kiem, Hans-Peter; Schiffer, Joshua T

2017-07-01

Primary HIV-1 infection induces a virus-specific adaptive/cytolytic immune response that impacts the plasma viral load set point and the rate of progression to AIDS. Combination antiretroviral therapy (cART) suppresses plasma viremia to undetectable levels that rebound upon cART treatment interruption. Following cART withdrawal, the memory component of the virus-specific adaptive immune response may improve viral control compared to primary infection. Here, using primary infection and treatment interruption data from macaques infected with simian/human immunodeficiency virus (SHIV), we observe a lower peak viral load but an unchanged viral set point during viral rebound. The addition of an autologous stem cell transplant before cART withdrawal alters viral dynamics: we found a higher rebound set point but similar peak viral loads compared to the primary infection. Mathematical modeling of the data that accounts for fundamental immune parameters achieves excellent fit to heterogeneous viral loads. Analysis of model output suggests that the rapid memory immune response following treatment interruption does not ultimately lead to better viral containment. Transplantation decreases the durability of the adaptive immune response following cART withdrawal and viral rebound. Our model's results highlight the impact of the endogenous adaptive immune response during primary SHIV infection. Moreover, because we capture adaptive immune memory and the impact of transplantation, this model will provide insight into further studies of cure strategies inspired by the Berlin patient. IMPORTANCE HIV patients who interrupt combination antiretroviral therapy (cART) eventually experience viral rebound, the return of viral loads to pretreatment levels. However, the "Berlin patient" remained free of HIV rebound over a decade after stopping cART. His cure is attributed to leukemia treatment that included an HIV-resistant stem cell transplant. Inspired by this case, we studied the impact

Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia

PubMed Central

Peterson, Christopher W.; Kiem, Hans-Peter

2017-01-01

ABSTRACT Primary HIV-1 infection induces a virus-specific adaptive/cytolytic immune response that impacts the plasma viral load set point and the rate of progression to AIDS. Combination antiretroviral therapy (cART) suppresses plasma viremia to undetectable levels that rebound upon cART treatment interruption. Following cART withdrawal, the memory component of the virus-specific adaptive immune response may improve viral control compared to primary infection. Here, using primary infection and treatment interruption data from macaques infected with simian/human immunodeficiency virus (SHIV), we observe a lower peak viral load but an unchanged viral set point during viral rebound. The addition of an autologous stem cell transplant before cART withdrawal alters viral dynamics: we found a higher rebound set point but similar peak viral loads compared to the primary infection. Mathematical modeling of the data that accounts for fundamental immune parameters achieves excellent fit to heterogeneous viral loads. Analysis of model output suggests that the rapid memory immune response following treatment interruption does not ultimately lead to better viral containment. Transplantation decreases the durability of the adaptive immune response following cART withdrawal and viral rebound. Our model's results highlight the impact of the endogenous adaptive immune response during primary SHIV infection. Moreover, because we capture adaptive immune memory and the impact of transplantation, this model will provide insight into further studies of cure strategies inspired by the Berlin patient. IMPORTANCE HIV patients who interrupt combination antiretroviral therapy (cART) eventually experience viral rebound, the return of viral loads to pretreatment levels. However, the “Berlin patient” remained free of HIV rebound over a decade after stopping cART. His cure is attributed to leukemia treatment that included an HIV-resistant stem cell transplant. Inspired by this case, we

Autologous transplantation of bone marrow-derived mesenchymal stem cells: a promising therapeutic strategy for prevention of skin-graft contraction.

PubMed

Xu, Y; Huang, S; Fu, X

2012-07-01

Hypertrophic scars result from abnormal healing of severe burns, and are characterized by loss of the original structure and function of the skin. Transplantation of autologous split skin is the preferred treatment after scar excision; however, there will be some unavoidable degree of contraction within the grafts. To our knowledge, it is very rare that bone marrow-derived mesenchymal stem cells (BM-MSCs) have been used for the treatment of skin-graft contraction. However, in our clinics, we found that during a 2-year follow-up analysis, areas treated with autologous BM-MSCs combined with transplantation of split skin were less likely to have contraction of the skin grafts than areas treated with skin grafts alone. This result indicates that BM-MSCs may be a potential and promising treatment to prevent contraction of skin grafts. © The Author(s). CED © 2012 British Association of Dermatologists.

IIVP salvage regimen induces high response rates in patients with relapsed lymphoma before autologous stem cell transplantation.

PubMed

Abali, Huseyin; Oyan, Basak; Koc, Yener; Kars, Ayse; Barista, Ibrahim; Uner, Aysegul; Turker, Alev; Demirkazik, Figen; Tekin, Fatma; Tekuzman, Gulten; Kansu, Emin

2005-06-01

Patients with relapsed lymphoma can be cured with high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). New therapeutic approaches with better cytoreductive capacity are needed for relapsed patients to keep their chance for cure with transplantation. We report 30 patients with relapsed lymphoma, median age 43 years, treated with IIVP salvage regimen consisting of ifosfamide, mesna, idarubicin, and etoposide for 2 or 3 cycles. Seventeen patients had non-Hodgkin lymphoma (NHL) and 13 patients had Hodgkin disease (HD). Fourteen (47%) patients were at their first relapse. Overall response rate was 86.6% (n = 26) with 19 patients (63.3%) achieving complete response. Overall response rate was 92% in patients with HD and 82% in NHL. The most frequent side effects observed were grade III-IV neutropenia (87%) and thrombocytopenia (73%). IIVP regimen is a highly effective salvage therapy for patients with relapsed HD or NHL who are candidates for autologous HSCT. Close follow up is necessary because of the high incidence of grade III-IV hematologic toxicity.

Design of a hybrid biomaterial for tissue engineering: Biopolymer-scaffold integrated with an autologous hydrogel carrying mesenchymal stem-cells.

PubMed

Weinstein-Oppenheimer, Caroline R; Brown, Donald I; Coloma, Rodrigo; Morales, Patricio; Reyna-Jeldes, Mauricio; Díaz, María J; Sánchez, Elizabeth; Acevedo, Cristian A

2017-10-01

Biologically active biomaterials as biopolymers and hydrogels have been used in medical applications providing favorable results in tissue engineering. In this research, a wound dressing device was designed by integration of an autologous clot hydrogel carrying mesenchymal stem-cells onto a biopolymeric scaffold. This hybrid biomaterial was tested in-vitro and in-vivo, and used in a human clinical case. The biopolymeric scaffold was made with gelatin, chitosan and hyaluronic acid, using a freeze-drying method. The scaffold was a porous material which was designed evaluating both physical properties (glass transition, melting temperature and pore size) and biological properties (cell viability and fibronectin expression). Two types of chitosan (120 and 300kDa) were used to manufacture the scaffold, being the high molecular weight the most biologically active and stable after sterilization with gamma irradiation (25kGy). A clot hydrogel was formulated with autologous plasma and calcium chloride, using an approach based on design of experiments. The optimum hydrogel was used to incorporate cells onto the porous scaffold, forming a wound dressing biomaterial. The wound dressing device was firstly tested in-vitro using human cells, and then, its biosecurity was evaluated in-vivo using a rabbit model. The in-vitro results showed high cell viability after one week (99.5%), high mitotic index (19.8%) and high fibronectin expression. The in-vivo application to rabbits showed adequate biodegradability capacity (between 1 and 2weeks), and the histological evaluation confirmed absence of rejection signs and reepithelization on the wound zone. Finally, the wound dressing biomaterial was used in a single human case to implant autologous cells on a skin surgery. The medical examination indicated high biocompatibility, partial biodegradation at one week, early regeneration capacity at 4weeks and absence of rejection signs. Copyright © 2017 Elsevier B.V. All rights reserved.

Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients.

PubMed

Carrion, F; Nova, E; Ruiz, C; Diaz, F; Inostroza, C; Rojo, D; Mönckeberg, G; Figueroa, F E

2010-03-01

Mesenchymal stem cells (MSCs) exert suppressive effects in several disease models including lupus prone mice. However, autologous MSC therapy has not been tested in human systemic lupus erythematosus (SLE). We evaluate the safety and efficacy of bone marrow (BM)-derived MSCs in two SLE patients; the suppressor effect of these cells in-vitro and the change in CD4+CD25+FoxP3+ T regulatory (Treg) cells in response to treatment. Two females (JQ and SA) of 19 and 25 years of age, fulfilling the 1997 American College of Rheumatology (ACR) criteria for SLE were infused with autologous BM-derived MSCs. Disease activity indexes and immunological parameters were assessed at baseline, 1, 2, 7 and 14 weeks. Peripheral blood lymphocyte (PBL) subsets and Treg cells were quantitated by flow cytometry, and MSCs tested for in-vitro suppression of activation and proliferation of normal PBLs. No adverse effects or change in disease activity indexes were noted during 14 weeks of follow-up, although circulating Treg cells increased markedly. Patient MSCs effectively suppressed in-vitro PBL function. However, JQ developed overt renal disease 4 months after infusion. MSC infusion was without adverse effects, but did not modify initial disease activity in spite of increasing CD4+CD25+FoxP3+ cell counts. One patient subsequently had a renal flare. We speculate that the suppressive effects of MSC-induced Treg cells might be dependent on a more inflammatory milieu, becoming clinically evident in patients with higher degrees of disease activity.

Ethical and Regulatory Challenges with Autologous Adult Stem Cells: A Comparative Review of International Regulations.

PubMed

Lysaght, Tamra; Kerridge, Ian H; Sipp, Douglas; Porter, Gerard; Capps, Benjamin J

2017-06-01

Cell and tissue-based products, such as autologous adult stem cells, are being prescribed by physicians across the world for diseases and illnesses that they have neither been approved for or been demonstrated as safe and effective in formal clinical trials. These doctors often form part of informal transnational networks that exploit differences and similarities in the regulatory systems across geographical contexts. In this paper, we examine the regulatory infrastructure of five geographically diverse but socio-economically comparable countries with the aim of identifying similarities and differences in how these products are regulated and governed within clinical contexts. We find that while there are many subtle technical differences in how these regulations are implemented, they are sufficiently similar that it is difficult to explain why these practices appear more prevalent in some countries and not in others. We conclude with suggestions for how international governance frameworks might be improved to discourage the exploitation of vulnerable patient populations while enabling innovation in the clinical application of cellular therapies.

Therapeutic potential of dental stem cells

PubMed Central

Chalisserry, Elna Paul; Nam, Seung Yun; Park, Sang Hyug; Anil, Sukumaran

2017-01-01

Stem cell biology has become an important field in regenerative medicine and tissue engineering therapy since the discovery and characterization of mesenchymal stem cells. Stem cell populations have also been isolated from human dental tissues, including dental pulp stem cells, stem cells from human exfoliated deciduous teeth, stem cells from apical papilla, dental follicle progenitor cells, and periodontal ligament stem cells. Dental stem cells are relatively easily obtainable and exhibit high plasticity and multipotential capabilities. The dental stem cells represent a gold standard for neural-crest-derived bone reconstruction in humans and can be used for the repair of body defects in low-risk autologous therapeutic strategies. The bioengineering technologies developed for tooth regeneration will make substantial contributions to understand the developmental process and will encourage future organ replacement by regenerative therapies in a wide variety of organs such as the liver, kidney, and heart. The concept of developing tooth banking and preservation of dental stem cells is promising. Further research in the area has the potential to herald a new dawn in effective treatment of notoriously difficult diseases which could prove highly beneficial to mankind in the long run. PMID:28616151

[Indications and follow-up for autologous hematopoietic stem cell transplantation in autoimmune and autoinflammatory diseases: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

PubMed

Pugnet, Grégory; Castilla-Llorente, Christina; Puyade, Mathieu; Terriou, Louis; Badoglio, Manuela; Deligny, Christophe; Guillaume-Jugnot, Perrine; Labeyrie, Céline; Benzidia, Ilham; Faivre, Hélène; Lansiaux, Pauline; Marjanovic, Zora; Bourhis, Jean-Henri; Faucher, Catherine; Furst, Sabine; Huynh, Anne; Martin, Thierry; Vermersch, Patrick; Yakoub-Agha, Ibrahim; Farge, Dominique

2017-12-01

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2017 in Lille, France and updated recommendations for indications and follow-up in autologous hematopoietic stem cell transplantation in autoimmune and autoinflammatory diseases, previously published under the auspices of SFGM-TC. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

[Role of stem cell transplantation in treatment of primary cutaneous T‑cell lymphoma].

PubMed

Stranzenbach, R; Theurich, S; Schlaak, M

2017-09-01

Within the heterogeneous group of cutaneous T‑cell lymphomas (CTCL) the therapeutic options for advanced and progressive forms are particularly limited. The therapeutic value of hematopoietic stem cell transplantation in CTCL was analyzed. A literature search using the keywords "hematopoietic stem cell transplantation" and "cutaneous T‑cell lymphoma" was performed in PubMed. Studies between 1990 and 2017 were taken into account. The studies identified were analyzed for relevance and being up to date. After reviewing the currently available literature no prospective randomized studies were found. Wu et al. showed a superiority of allogeneic transplantation in a comparison of autologous and allogeneic stem cell transplantation for cutaneous lymphoma. The graft-versus-lymphoma effect plays a significant role in a prolonged progression-free survival after allogeneic transplantation. By using a non-myeloablative conditioning regimen, stem cell transplantation can also be an option for elderly patients. The most extensive long-term data after allogeneic stem cell transplantation were reported by Duarte et al. in 2014. Autologous stem cell transplantation does not currently represent a therapeutic option, whereas allogeneic stem cell transplantation for advanced cutaneous T‑cell lymphoma, using a non-myeloablative conditioning scheme, does represent a therapeutic option. However, there is no consensus on the appropriate patients and the right timing. Morbidity and mortality of complications should be taken into account. Thus, this procedure is currently subject to an individual case decision.

Autologous bone marrow stem cell transplantation attenuates hepatocyte apoptosis in a rat model of ex vivo liver resection and liver autotransplantation.

PubMed

Xu, Tubing; Wang, Xiaojun; Chen, Geng; He, Yu; Bie, Ping

2013-10-01

To investigate the efficacy of autologous bone marrow stem cell (BMSC) transplantation in the treatment of hepatic injury in ex vivo liver resection and liver autotransplantation (ELRLA). Rat hepatic fibrosis was induced by intraperitoneal injection of 50% CCl4-olive oil solution at a dose of 2 mL/kg twice weekly for 4 wk. ELRLA was performed 3 d post the last injection of CCl4. Six rats in each group were killed 12, 24, 48, 72, and 168 h after the operation. Hepatocyte apoptosis was determined by TUNEL assay. The expression of Bcl-2, Bax, transforming growth factor (TGF) β1, TGFβ1 receptor1/2, and phosphorylated p38 MAPK were determined by Western blot. Autologous BMSC transplantation significantly inhibited the increase of alanine aminotransferease and aspartate aminotransferase at 12, 24, and 48 h post operation and attenuated ELRLA-induced hepatocyte apoptosis. In BMSC-treated rats, the expression of Bcl-2 was significantly upregulated, whereas there were no obvious changes in Bax level. The expression of TGFβ1 was significantly upregulated in the rat liver after the surgery. Autologous BMSC transplantation significantly downregulated the TGFβ1 levels at 48, 72, and 168 h post surgery. However, autologous BMSC transplantation showed little effect on the levels of TGFβ receptor 1/2 at all the time points observed. Furthermore, autologous BMSC transplantation significantly inhibited the activation of p38 MAPK. Autologous BMSC transplantation may reduce ELRLA-induced liver injury and improve survival rates in hepatic fibrosis rats. Autologous BMSC transplantation may be useful to improve the outcome of patients who undergo ELRLA. Copyright © 2013 Elsevier Inc. All rights reserved.

Reprogramming of Melanoma Tumor-Infiltrating Lymphocytes to Induced Pluripotent Stem Cells

PubMed Central

Saito, Hidehito; Okita, Keisuke; Fusaki, Noemi; Sabel, Michael S.; Chang, Alfred E.; Ito, Fumito

2016-01-01

Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients hold great promise for autologous cell therapies. One of the possible applications of iPSCs is to use them as a cell source for producing autologous lymphocytes for cell-based therapy against cancer. Tumor-infiltrating lymphocytes (TILs) that express programmed cell death protein-1 (PD-1) are tumor-reactive T cells, and adoptive cell therapy with autologous TILs has been found to achieve durable complete response in selected patients with metastatic melanoma. Here, we describe the derivation of human iPSCs from melanoma TILs expressing high level of PD-1 by Sendai virus-mediated transduction of the four transcription factors, OCT3/4, SOX2, KLF4, and c-MYC. TIL-derived iPSCs display embryonic stem cell-like morphology, have normal karyotype, express stem cell-specific surface antigens and pluripotency-associated transcription factors, and have the capacity to differentiate in vitro and in vivo. A wide variety of T cell receptor gene rearrangement patterns in TIL-derived iPSCs confirmed the heterogeneity of T cells infiltrating melanomas. The ability to reprogram TILs containing patient-specific tumor-reactive repertoire might allow the generation of patient- and tumor-specific polyclonal T cells for cancer immunotherapy. PMID:27057178

Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma.

PubMed

Mark, Tomer; Stern, Jessica; Furst, Jessica R; Jayabalan, David; Zafar, Faiza; LaRow, April; Pearse, Roger N; Harpel, John; Shore, Tsiporah; Schuster, Michael W; Leonard, John P; Christos, Paul J; Coleman, Morton; Niesvizky, Ruben

2008-07-01

A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte-colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P < .0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide.

Stem Cell Mobilization with Cyclophosphamide Overcomes the Suppressive Effect of Lenalidomide Therapy on Stem Cell Collection in Multiple Myeloma

PubMed Central

Mark, Tomer; Stern, Jessica; Furst, Jessica R.; Jayabalan, David; Zafar, Faiza; LaRow, April; Pearse, Roger N.; Harpel, John; Shore, Tsiporah; Schuster, Michael W.; Leonard, John P.; Christos, Paul J.; Coleman, Morton; Niesvizky, Ruben

2013-01-01

A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte- colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P<.0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide. PMID:18541199

Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn’s Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD—Low Intensity Therapy Evaluation Study Investigators

PubMed Central

Pockley, Alan Graham; Lindsay, James O.; Foulds, Gemma A.; Rutella, Sergio; Gribben, John G.; Alexander, Tobias; Snowden, John A.

2018-01-01

Patients with treatment refractory Crohn’s disease (CD) suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD—Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT. PMID:29670622

Synovial Mesenchymal Stem Cells Promote Meniscus Regeneration Augmented by an Autologous Achilles Tendon Graft in a Rat Partial Meniscus Defect Model

PubMed Central

Ozeki, Nobutake; Muneta, Takeshi; Matsuta, Seiya; Koga, Hideyuki; Nakagawa, Yusuke; Mizuno, Mitsuru; Tsuji, Kunikazu; Mabuchi, Yo; Akazawa, Chihiro; Kobayashi, Eiji; Saito, Tomoyuki; Sekiya, Ichiro

2015-01-01

Although meniscus defects and degeneration are strongly correlated with the later development of osteoarthritis, the promise of regenerative medicine strategies is to prevent and/or delay the disease's progression. Meniscal reconstruction has been shown in animal models with tendon grafting and transplantation of mesenchymal stem cells (MSCs); however, these procedures have not shown the same efficacy in clinical studies. Here, our aim was to investigate the ability of tendon grafts pretreated with exogenous synovial-derived MSCs to prevent cartilage degeneration in a rat partial meniscus defect model. We removed the anterior half of the medial meniscus and grafted autologous Achilles tendons with or without a 10-minute pretreatment of the tendon with synovial MSCs. The meniscus and surrounding cartilage were evaluated at 2, 4, and 8 weeks (n = 5). Tendon grafts increased meniscus size irrespective of synovial MSCs. Histological scores for regenerated menisci were better in the tendon + MSC group than in the other two groups at 4 and 8 weeks. Both macroscopic and histological scores for articular cartilage were significantly better in the tendon + MSC group at 8 weeks. Implanted synovial MSCs survived around the grafted tendon and native meniscus integration site by cell tracking assays with luciferase+, LacZ+, DiI+, and/or GFP+ synovial MSCs and/or GFP+ tendons. Flow cytometric analysis showed that transplanted synovial MSCs retained their MSC properties at 7 days and host synovial tissue also contained cells with MSC characteristics. Synovial MSCs promoted meniscus regeneration augmented by autologous Achilles tendon grafts and prevented cartilage degeneration in rats. Stem Cells 2015;33:1927–1938 PMID:25993981

Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant

PubMed Central

Massey, Jennifer C.; Sutton, Ian J.; Ma, David D. F.; Moore, John J.

2018-01-01

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system where evidence implicates an aberrant adaptive immune response in the accrual of neurological disability. The inflammatory phase of the disease responds to immunomodulation to varying degrees of efficacy; however, no therapy has been proven to arrest progression of disability. Recently, more intensive therapies, including immunoablation with autologous hematopoietic stem cell transplantation (AHSCT), have been offered as a treatment option to retard inflammatory disease, prior to patients becoming irreversibly disabled. Empirical clinical observations support the notion that the immune reconstitution (IR) that occurs following AHSCT is associated with a sustained therapeutic benefit; however, neither the pathogenesis of MS nor the mechanism by which AHSCT results in a therapeutic benefit has been clearly delineated. Although the antigenic target of the aberrant immune response in MS is not defined, accumulated data suggest that IR following AHSCT results in an immunotolerant state through deletion of pathogenic clones by a combination of direct ablation and induction of a lymphopenic state driving replicative senescence and clonal attrition. Restoration of immunoregulation is evidenced by changes in regulatory T cell populations following AHSCT and normalization of genetic signatures of immune homeostasis. Furthermore, some evidence exists that AHSCT may induce a rebooting of thymic function and regeneration of a diversified naïve T cell repertoire equipped to appropriately modulate the immune system in response to future antigenic challenge. In this review, we discuss the immunological mechanisms of IR therapies, focusing on AHSCT, as a means of recalibrating the dysfunctional immune response observed in MS. PMID:29593711

Limbal Stem Cell Deficiency and Treatment with Stem Cell Transplantation.

PubMed

Barut Selver, Özlem; Yağcı, Ayşe; Eğrilmez, Sait; Gürdal, Mehmet; Palamar, Melis; Çavuşoğlu, Türker; Ateş, Utku; Veral, Ali; Güven, Çağrı; Wolosin, Jose Mario

2017-10-01

The cornea is the outermost tissue of the eye and it must be transparent for the maintenance of good visual function. The superficial epithelium of the cornea, which is renewed continuously by corneal stem cells, plays a critical role in the permanence of this transparency. These stem cells are localized at the cornea-conjunctival transition zone, referred to as the limbus. When this zone is affected/destroyed, limbal stem cell deficiency ensues. Loss of limbal stem cell function allows colonization of the corneal surface by conjunctival epithelium. Over 6 million people worldwide are affected by corneal blindness, and limbal stem cell deficiency is one of the main causes. Fortunately, it is becoming possible to recover vision by autologous transplantation of limbal cells obtained from the contralateral eye in unilateral cases. Due to the potential risks to the donor eye, only a small amount of tissue can be obtained, in which only 1-2% of the limbal epithelial cells are actually limbal stem cells. Vigorous attempts are being made to expand limbal stem cells in culture to preserve or even enrich the stem cell population. Ex vivo expanded limbal stem cell treatment in limbal stem cell deficiency was first reported in 1997. In the 20 years since, various protocols have been developed for the cultivation of limbal epithelial cells. It is still not clear which method promotes effective stem cell viability and this remains a subject of ongoing research. The most preferred technique for limbal cell culture is the explant culture model. In this approach, a small donor eye limbal biopsy is placed as an explant onto a biocompatible substrate (preferably human amniotic membrane) for expansion. The outgrowth (cultivated limbal epithelial cells) is then surgically transferred to the recipient eye. Due to changing regulations concerning cell-based therapy, the implementation of cultivated limbal epithelial transplantation in accordance with Good Laboratory Practice using

Application of stem cells for cardiovascular grafts tissue engineering.

PubMed

Wu, Kaihong; Liu, Ying Long; Cui, Bin; Han, Zhongchao

2006-06-01

Congenital and acquired heart diseases are leading causes of morbidity and mortality world-wide. Currently, the synthetic materials or bioprosthetic replacement devices for cardiovascular surgery are imperfect and subject patients to one or more ongoing risks including thrombosis, limited durability and need for reoperations due to lack of growth in children and young adults. Suitable replacement grafts should have appropriate characteristics, including resistance to infection, low immunogenicity, good biocompatability and thromboresistance, with appropriate mechanical and physiological properties. Tissue engineering is a new scientific field aiming at fabrication of living, autologous grafts having structure or function properties that can be used to restore, maintain or improve tissue function. The use of autologous stem cells in cardiovascular tissue engineering is quite promising due to their capacity of self-renewal, high proliferation, and differentiation into specialized progeny. Progress has been made in engineering the various components of the cardiovascular system, including myocardial constructs, heart valves, and vascular patches or conduits with autologous stem cells. This paper will review the current achievements in stem cell-based cardiovascular grafts tissue engineering, with an emphasis on its clinical or possible clinical use in cardiovascular surgery.

Pluripotent stem cells.

PubMed

Verfaillie, C

2009-05-01

The isolation of human embryonic stem cells (ESC) in 1998 has created the hope that stem cells will one day be used to regenerate tissues and organs, even though it is obvious that a number of hurdles will need to be overcome for such therapies to become reality. The cloning of "Dolly" in 1997, more than 40 years after the first frogs were cloned, combined with the very fast progress made in our understanding of the molecular processes that govern the pluripotency of ESC has lead to the ability of scientists to recreate a pluripotent state in fibroblasts and other cells from mouse, rat and man, named induced pluripotent stem cells (iPSC). This feat makes it theoretically possible to create patient specific pluripotent stem cells whose differentiated progeny could be used in an autologous manner obviating the need for immunosuppression that would be needed to use allogeneic ESC-derived differentiated cells. In addition, the ability to generate custom made pluripotent stem cells will no doubt lead to the development of protein or small molecule drugs that can induce differentiation not only of iPSC or ESC to mature tissue cells, but also endogenous tissue stem cells. Moreover, it allows scientists to create models of human diseases and may aid the pharmaceutical industry in testing more rigorously toxicity of drugs for human differentiated cells. Thus, there is little doubt that progress in stem cell biology will change many aspects of medicine as we know it in the next one to two decades.

Repair of Torn Avascular Meniscal Cartilage Using Undifferentiated Autologous Mesenchymal Stem Cells: From In Vitro Optimization to a First-in-Human Study.

PubMed

Whitehouse, Michael R; Howells, Nicholas R; Parry, Michael C; Austin, Eric; Kafienah, Wael; Brady, Kyla; Goodship, Allen E; Eldridge, Jonathan D; Blom, Ashley W; Hollander, Anthony P

2017-04-01

Meniscal cartilage tears are common and predispose to osteoarthritis (OA). Most occur in the avascular portion of the meniscus where current repair techniques usually fail. We described previously the use of undifferentiated autologous mesenchymal stem cells (MSCs) seeded onto a collagen scaffold (MSC/collagen-scaffold) to integrate meniscal tissues in vitro. Our objective was to translate this method into a cell therapy for patients with torn meniscus, with the long-term goal of delaying or preventing the onset of OA. After in vitro optimization, we tested an ovine-MSC/collagen-scaffold in a sheep meniscal cartilage tear model with promising results after 13 weeks, although repair was not sustained over 6 months. We then conducted a single center, prospective, open-label first-in-human safety study of patients with an avascular meniscal tear. Autologous MSCs were isolated from an iliac crest bone marrow biopsy, expanded and seeded into the collagen scaffold. The resulting human-MSC/collagen-scaffold implant was placed into the meniscal tear prior to repair with vertical mattress sutures and the patients were followed for 2 years. Five patients were treated and there was significant clinical improvement on repeated measures analysis. Three were asymptomatic at 24 months with no magnetic resonance imaging evidence of recurrent tear and clinical improvement in knee function scores. Two required subsequent meniscectomy due to retear or nonhealing of the meniscal tear at approximately 15 months after implantation. No other adverse events occurred. We conclude that undifferentiated MSCs could provide a safe way to augment avascular meniscal repair in some patients. Registration: EU Clinical Trials Register, 2010-024162-22. Stem Cells Translational Medicine 2017;6:1237-1248. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Autologous human plasma in stem cell culture and cryopreservation in the creation of a tissue-engineered vascular graft.

PubMed

Zhang, Ping; Policha, Aleksandra; Tulenko, Thomas; DiMuzio, Paul

2016-03-01

Previous work demonstrated the effectiveness of autologous adipose-derived stem cells (ASCs) as endothelial cell (EC) substitutes in vascular tissue engineering. We further this work toward clinical translation by evaluating ASC function after (1) replacement of fetal bovine serum (FBS) with autologous human plasma (HP) in culture and (2) cryopreservation. Human ASCs and plasma, isolated from periumbilical fat and peripheral blood, respectively, were collected from the same donors. ASCs were differentiated in endothelial growth medium supplemented with FBS (2%) vs HP (2%). Proliferation was measured by growth curves and MTT assay. Endothelial differentiation was measured by quantitative polymerase chain reaction, assessment of acetylated low-density lipoprotein uptake, and cord formation after plating on Matrigel (BD Biosciences, San Jose, Calif). Similar studies were conducted before and after cryopreservation of ASCs and included assessment of cell retention on the luminal surface of a vascular graft. ASCs expanded in HP-supplemented medium showed (1) similar proliferation to FBS-cultured ASCs, (2) consistent differentiation toward an EC lineage (increases in CD31, von Willebrand factor, and CD144 message; acetylated low-density lipoprotein uptake; and cord formation on Matrigel), and (3) retention on the luminal surface after seeding and subsequent flow conditioning. Cryopreservation did not significantly alter ASC viability, proliferation, acquisition of endothelial characteristics, or retention after seeding onto a vascular graft. This study suggests that (1) replacement of FBS with autologous HP--a step necessary for the translation of this technology into human use--does not significantly impair proliferation or endothelial differentiation of ASCs used as EC substitutes and (2) ASCs are tolerant to cryopreservation in terms of maintaining EC characteristics and retention on a vascular graft. Copyright © 2016 Society for Vascular Surgery. Published by

Tbo-Filgrastim versus Filgrastim during Mobilization and Neutrophil Engraftment for Autologous Stem Cell Transplantation.

PubMed

Elayan, Mohammed M; Horowitz, Justin G; Magraner, Jose M; Shaughnessy, Paul J; Bachier, Carlos

2015-11-01

There are limited data available supporting the use of the recombinant granulocyte colony-stimulating factor (G-CSF), tbo-filgrastim, rather than traditionally used filgrastim to mobilize peripheral blood stem cells (PBSC) or to accelerate engraftment after autologous stem cell transplantation (ASCT). We sought to compare the efficacy and cost of tbo-filgrastim to filgrastim in these settings. Patients diagnosed with lymphoma or plasma cell disorders undergoing G-CSF mobilization, with or without plerixafor, were included in this retrospective analysis. The primary outcome was total collected CD34(+) cells/kg. Secondary mobilization endpoints included peripheral CD34(+) cells/μL on days 4 and 5 of mobilization, adjunctive use of plerixafor, CD34(+) cells/kg collected on day 5, number of collection days and volumes processed, number of collections reaching 5 million CD34(+) cells/kg, and percent reaching target collection goal in 1 day. Secondary engraftment endpoints included time to neutrophil and platelet engraftment, number of blood product transfusions required before engraftment, events of febrile neutropenia, and length of stay. A total of 185 patients were included in the final analysis. Patients receiving filgrastim (n = 86) collected a median of 5.56 × 10(6) CD34(+) cells/kg, compared with a median of 5.85 × 10(6) CD34(+) cells/kg in the tbo-filgrastim group (n = 99; P = .58). There were no statistically significant differences in all secondary endpoints with the exception of apheresis volumes processed (tbo-filgrastim, 17.0 liters versus filgrastim, 19.7 liters; P < .01) and mean platelet transfusions (tbo-filgrastim, 1.7 units versus filgrastim, 1.4 units; P = .04). In conclusion, tbo-filgrastim demonstrated similar CD34(+) yield compared with filgrastim in mobilization and post-transplantation settings, with no clinically meaningful differences in secondary efficacy and safety endpoints. Furthermore, tbo-filgrastim utilization was associated

Consolidative autologous hematopoietic stem-cell transplantation in first remission for non-Hodgkin lymphoma: current indications and future perspective.

PubMed

Iams, Wade; Reddy, Nishitha M

2014-10-01

The non-Hodgkin lymphomas (NHLs) are a heterogeneous group of diseases with variable clinical outcomes. Autologous hematopoietic stem-cell transplantation (ASCT) as frontline, consolidative therapy has been evaluated based upon histological subtype of NHL. In this review, we summarize the major clinical trials guiding the use of frontline ASCT in NHL. With the constantly changing landscape of upfront therapy and multiple promising novel agents, the ability to conduct randomized trials to evaluate the benefit of consolidative ASCT is not only challenging but may be considered by some an inept utilization of resources. Our recommendation for consolidative ASCT is based on analyzing the current available data.

Benefit from autologous stem cell transplantation in primary refractory myeloma? Different outcomes in progressive versus stable disease

PubMed Central

Rosiñol, Laura; García-Sanz, Ramón; Lahuerta, Juan José; Hernández-García, Miguel; Granell, Miquel; de la Rubia, Javier; Oriol, Albert; Hernández-Ruiz, Belén; Rayón, Consuelo; Navarro, Isabel; García-Ruiz, Juan Carlos; Besalduch, Joan; Gardella, Santiago; Jiménez, Javier López; Díaz-Mediavilla, Joaquín; Alegre, Adrián; Miguel, Jesús San; Bladé, Joan

2012-01-01

Background Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. Design and Methods In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (≥25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. Results There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). Conclusions Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease. (ClinicalTrials.gov:NCT00560053) PMID:22058223

Advances in Bone Marrow Stem Cell Therapy for Retinal Dysfunction

PubMed Central

Park, Susanna S.; Moisseiev, Elad; Bauer, Gerhard; Anderson, Johnathon D.; Grant, Maria B.; Zam, Azhar; Zawadzki, Robert J.; Werner, John S.; Nolta, Jan A.

2016-01-01

The most common cause of untreatable vision loss is dysfunction of the retina. Conditions, such as age-related macular degeneration, diabetic retinopathy and glaucoma remain leading causes of untreatable blindness worldwide. Various stem cell approaches are being explored for treatment of retinal regeneration. The rationale for using bone marrow stem cells to treat retinal dysfunction is based on preclinical evidence showing that bone marrow stem cells can rescue degenerating and ischemic retina. These stem cells have primarily paracrine trophic effects although some cells can directly incorporate into damaged tissue. Since the paracrine trophic effects can have regenerative effects on multiple cells in the retina, the use of this cell therapy is not limited to a particular retinal condition. Autologous bone marrow-derived stem cells are being explored in early clinical trials as therapy for various retinal conditions. These bone marrow stem cells include mesenchymal stem cells, mononuclear cells and CD34+ cells. Autologous therapy requires no systemic immunosuppression or donor matching. Intravitreal delivery of CD34+ cells and mononuclear cells appears to be tolerated and is being explored since some of these cells can home into the damaged retina after intravitreal administration. The safety of intravitreal delivery of mesenchymal stem cells has not been well established. This review provides an update of the current evidence in support of the use of bone marrow stem cells as treatment for retinal dysfunction. The potential limitations and complications of using certain forms of bone marrow stem cells as therapy are discussed. Future directions of research include methods to optimize the therapeutic potential of these stem cells, non-cellular alternatives using extracellular vesicles, and in vivo high-resolution retinal imaging to detect cellular changes in the retina following cell therapy. PMID:27784628

Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman's syndrome and endometrial atrophy: a pilot cohort study.

PubMed

Santamaria, Xavier; Cabanillas, Sergio; Cervelló, Irene; Arbona, Cristina; Raga, Francisco; Ferro, Jaime; Palmero, Julio; Remohí, Jose; Pellicer, Antonio; Simón, Carlos

2016-05-01

Could cell therapy using autologous peripheral blood CD133+ bone marrow-derived stem cells (BMDSCs) offer a safe and efficient therapeutic approach for patients with refractory Asherman's syndrome (AS) and/or endometrial atrophy (EA) and a wish to conceive? In the first 3 months, autologous cell therapy, using CD133+ BMDSCs in conjunction with hormonal replacement therapy, increased the volume and duration of menses as well as the thickness and angiogenesis processes of the endometrium while decreasing intrauterine adhesion scores. AS is characterized by the presence of intrauterine adhesions and EA prevents the endometrium from growing thicker than 5 mm, resulting in menstruation disorders and infertility. Many therapies have been attempted for these conditions, but none have proved effective. This was a prospective, experimental, non-controlled study. There were 18 patients aged 30-45 years with refractory AS or EA were recruited, and 16 of these completed the study. Medical history, physical examination, endometrial thickness, intrauterine adhesion score and neoangiogenesis were assessed before and 3 and 6 months after cell therapy. After the initial hysteroscopic diagnosis, BMDSC mobilization was performed by granulocyte-CSF injection, then CD133+ cells were isolated through peripheral blood aphaeresis to obtain a mean of 124.39 million cells (range 42-236), which were immediately delivered into the spiral arterioles by catheterization. Subsequently, endometrial treatment after stem cell therapy was assessed in terms of restoration of menses, endometrial thickness (by vaginal ultrasound), adhesion score (by hysteroscopy), neoangiogenesis and ongoing pregnancy rate. The study was conducted at Hospital Clínico Universitario of Valencia and IVI Valencia (Spain). All 11 AS patients exhibited an improved uterine cavity 2 months after stem cell therapy. Endometrial thickness increased from an average of 4.3 mm (range 2.7-5) to 6.7 mm (range 3.1-12) ( ITALIC! P = 0

Stem cell-based biological tooth repair and regeneration

PubMed Central

Volponi, Ana Angelova; Pang, Yvonne; Sharpe, Paul T.

2010-01-01

Teeth exhibit limited repair in response to damage, and dental pulp stem cells probably provide a source of cells to replace those damaged and to facilitate repair. Stem cells in other parts of the tooth, such as the periodontal ligament and growing roots, play more dynamic roles in tooth function and development. Dental stem cells can be obtained with ease, making them an attractive source of autologous stem cells for use in restoring vital pulp tissue removed because of infection, in regeneration of periodontal ligament lost in periodontal disease, and for generation of complete or partial tooth structures to form biological implants. As dental stem cells share properties with mesenchymal stem cells, there is also considerable interest in their wider potential to treat disorders involving mesenchymal (or indeed non-mesenchymal) cell derivatives, such as in Parkinson's disease. PMID:21035344

The emerging role of PET in Hodgkin lymphoma patients receiving autologous stem cell transplant.

PubMed

von Tresckow, Bastian; Engert, Andreas

2012-10-01

High-dose chemotherapy followed by autologous stem cell transplant (ASCT) is the standard therapy for patients with relapsed or refractory Hodgkin lymphoma. Several analyses have reported risk factors for a poor outcome after ASCT to allow for an individualized treatment, but there is no consensus on how the outcome in high-risk patients might be improved. A recent study by Cocorocchio et al. analyzes risk factors in 97 patients who received ASCT. Besides the established risk factor remission status after induction, result of positron emission tomography before and after transplant was the most important prognostic factor for progression-free survival and overall survival. This result is in line with other retrospective analyses and might allow for the selection of high-risk patients who should receive alternative treatment approaches, such as second-line salvage therapy, tandem ASCT, new drugs or maintenance therapy. Randomized trials characterizing the best therapeutic option for high-risk patients are highly warranted.

Pluripotent Stem Cells and Gene Therapy

PubMed Central

Simara, Pavel; Motl, Jason A.; Kaufman, Dan S.

2013-01-01

Human pluripotent stem cells represent an accessible cell source for novel cell-based clinical research and therapies. With the realization of induced pluripotent stem cells (iPSCs), it is possible to produce almost any desired cell type from any patient's cells. Current developments in gene modification methods have opened the possibility for creating genetically corrected human iPSCs for certain genetic diseases that could be used later in autologous transplantation. Promising preclinical studies have demonstrated correction of disease-causing mutations in a number of hematological, neuronal and muscular disorders. This review aims to summarize these recent advances with a focus on iPSC generation techniques, as well as gene modification methods. We will then further discuss some of the main obstacles remaining to be overcome before successful application of human pluripotent stem cell-based therapy arrives in the clinic and what the future of stem cell research may look like. PMID:23353080

Insulin-secreting adipose-derived mesenchymal stromal cells with bone marrow-derived hematopoietic stem cells from autologous and allogenic sources for type 1 diabetes mellitus.

PubMed

Thakkar, Umang G; Trivedi, Hargovind L; Vanikar, Aruna V; Dave, Shruti D

2015-07-01

Stem cell therapy (SCT) is now the up-coming therapeutic modality for treatment of type 1 diabetes mellitus (T1DM). Our study was a prospective, open-labeled, two-armed trial for 10 T1DM patients in each arm of allogenic and autologous adipose-derived insulin-secreting mesenchymal stromal cells (IS-AD-MSC)+bone marrow-derived hematopoietic stem cell (BM-HSC) infusion. Group 1 received autologous SCT: nine male patients and one female patient; mean age, 20.2 years, disease duration 8.1 years; group 2 received allogenic SCT: six male patients and four female patients, mean age, 19.7 years and disease duration, 7.9 years. Glycosylated hemoglobin (HbA1c) was 10.99%; serum (S.) C-peptide, 0.22 ng/mL and insulin requirement, 63.9 IU/day in group 1; HbA1c was 11.93%, S.C-peptide, 0.028 ng/mL and insulin requirement, 57.55 IU/day in group 2. SCs were infused into the portal+thymic circulation and subcutaneous tissue under non-myelo-ablative conditioning. Patients were monitored for blood sugar, S.C-peptide, glutamic acid decarboxylase antibodies and HbA1c at 3-month intervals. Group 1 received mean SCs 103.14 mL with 2.65 ± 0.8 × 10(4) ISCs/kg body wt, CD34+ 0.81% and CD45-/90+/73+, 81.55%. Group 2 received mean SCs 95.33 mL with 2.07 ± 0.67 × 10(4) ISCs/kg body wt, CD34+ 0.32% and CD45-/90+/73+ 54.04%. No untoward effect was observed with sustained improvement in HbA1c and S.C-peptide in both groups with a decrease in glutamic acid decarboxylase antibodies and reduction in mean insulin requirement. SCT is a safe and viable treatment option for T1DM. Autologous IS-AD-MSC+ BM-HSC co-infusion offers better long-term control of hyperglycemia as compared with allogenic SCT. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Improvement of skin-graft survival after autologous transplantation of adipose-derived stem cells in rats.

PubMed

Zografou, A; Tsigris, C; Papadopoulos, O; Kavantzas, N; Patsouris, E; Donta, I; Perrea, D

2011-12-01

Skin grafts are frequently used for a variety of indications in plastic and reconstructive surgery. Their necrosis is a common complication, while different therapies have been proposed. Currently, adipose-derived stem cells (ASCs) hold great promise for their angiogenic potential and role during tissue repair. In this study, autologous transplantation of ASCs was used in skin grafts in rats to determine if it increases angiogenesis, skin-graft survival and wound healing. ASCs were isolated, cultured, labelled with fluorescent dye and injected under full-thickness skin grafts in 10 rats (group 1), while 10 others served as controls (group 2). Skin grafts were analysed after 1 week. Collagen's framework was assessed with Masson's trichrome stain and angiogenesis with von Willebrand factor (vWF) immunohistochemistry. In addition, immunohistochemical staining intensity of vascular endothelial growth factor (VEGF) and transforming growth factor b3 (TGFb3) was assessed in all grafts. Mean area of graft necrosis was significantly less in group 1 than in group 2 (6.12% vs. 32.62%, p<0.01). Statistically significant increase of microvessel density, collagen density, VEGF and TGFb3 expression was noted in group 1 compared with group 2 (all: p<0.01). These findings suggest that autologous ASCs transplantation increases full-thickness skin-graft survival and shows promise for use in skin-graft surgery. This might be both due to in situ differentiation of ASCs into endothelial cells and increased secretion by ASCs of growth factors, such as VEGF and TGFb3 that enhance angiogenesis and wound healing. Copyright © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells.

PubMed

Burkhardt, Ute E; Hainz, Ursula; Stevenson, Kristen; Goldstein, Natalie R; Pasek, Mildred; Naito, Masayasu; Wu, Di; Ho, Vincent T; Alonso, Anselmo; Hammond, Naa Norkor; Wong, Jessica; Sievers, Quinlan L; Brusic, Ana; McDonough, Sean M; Zeng, Wanyong; Perrin, Ann; Brown, Jennifer R; Canning, Christine M; Koreth, John; Cutler, Corey; Armand, Philippe; Neuberg, Donna; Lee, Jeng-Shin; Antin, Joseph H; Mulligan, Richard C; Sasada, Tetsuro; Ritz, Jerome; Soiffer, Robert J; Dranoff, Glenn; Alyea, Edwin P; Wu, Catherine J

2013-09-01

Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity. We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated. At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8+ T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8+ T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens. Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control following allo-HSCT. Clinicaltrials.gov NCT00442130. NCI (5R21CA115043-2), NHLBI (5R01HL103532-03), and Leukemia and Lymphoma Society Translational Research Program.

Addition of autologous mesenchymal stem cells to whole blood for bioenhanced ACL repair has no benefit in the porcine model.

PubMed

Proffen, Benedikt L; Vavken, Patrick; Haslauer, Carla M; Fleming, Braden C; Harris, Chad E; Machan, Jason T; Murray, Martha M

2015-02-01

Coculture of mesenchymal stem cells (MSCs) from the retropatellar fat pad and peripheral blood has been shown to stimulate anterior cruciate ligament (ACL) fibroblast proliferation and collagen production in vitro. Current techniques of bioenhanced ACL repair in animal studies involve adding a biologic scaffold, in this case an extracellular matrix-based scaffold saturated with autologous whole blood, to a simple suture repair of the ligament. Whether the enrichment of whole blood with MSCs would further improve the in vivo results of bioenhanced ACL repair was investigated. The addition of MSCs derived from adipose tissue or peripheral blood to the blood-extracellular matrix composite, which is used in bioenhanced ACL repair to stimulate healing, would improve the biomechanical properties of a bioenhanced ACL repair after 15 weeks of healing. Controlled laboratory study. Twenty-four adolescent Yucatan mini-pigs underwent ACL transection followed by (1) bioenhanced ACL repair, (2) bioenhanced ACL repair with the addition of autologous adipose-derived MSCs, and (3) bioenhanced ACL repair with the addition of autologous peripheral blood derived MSCs. After 15 weeks of healing, the structural properties of the ACL (yield load, failure load, and linear stiffness) were measured. Cell and vascular density were measured in the repaired ACL via histology, and its tissue structure was qualitatively evaluated using the advanced Ligament Maturity Index. After 15 weeks of healing, there were no significant improvements in the biomechanical or histological properties with the addition of adipose-derived MSCs. The only significant change with the addition of peripheral blood MSCs was an increase in knee anteroposterior laxity when measured at 30° of flexion. These findings suggest that the addition of adipose or peripheral blood MSCs to whole blood before saturation of an extracellular matrix carrier with the blood did not improve the functional results of bioenhanced ACL

Development of model for analysing respective collections of intended hematopoietic stem cells and harvests of unintended mature cells in apheresis for autologous hematopoietic stem cell collection.

PubMed

Hequet, O; Le, Q H; Rodriguez, J; Dubost, P; Revesz, D; Clerc, A; Rigal, D; Salles, G; Coiffier, B

2014-04-01

Hematopoietic stem cells (HSCs) required to perform peripheral hematopoietic autologous stem cell transplantation (APBSCT) can be collected by processing several blood volumes (BVs) in leukapheresis sessions. However, this may cause granulocyte harvest in graft and decrease in patient's platelet blood level. Both consequences may induce disturbances in patient. One apheresis team's current purpose is to improve HSC collection by increasing HSC collection and prevent increase in granulocyte and platelet harvests. Before improving HSC collection it seemed important to know more about the way to harvest these types of cells. The purpose of our study was to develop a simple model for analysing respective collections of intended CD34+ cells among HSC (designated here as HSC) and harvests of unintended platelets or granulocytes among mature cells (designated here as mature cells) considering the number of BVs processed and factors likely to influence cell collection or harvest. For this, we processed 1, 2 and 3 BVs in 59 leukapheresis sessions and analysed corresponding collections and harvests with a referent device (COBE Spectra). First we analysed the amounts of HSC collected and mature cells harvested and second the evolution of the respective shares of HSC and mature cells collected or harvested throughout the BV processes. HSC collections and mature cell harvests increased globally (p<0.0001) and their respective shares remained stable throughout the BV processes (p non-significant). We analysed the role of intrinsic (patient's features) and extrinsic (features before starting leukapheresis sessions) factors in collections and harvests, which showed that only pre-leukapheresis blood levels (CD34+cells and platelets) influenced both cell collections and harvests (CD34+cells and platelets) (p<0.001) and shares of HSC collections and mature unintended cells harvests (p<0.001) throughout the BV processes. Altogether, our results suggested that the main factors likely

Synovium-derived stem cells: a tissue-specific stem cell for cartilage engineering and regeneration.

PubMed

Jones, Brendan A; Pei, Ming

2012-08-01

Articular cartilage is difficult to heal once injury or disease occurs. Autologous chondrocyte transplantation is a biological treatment with good prognosis, but donor site morbidity and limited cell source are disadvantages. Currently, mesenchymal stem cells (MSCs) are a promising approach for cartilage regeneration. Despite there being various sources, the best candidate for cartilage regeneration is the one with the greatest chondrogenic potential and the least hypertrophic differentiation. These properties are able to insure that the regenerated tissue is hyaline cartilage of high quality. This review article will summarize relevant literature to justify synovium-derived stem cells (SDSCs) as a tissue-specific stem cell for chondrogenesis by comparing synovium and cartilage with respect to anatomical location and functional structure, comparing the growth characterization and chondrogenic capacity of SDSCs and MSCs, evaluating the application of SDSCs in regenerative medicine and diseases, and discussing potential future directions.

Induced pluripotent stem cells: advances to applications

PubMed Central

Nelson, Timothy J; Martinez-Fernandez, Almudena; Yamada, Satsuki; Ikeda, Yasuhiro; Perez-Terzic, Carmen; Terzic, Andre

2010-01-01

Induced pluripotent stem cell (iPS) technology has enriched the armamentarium of regenerative medicine by introducing autologous pluripotent progenitor pools bioengineered from ordinary somatic tissue. Through nuclear reprogramming, patient-specific iPS cells have been derived and validated. Optimizing iPS-based methodology will ensure robust applications across discovery science, offering opportunities for the development of personalized diagnostics and targeted therapeutics. Here, we highlight the process of nuclear reprogramming of somatic tissues that, when forced to ectopically express stemness factors, are converted into bona fide pluripotent stem cells. Bioengineered stem cells acquire the genuine ability to generate replacement tissues for a wide-spectrum of diseased conditions, and have so far demonstrated therapeutic benefit upon transplantation in model systems of sickle cell anemia, Parkinson’s disease, hemophilia A, and ischemic heart disease. The field of regenerative medicine is therefore primed to adopt and incorporate iPS cell-based advancements as a next generation stem cell platforms. PMID:21165156

Production of urothelium from pluripotent stem cells for regenerative applications.

PubMed

Osborn, Stephanie L; Kurzrock, Eric A

2015-01-01

As bladder reconstruction strategies evolve, a feasible and safe source of transplantable urothelium becomes a major consideration for patients with advanced bladder disease, particularly cancer. Pluripotent stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are attractive candidates from which to derive urothelium as they renew and proliferate indefinitely in vitro and fulfill the non-autologous and/or non-urologic criteria, respectively, that is required for many patients. This review presents the latest advancements in differentiating urothelium from pluripotent stem cells in vitro in the context of current bladder tissue engineering strategies.

Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin’s lymphoma responding to prior salvage therapy

PubMed Central

Devillier, Raynier; Coso, Diane; Castagna, Luca; Brenot Rossi, Isabelle; Anastasia, Antonella; Chiti, Arturo; Ivanov, Vadim; Schiano, Jean Marc; Santoro, Armando; Chabannon, Christian; Balzarotti, Monica; Blaise, Didier; Bouabdallah, Reda

2012-01-01

Background High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin’s lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin’s lymphoma. Design and Methods We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin’s lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. Results Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to

Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients.

PubMed

Phondeechareon, Tanapol; Wattanapanitch, Methichit; U-Pratya, Yaowalak; Damkham, Chanapa; Klincumhom, Nuttha; Lorthongpanich, Chanchao; Kheolamai, Pakpoom; Laowtammathron, Chuti; Issaragrisil, Surapol

2016-10-01

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients.

Cord Blood Banking Standards: Autologous Versus Altruistic

PubMed Central

Armitage, Sue

2016-01-01

Cord blood (CB) is either donated to public CB banks for use by any patient worldwide for whom it is a match or stored in a private bank for potential autologous or family use. It is a unique cell product that has potential for treating life-threatening diseases. The majority of CB products used today are for hematopoietic stem cell transplantation and are accessed from public banks. CB is still evolving as a hematopoietic stem cell source, developing as a source for cellular immunotherapy products, such as natural killer, dendritic, and T-cells, and fast emerging as a non-hematopoietic stem cell source in the field of regenerative medicine. This review explores the regulations, standards, and accreditation schemes that are currently available nationally and internationally for public and private CB banking. Currently, most of private banking is under regulated as compared to public banking. Regulations and standards were initially developed to address the public arena. Early responses from the medical field regarding private CB banking was that at the present time, because of insufficient scientific data to support autologous banking and given the difficulty of making an accurate estimate of the need for autologous transplantation, private storage of CB as “biological insurance” should be discouraged (1, 2, 3). To ensure success and the true realization of the full potential of CB, whether for autologous or allogeneic use, it is essential that each and every product provided for current and future treatments meets high-quality, international standards. PMID:26779485

Five year follow-up after autologous peripheral blood hematopoietic stem cell transplantation for refractory, chronic, corticosteroid-dependent systemic lupus erythematosus: effect of conditioning regimen on outcome.

PubMed

Burt, Richard K; Han, Xiaoqiang; Gozdziak, Paula; Yaung, Kim; Morgan, Amy; Clendenan, Allison M; Henry, Jacquelyn; Calvario, Michelle A; Datta, Syamal K; Helenowski, Irene; Schroeder, James

2018-05-31

Some patients with systemic lupus erythematosus (SLE) are refractory to traditional therapies, dependent on chronic corticosteroids, have organ damage, and are at high risk of mortality. In this group of patients, we report outcome at a median of five years after autologous hematopoietic stem cell transplant (HSCT) using two different non-myeloablative regimens. Four patients received a conditioning regimen of cyclophosphamide (200 mg/kg) and alemtuzumab (60 mg), while 26 patients underwent conditioning with cyclophosphamide (200 mg/kg), rATG (Thymoglobulin) (5.5 mg/kg), and rituximab 1000 mg. Unselected peripheral blood stem cells were infused on day 0. There were no treatment related deaths. Of the four patients treated with cyclophosphamide and alemtuzumab, none entered remission. For the 26 patients treated with cyclophosphamide, rATG, and rituximab, disease remission defined as no immune suppressive drugs except hydroxychloroquine and/or 10 mg or less of prednisone a day was 92% at 6 months, 92% at one year, 81% at 2 years, 71% at 3 years, and 62% at 4 and 5 years post-HSCT. Autologous HSCT outcome is dependent on the conditioning regimen but prior organ damage may cause lingering symptoms.

Microbial contamination of autologous peripheral blood stem cell products: incidence, clinical outcome, quality control and management strategies.

PubMed

Cheah, Poh Lin; Ong, Chong Wei; Crispin, Philip

2011-06-01

Microbial screening is part of quality control for autologous peripheral blood stem cell (PBSC) manipulation. The incidence of culture positive products varies widely. The clinical significance of infusing culture positive products is uncertain, with no consensus on the interventions required. Microbial cultures of 606 consecutive autologous PBSC products from 278 patients between 1995 and 2005 were retrospectively analysed to determine the incidence of culture positivity and classified according to likely clinical significance. Clinical outcomes of patients who received culture positive products were reviewed. Using the baseline probability of contamination, a quality control method to detect a systematic source of contamination during product manipulation was developed. Eleven (1.8%) of 606 products were culture positive in eight (2.9%) patients. Ten products yielded coagulase negative Staphylococcus species and one Corynebacterium accolens. One patient had catheter sepsis during collection. Five patients received culture positive products, with prophylactic antibiotics when there was known coagulase negative Staphylococcus species. None had clinical evidence of infection following product infusion. The incidence of culture positive products was comparable to published series. Only skin commensals were isolated. Infusion of skin commensal positive products appears safe with antibiotic prophylaxis. Using local and published experience, clinical and laboratory policies were developed for culture positive products.

Autologous Bone Marrow Mesenchymal Stem Cells Improve the Quality and Stability of Vascularized Flap Surgery of Irradiated Skin in Pigs.

PubMed

Linard, Christine; Brachet, Michel; Strup-Perrot, Carine; L'homme, Bruno; Busson, Elodie; Squiban, Claire; Holler, Valerie; Bonneau, Michel; Lataillade, Jean-Jacques; Bey, Eric; Benderitter, Marc

2018-05-18

Cutaneous radiation syndrome has severe long-term health consequences. Because it causes an unpredictable course of inflammatory waves, conventional surgical treatment is ineffective and often leads to a fibronecrotic process. Data about the long-term stability of healed wounds, with neither inflammation nor resumption of fibrosis, are lacking. In this study, we investigated the effect of injections of local autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs), combined with plastic surgery for skin necrosis, in a large-animal model. Three months after irradiation overexposure to the rump, minipigs were divided into three groups: one group treated by simple excision of the necrotic tissue, the second by vascularized-flap surgery, and the third by vascularized-flap surgery and local autologous BM-MSC injections. Three additional injections of the BM-MSCs were performed weekly for 3 weeks. The quality of cutaneous wound healing was examined 1 year post-treatment. The necrotic tissue excision induced a pathologic scar characterized by myofibroblasts, excessive collagen-1 deposits, and inadequate vascular density. The vascularized-flap surgery alone was accompanied by inadequate production of extracellular matrix (ECM) proteins (decorin, fibronectin); the low col1/col3 ratio, associated with persistent inflammatory nodules, and the loss of vascularization both attested to continued immaturity of the ECM. BM-MSC therapy combined with vascularized-flap surgery provided mature wound healing characterized by a col1/col3 ratio and decorin and fibronectin expression that were all similar to that of nonirradiated skin, with no inflammation, and vascular stability. In this preclinical model, vascularized flap surgery successfully and lastingly remodeled irradiated skin only when combined with BM-MSC therapy. Stem Cells Translational Medicine 2018. © 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of Alpha

Direct-to-Consumer Stem Cell Marketing and Regulatory Responses

PubMed Central

2013-01-01

Summary There is a large, poorly regulated international market of putative stem cell products, including transplants of processed autologous stem cells from various tissues, cell processing devices, cosmetics, and nutritional supplements. Despite the absence of rigorous scientific research in the form of randomized clinical trials to support the routine use of such products, the market appears to be growing and diversifying. Very few stem cell biologics have passed regulatory scrutiny, and authorities in many countries, including the United States, have begun to step up their enforcement activities to protect patients and the integrity of health care markets. PMID:23934911

Direct-to-consumer stem cell marketing and regulatory responses.

PubMed

Sipp, Douglas

2013-09-01

There is a large, poorly regulated international market of putative stem cell products, including transplants of processed autologous stem cells from various tissues, cell processing devices, cosmetics, and nutritional supplements. Despite the absence of rigorous scientific research in the form of randomized clinical trials to support the routine use of such products, the market appears to be growing and diversifying. Very few stem cell biologics have passed regulatory scrutiny, and authorities in many countries, including the United States, have begun to step up their enforcement activities to protect patients and the integrity of health care markets.

Transplantation of autologous synovial mesenchymal stem cells promotes meniscus regeneration in aged primates.

PubMed

Kondo, Shimpei; Muneta, Takeshi; Nakagawa, Yusuke; Koga, Hideyuki; Watanabe, Toshifumi; Tsuji, Kunikazu; Sotome, Shinichi; Okawa, Atsushi; Kiuchi, Shinji; Ono, Hideo; Mizuno, Mitsuru; Sekiya, Ichiro

2017-06-01

Transplantation of aggregates of synovial mesenchymal stem cells (MSCs) enhanced meniscus regeneration in rats. Anatomy and biological properties of the meniscus depend on animal species. To apply this technique clinically, it is valuable to investigate the use of animals genetically close to humans. We investigated whether transplantation of aggregates of autologous synovial MSCs promoted meniscal regeneration in aged primates. Chynomolgus primates between 12 and 13 years old were used. After the anterior halves of the medial menisci in both knees were removed, an average of 14 aggregates consisting of 250,000 synovial MSCs were transplanted onto the meniscus defect. No aggregates were transplanted to the opposite knee for the control. Meniscus and articular cartilage were analyzed macroscopically, histologically, and by MRI T1rho mapping at 8 (n = 3) and 16 weeks (n = 4). The medial meniscus was larger and the modified Pauli's histological score for the regenerated meniscus was better in the MSC group than in the control group in each primate at 8 and 16 weeks. Mankin's score for the medial femoral condyle cartilage was better in the MSC group than in the control group in all primates at 16 weeks. T1rho value for both the regenerated meniscus and adjacent articular cartilage in the MSC group was closer to the normal meniscus than in the control group in all primates at 16 weeks. Transplantation of aggregates of autologous synovial MSCs promoted meniscus regeneration and delayed progression of degeneration of articular cartilage in aged primates. This is the first report dealing with meniscus regeneration in primates. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1274-1282, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Sowing the Seeds of a Fruitful Harvest: Hematopoietic Stem Cell Mobilization

PubMed Central

Hoggatt, Jonathan; Speth, Jennifer M.; Pelus, Louis M.

2014-01-01

Hematopoietic stem cell transplantation is the only curative option for a number of malignant and non-malignant diseases. As the use of hematopoietic transplant has expanded, so too has the source of stem and progenitor cells. The predominate source of stem and progenitors today, particularly in settings of autologous transplantation, is mobilized peripheral blood. This review will highlight the historical advances which lead to the widespread use of peripheral blood stem cells for transplantation, with a look towards future enhancements to mobilization strategies. PMID:24123398

The Immunogenicity and Immune Tolerance of Pluripotent Stem Cell Derivatives

PubMed Central

Liu, Xin; Li, Wenjuan; Fu, Xuemei; Xu, Yang

2017-01-01

Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and differentiate into all cell types in human body, and therefore hold great potential for cell therapy of currently incurable diseases including neural degenerative diseases, heart failure, and macular degeneration. This potential is further underscored by the promising safety and efficacy data from the ongoing clinical trials of hESC-based therapy of macular degeneration. However, one main challenge for the clinical application of hESC-based therapy is the allogeneic immune rejection of hESC-derived cells by the recipient. The breakthrough of the technology to generate autologous-induced pluripotent stem cells (iPSCs) by nuclear reprogramming of patient’s somatic cells raised the possibility that autologous iPSC-derived cells can be transplanted into the patients without the concern of immune rejection. However, accumulating data indicate that certain iPSC-derived cells can be immunogenic. In addition, the genomic instability associated with iPSCs raises additional safety concern to use iPSC-derived cells in human cell therapy. In this review, we will discuss the mechanism underlying the immunogenicity of the pluripotent stem cells and recent progress in developing immune tolerance strategies of human pluripotent stem cell (hPSC)-derived allografts. The successful development of safe and effective immune tolerance strategy will greatly facilitate the clinical development of hPSC-based cell therapy. PMID:28626459

De novo generation of HSCs from somatic and pluripotent stem cell sources

PubMed Central

Vo, Linda T.

2015-01-01

Generating human hematopoietic stem cells (HSCs) from autologous tissues, when coupled with genome editing technologies, is a promising approach for cellular transplantation therapy and for in vitro disease modeling, drug discovery, and toxicology studies. Human pluripotent stem cells (hPSCs) represent a potentially inexhaustible supply of autologous tissue; however, to date, directed differentiation from hPSCs has yielded hematopoietic cells that lack robust and sustained multilineage potential. Cellular reprogramming technologies represent an alternative platform for the de novo generation of HSCs via direct conversion from heterologous cell types. In this review, we discuss the latest advancements in HSC generation by directed differentiation from hPSCs or direct conversion from somatic cells, and highlight their applications in research and prospects for therapy. PMID:25762177

Murine pluripotent stem cells derived scaffold-free cartilage grafts from a micro-cavitary hydrogel platform.

PubMed

He, Pengfei; Fu, Jiayin; Wang, Dong-An

2016-04-15

By means of appropriate cell type and scaffold, tissue-engineering approaches aim to construct grafts for cartilage repair. Pluripotent stem cells especially induced pluripotent stem cells (iPSCs) are of promising cell candidates due to the pluripotent plasticity and abundant cell source. We explored three dimensional (3D) culture and chondrogenesis of murine iPSCs (miPSCs) on an alginate-based micro-cavity hydrogel (MCG) platform in pursuit of fabricating synthetic-scaffold-free cartilage grafts. Murine embryonic stem cells (mESCs) were employed in parallel as the control. Chondrogenesis was fulfilled using a consecutive protocol via mesoderm differentiation followed by chondrogenic differentiation; subsequently, miPSC and mESC-seeded constructs were further respectively cultured in chondrocyte culture (CC) medium. Alginate phase in the constructs was then removed to generate a graft only comprised of induced chondrocytic cells and cartilaginous extracellular matrix (ECMs). We found that from the mESC-seeded constructs, formation of intact grafts could be achieved in greater sizes with relatively fewer chondrocytic cells and abundant ECMs; from miPSC-seeded constructs, relatively smaller sized cartilaginous grafts could be formed by cells with chondrocytic phenotype wrapped by abundant and better assembled collagen type II. This study demonstrated successful creation of pluripotent stem cells-derived cartilage/chondroid graft from a 3D MCG interim platform. By the support of materials and methodologies established from this study, particularly given the autologous availability of iPSCs, engineered autologous cartilage engraftment may be potentially fulfilled without relying on the limited and invasive autologous chondrocytes acquisition. In this study, we explored chondrogenic differentiation of pluripotent stem cells on a 3D micro-cavitary hydrogel interim platform and creation of pluripotent stem cells-derived cartilage/chondroid graft via a consecutive

Chemomobilization: Overview of an Educational Quality Improvement Project for Recipients of Autologous Stem Cell Transplantation
.

PubMed

Rivera, Zandra R; Nurse, Rachelle; Fellman, Bryan; Brunelle, Nicole; Brassil, Kelly J

2017-08-01

In preparation for an autologous stem cell transplantation, patients undergo chemomobilization; however, a dearth of standardized, evidence-based patient education on chemomobilization exists in the literature and in practice.
. The purpose of this quality improvement educational initiative is to identify an 
evidence-based approach to appraise the educational needs of patients and their caregivers and to enhance chemomobilization education. 
. A review of the literature related to chemomobilization was conducted, as well as an informal survey of educational practices at five 
National Cancer Institute-designated comprehensive cancer centers. A 14-item survey was administered to 50 patients who underwent chemomobilization to assess their educational needs, experiences, and preferences. 
. Patients prefer written information to review. Receiving verbal education from reliable healthcare providers in a structured format may enhance effective comprehension and retention. Patients identified timing, process, side effects, and expectations about chemomobilization as the most important topics to include in education.

Addition of Autologous Mesenchymal Stem Cells to Whole Blood for Bio-Enhanced ACL Repair has No Benefit in the Porcine Model

PubMed Central

Proffen, Benedikt L.; Vavken, Patrick; Haslauer, Carla M.; Fleming, Braden C.; Harris, Chad E.; Machan, Jason T.; Murray, Martha M.

2015-01-01

Background Co-culture of mesenchymal stem cells (MSCs) from the retropatellar fat pad and peripheral blood has been shown to stimulate anterior cruciate ligament (ACL) fibroblast proliferation and collagen production in vitro. Current techniques of bio-enhanced ACL repair in animal studies involve adding a biologic scaffold, in this case an extracellular matrix based scaffold saturated with autologous whole blood, to a simple suture repair of the ligament. Whether the enrichment of whole blood with MSCs would further improve the in vivo results of bio-enhanced ACL repair was investigated. Hypothesis/Purpose The hypothesis was that the addition of MSCs derived from adipose tissue or peripheral blood to the blood-extracellular matrix composite, which is used in bio-enhanced ACL repair to stimulate healing, would improve the biomechanical properties of a bio-enhanced ACL repair after 15 weeks of healing. Study Design Controlled laboratory study. Methods Twenty-four adolescent Yucatan mini-pigs underwent ACL transection followed by: 1) bio-enhanced ACL repair, 2) bio-enhanced ACL repair with the addition of autologous adipose-derived MSCs and 3) bio-enhanced ACL repair with the addition of autologous peripheral blood derived MSCs. After fifteen weeks of healing, structural properties of the ACL (yield & failure load, linear stiffness) were measured. Cell and vascular density were measured in the repaired ACL via histology, and its tissue structure was qualitatively evaluated using the Advanced Ligament Maturity Index. Results After fifteen weeks of healing, there were no significant improvements in the biomechanical or histological properties with the addition of adipose-derived MSCs. The only significant change with the addition of peripheral blood MSCs was an increase in knee anteroposterior (AP) laxity when measured at 30 degrees of flexion. Conclusions These findings suggest that the addition of adipose or peripheral blood MSCs to whole blood prior to saturation of

Combined use of decellularized allogeneic artery conduits with autologous transdifferentiated adipose-derived stem cells for facial nerve regeneration in rats.

PubMed

Sun, Fei; Zhou, Ke; Mi, Wen-juan; Qiu, Jian-hua

2011-11-01

Natural biological conduits containing seed cells have been widely used as an alternative strategy for nerve gap reconstruction to replace traditional nerve autograft techniques. The purpose of this study was to investigate the effects of a decellularized allogeneic artery conduit containing autologous transdifferentiated adipose-derived stem cells (dADSCs) on an 8-mm facial nerve branch lesion in a rat model. After 8 weeks, functional evaluation of vibrissae movements and electrophysiological assessment, retrograde labeling of facial motoneurons and morphological analysis of regenerated nerves were performed to assess nerve regeneration. The transected nerves reconstructed with dADSC-seeded artery conduits achieved satisfying regenerative outcomes associated with morphological and functional improvements which approached those achieved with Schwann cell (SC)-seeded artery conduits, and superior to those achieved with artery conduits alone or ADSC-seeded artery conduits, but inferior to those achieved with nerve autografts. Besides, numerous transplanted PKH26-labeled dADSCs maintained their acquired SC-phenotype and myelin sheath-forming capacity inside decellularized artery conduits and were involved in the process of axonal regeneration and remyelination. Collectively, our combined use of decellularized allogeneic artery conduits with autologous dADSCs certainly showed beneficial effects on nerve regeneration and functional restoration, and thus represents an alternative approach for the reconstruction of peripheral facial nerve defects. Copyright © 2011 Elsevier Ltd. All rights reserved.

Comparative epigenetic influence of autologous versus fetal bovine serum on mesenchymal stem cells through in vitro osteogenic and adipogenic differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fani, Nesa; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran

Mesenchymal stem cells (MSCs) derived from bone marrow (BM) represents a useful source of adult stem cells for cell therapy and tissue engineering. MSCs are present at a low frequency in the BM; therefore expansion is necessary before performing clinical studies. Fetal bovine serum (FBS) as a nutritional supplement for in vitro culture of MSCs is a suitable additive for human cell culture, but not regarding subsequent use of these cells for clinical treatment of human patients due to the risk of viral and prion transmission as well as xenogeneic immune responses after transplantation. Recently, autologous serum (AS) has beenmore » as a supplement to replace FBS in culture medium. We compared the effect of FBS versus AS on the histone modification pattern of MSCs through in vitro osteogenesis and adipogenesis. Differentiation of stem cells under various serum conditions to a committed state involves global changes in epigenetic patterns that are critically determined by chromatin modifications. Chromatin immunoprecipitation (ChIP) coupled with real-time PCR showed significant changes in the acetylation and methylation patterns in lysine 9 (Lys9) of histone H3 on the regulatory regions of stemness (Nanog, Sox2, Rex1), osteogenic (Runx2, Oc, Sp7) and adipogenic (Ppar-γ, Lpl, adiponectin) marker genes in undifferentiated MSCs, FBS and AS. All epigenetic changes occurred in a serum dependent manner which resulted in higher expression level of stemness genes in undifferentiated MSCs compared to differentiated MSCs and increased expression levels of osteogenic genes in AS compared to FBS. Adipogenic genes showed greater expression in FBS compared to AS. These findings have demonstrated the epigenetic influence of serum culture conditions on differentiation potential of MSCs, which suggest that AS is possibly more efficient serum for osteogenic differentiation of MSCs in cell therapy purposes. - Highlights: • Bone marrow derived MSC could proliferate in AS as well as

The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin.

PubMed

Pellegrini, G; Ranno, R; Stracuzzi, G; Bondanza, S; Guerra, L; Zambruno, G; Micali, G; De Luca, M

1999-09-27

Cell therapy is an emerging therapeutic strategy aimed at replacing or repairing severely damaged tissues with cultured cells. Epidermal regeneration obtained with autologous cultured keratinocytes (cultured autografts) can be life-saving for patients suffering from massive full-thickness burns. However, the widespread use of cultured autografts has been hampered by poor clinical results that have been consistently reported by different burn units, even when cells were applied on properly prepared wound beds. This might arise from the depletion of epidermal stem cells (holoclones) in culture. Depletion of holoclones can occur because of (i) incorrect culture conditions, (ii) environmental damage of the exposed basal layer of cultured grafts, or (iii) use of new substrates or culture technologies not pretested for holoclone preservation. The aim of this study was to show that, if new keratinocyte culture technologies and/or "delivery systems" are proposed, a careful evaluation of epidermal stem cell preservation is essential for the clinical performance of this life-saving technology. Fibrin was chosen as a potential substrate for keratinocyte cultivation. Stem cells were monitored by clonal analysis using the culture system originally described by Rheinwald and Green as a reference. Massive full-thickness burns were treated with the composite allodermis/cultured autograft technique. We show that: (i) the relative percentage of holoclones, meroclones, and paraclones is maintained when keratinocytes are cultivated on fibrin, proving that fibrin does not induce clonal conversion and consequent loss of epidermal stem cells; (ii) the clonogenic ability, growth rate, and long-term proliferative potential are not affected by the new culture system; (iii) when fibrin-cultured autografts bearing stem cells are applied on massive full-thickness burns, the "take" of keratinocytes is high, reproducible, and permanent; and (iv) fibrin allows a significant reduction of the cost

The happy destiny of frozen haematopoietic stem cells: from immature stem cells to mature applications.

PubMed

de Vries, E G E; Vellenga, E; Kluin-Nelemans, J C; Mulder, N H

2004-09-01

Forty years ago, van Putten described in the European Journal of Cancer (see this issue) quantitative studies on the optimal storage techniques of mouse and monkey bone marrow suspensions. Survival of the animals after irradiation following injection with stored bone marrow cell suspensions was the endpoint. He observed some species differences, but based on the data obtained considered a careful trial of the glycerol-polyvinylpyrrolide (PVP) combination for storage of marrow in man was indicated. In spite of this, dimethyl sulphoxide has become the 'standard' cryopreservant for human marrow stem cells. Over the last 40 years, there has been a tremendous increase in knowledge about haematopoietic stem cells and their use in the clinic. Haematopoietic stem cells are now known to travel between the bone marrow and peripheral blood and are the best-characterised adult stem cells. These cells are currently widely used for transplantations in the clinic and are obtained from a wide variety of sources. These include the bone marrow, peripheral blood, cord blood, autologous as well as allogeneic stem cells from related or unrelated donors. Increasingly, data has become available that adult haematopoietic stem cells can generate differentiated cells belonging to other cell types, a process called "developmental plasticity". Thus, they may contribute to non-haematopoietic tissue repair in multiple organ systems. This has created a whole new potential therapeutic armamentarium for the application of haematopoietic stem cells outside of the area of malignancies and haematopoietic disorders.

Stem cells in nephrology: present status and future.

PubMed

Watorek, Ewa; Klinger, Marian

2006-01-01

Stem cell biology is currently developing rapidly because of the potential therapeutic utility of stem cells. The ability to acquire any desired phenotype raises hope for regenerative therapies. Manipulation of these cells is a potentially valuable tool; however, the mechanisms of stem cell differentiation and plasticity are currently beyond our control. In the field of nephrology, the presence of adult kidney stem cells has been debated. Renal adult stem cells may be descendants of some early kidney progenitors, or may be derived from bone marrow. Evidence of a hematopoietic stem-cell contribution to renal repair encourages the possibility of bone marrow or stem cell transplantation as a means of treating autoimmune glomerulopathies. The transplantation of fetal kidney tissue containing renal progenitors, which then develop into functional nephrons, is a step towards renal regeneration. According to recent reports, the development of functional nephrons from human mesenchymal stem cells in rodent whole-embryo culture is possible. Establishing in vitro self organs from autologous stem cells would be a promising therapeutic solution in light of the shortage of allogenic organs and the unresolved problem of chronic allograft rejection.

Fetal stem cell transplantation: Past, present, and future

PubMed Central

Ishii, Tetsuya; Eto, Koji

2014-01-01

Since 1928, human fetal tissues and stem cells have been used worldwide to treat various conditions. Although the transplantation of the fetal midbrain substantia nigra and dopaminergic neurons in patients suffering from Parkinson’s disease is particularly noteworthy, the history of other types of grafts, such as those of the fetal liver, thymus, and pancreas, should be addressed as there are many lessons to be learnt for future stem cell transplantation. This report describes previous practices and complications that led to current clinical trials of isolated fetal stem cells and embryonic stem (ES) cells. Moreover, strategies for transplantation are considered, with a particular focus on donor cells, cell processing, and the therapeutic cell niche, in addition to ethical issues associated with fetal origin. With the advent of autologous induced pluripotent stem cells and ES cells, clinical dependence on fetal transplantation is expected to gradually decline due to lasting ethical controversies, despite landmark achievements. PMID:25258662

Toward Personalized Cell Therapies: Autologous Menstrual Blood Cells for Stroke

PubMed Central

Rodrigues, Maria Carolina O.; Glover, Loren E.; Weinbren, Nathan; Rizzi, Jessica A.; Ishikawa, Hiroto; Shinozuka, Kazutaka; Tajiri, Naoki; Kaneko, Yuji; Sanberg, Paul R.; Allickson, Julie G.; Kuzmin-Nichols, Nicole; Garbuzova-Davis, Svitlana; Voltarelli, Julio Cesar; Cruz, Eduardo; Borlongan, Cesar V.

2011-01-01

Cell therapy has been established as an important field of research with considerable progress in the last years. At the same time, the progressive aging of the population has highlighted the importance of discovering therapeutic alternatives for diseases of high incidence and disability, such as stroke. Menstrual blood is a recently discovered source of stem cells with potential relevance for the treatment of stroke. Migration to the infarct site, modulation of the inflammatory reaction, secretion of neurotrophic factors, and possible differentiation warrant these cells as therapeutic tools. We here propose the use of autologous menstrual blood cells in the restorative treatment of the subacute phase of stroke. We highlight the availability, proliferative capacity, pluripotency, and angiogenic features of these cells and explore their mechanistic pathways of repair. Practical aspects of clinical application of menstrual blood cells for stroke will be discussed, from cell harvesting and cryopreservation to administration to the patient. PMID:22162629

DNA Methylation and Hydroxymethylation Profile of CD34+-Enriched Cell Products Intended for Autologous CD34+ Cell Transplantation.

PubMed

Rozman, Jasmina-Ziva; Pohar Perme, Maja; Jez, Mojca; Malicev, Elvira; Krasna, Metka; Vrtovec, Bojan; Rozman, Primoz

2017-09-01

Epigenetic dysregulation has been shown to limit functional capacity of aging hematopoietic stem cells, which may contribute to impaired outcome of hematopoietic stem cell-based therapies. The aim of our study was to gain better insight into the epigenetic profile of CD34 + -enriched cell products intended for autologous CD34 + cell transplantation in patients with cardiomyopathy. We found global DNA methylation content significantly higher in immunoselected CD34 + cells compared to leukocytes in leukapheresis products (2.33 ± 1.03% vs. 1.84 ± 0.86%, p = 0.04). Global DNA hydroxymethylation content did not differ between CD34 + cells and leukocytes (p = 0.30). By measuring methylation levels of 94 stem cell transcription factors on a ready-to-use array, we identified 15 factors in which average promoter methylation was significantly different between leukocytes and CD34 + cells. The difference was highest for HOXC12 (58.18 ± 6.47% vs. 13.34 ± 24.18%, p = 0.0009) and NR2F2 (51.65 ± 25.89% vs. 7.66 ± 21.43%, p = 0.0045) genes. Our findings suggest that global DNA methylation and hydroxymethylation patterns as well as target methylation profile of selected genes in CD34 + -enriched cell products do not differ significantly compared to leukapheresis products and, thus, can tell us little about the functional capacity and regenerative properties of CD34 + cells. Future studies should examine other CD34 + cell graft characteristics, which may serve as prognostic tools for autologous CD34 + cell transplantation.

Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy.

PubMed

Meng, Jinhong; Counsell, John R; Reza, Mojgan; Laval, Steven H; Danos, Olivier; Thrasher, Adrian; Lochmüller, Hanns; Muntoni, Francesco; Morgan, Jennifer E

2016-01-27

Autologous stem cells that have been genetically modified to express dystrophin are a possible means of treating Duchenne Muscular Dystrophy (DMD). To maximize the therapeutic effect, dystrophin construct needs to contain as many functional motifs as possible, within the packaging capacity of the viral vector. Existing dystrophin constructs used for transduction of muscle stem cells do not contain the nNOS binding site, an important functional motif within the dystrophin gene. In this proof-of-concept study, using stem cells derived from skeletal muscle of a DMD patient (mdcs) transplanted into an immunodeficient mouse model of DMD, we report that two novel dystrophin constructs, C1 (ΔR3-R13) and C2 (ΔH2-R23), can be lentivirally transduced into mdcs and produce dystrophin. These dystrophin proteins were functional in vivo, as members of the dystrophin glycoprotein complex were restored in muscle fibres containing donor-derived dystrophin. In muscle fibres derived from cells that had been transduced with construct C1, the largest dystrophin construct packaged into a lentiviral system, nNOS was restored. The combination of autologous stem cells and a lentivirus expressing a novel dystrophin construct which optimally restores proteins of the dystrophin glycoprotein complex may have therapeutic application for all DMD patients, regardless of their dystrophin mutation.

Therapy with stem cells in inflammatory bowel disease

PubMed Central

Martínez-Montiel, María del Pilar; Gómez-Gómez, Gonzalo Jesús; Flores, Ana Isabel

2014-01-01

Inflammatory bowel disease (IBD) affects a part of the young population and has a strong impact upon quality of life. The underlying etiology is not known, and the existing treatments are not curative. Furthermore, a significant percentage of patients are refractory to therapy. In recent years there have been great advances in our knowledge of stem cells and their therapeutic applications. In this context, autologous hematopoietic stem cell transplantation (HSCT) has been used in application to severe refractory Crohn’s disease (CD), with encouraging results. Allogenic HSCT would correct the genetic defects of the immune system, but is currently not accepted for the treatment of IBD because of its considerable risks. Mesenchymal stem cells (MSCs) have immune regulatory and regenerative properties, and low immunogenicity (both autologous and allogenic MSCs). Based on these properties, MSCs have been used via the systemic route in IBD with promising results, though it is still too soon to draw firm conclusions. Their local administration in perianal CD is the field where most progress has been made in recent years, with encouraging results. The next few years will be decisive for defining the role of such therapy in the management of IBD. PMID:24574796

Repair of facial nerve defects with decellularized artery allografts containing autologous adipose-derived stem cells in a rat model.

PubMed

Sun, Fei; Zhou, Ke; Mi, Wen-Juan; Qiu, Jian-Hua

2011-07-20

The purpose of this study was to investigate the effects of a decellularized artery allograft containing autologous adipose-derived stem cells (ADSCs) on an 8-mm facial nerve branch lesion in a rat model. At 8 weeks postoperatively, functional evaluation of unilateral vibrissae movements, morphological analysis of regenerated nerve segments and retrograde labeling of facial motoneurons were all analyzed. Better regenerative outcomes associated with functional improvement, great axonal growth, and improved target reinnervation were achieved in the artery-ADSCs group (2), whereas the cut nerves sutured with artery conduits alone (group 1) achieved inferior restoration. Furthermore, transected nerves repaired with nerve autografts (group 3) resulted in significant recovery of whisking, maturation of myelinated fibers and increased number of labeled facial neurons, and the latter two parameters were significantly different from those of group 2. Collectively, though our combined use of a decellularized artery allograft with autologous ADSCs achieved regenerative outcomes inferior to a nerve autograft, it certainly showed a beneficial effect on promoting nerve regeneration and thus represents an alternative approach for the reconstruction of peripheral facial nerve defects. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Lower Oncogenic Potential of Human Mesenchymal Stem Cells Derived from Cord Blood Compared to Induced Pluripotent Stem Cells

PubMed Central

Foroutan, T.; Najmi, M.; Kazemi, N.; Hasanlou, M.; Pedram, A.

2015-01-01

Background: In regenerative medicine, use of each of the mesenchymal stem cells derived from bone marrow, cord blood, and adipose tissue, has several cons and pros. Mesenchymal stem cells derived from cord blood have been considered the best source for precursor transplantation. Direct reprogramming of a somatic cell into induced pluripotent stem cells by over-expression of 6 transcription factors Oct4, Sox2, Klf4, lin28, Nanog, and c-Myc has great potential for regenerative medicine, eliminating the ethical issues of embryonic stem cells and the rejection problems of using non-autologous cells. Objective: To compare reprogramming and pluripotent markers OCT4, Sox-2, c-Myc, Klf4, Nanog, and lin28 in mesenchymal stem cells derived from cord blood and induced pluripotent stem cells. Methods: We analyzed the expression level of OCT4, Sox-2, c-Myc, Klf4, Nanog and lin28 genes in human mesenchymal stem cells derived from cord blood and induced pluripotent stem cells by cell culture and RT-PCR. Results: The expression level of pluripotent genes OCT4 and Sox-2, Nanog and lin28 in mesenchymal stem cells derived from cord blood were significantly higher than those in induced pluripotent stem cells. In contrast to OCT-4A and Sox-2, Nanog and lin28, the expression level of oncogenic factors c-Myc and Klf4 were significantly higher in induced pluripotent stem cells than in mesenchymal stem cells derived from cord blood. Conclusion: It could be concluded that mesenchymal stem cells derived from human cord blood have lower oncogenic potential compared to induced pluripotent stem cells. PMID:26306155

Persistent positive metaiodobenzylguanidine scans after autologous peripheral blood stem cell transplantation may indicate maturation of stage 4 neuroblastoma.

PubMed

Okamoto, Yasuhiro; Kodama, Yuichi; Nishikawa, Takuro; Rindiarti, Almitra; Tanabe, Takayuki; Nakagawa, Shunsuke; Yoshioka, Takako; Takumi, Koji; Kaji, Tatsuru; Kawano, Yoshifumi

2017-04-01

Metaiodobenzylguanidine (MIBG) scans are sensitive testing tools for neuroblastoma. Persistent positive MIBG scans in patients with stage 3 neuroblastoma have previously been found to indicate maturation rather than regression. We assessed the significance of this finding in stage 4 neuroblastoma in the present study. Fifteen consecutive pediatric patients with stage 4 neuroblastoma treated between 2004 and 2014 at the Kagoshima University Hospital were retrospectively examined. Treatment involved a combination of multiagent chemotherapy, resection, autologous peripheral blood stem cell transplantation (PBSCT), radiotherapy, and maintenance therapy with retinoic acid. The MIBG uptake in each patient during treatment was assessed using a Curie score. The 5-year event-free and overall survival rates in 15 patients were 38.9% and 58.7%, respectively. Four patients with persistent positive MIBG scans who underwent autologous PBSCT but experienced decreased 123 I-MIBG uptake during the clinical course survived without progression, and their event-free survival (EFS) was significantly superior to that of patients who showed negative MIBG scans after PBSCT (5-year EFS rate: 18.2%, p = 0.0176). Therefore, persistent positive MIBG scans with gradually decreased uptake after PBSCT do not always indicate neuroblastoma progression, and may instead indicate tumor maturation in some selected cases, if not all cases, of stage 4 neuroblastoma.

Tantalum coating of porous carbon scaffold supplemented with autologous bone marrow stromal stem cells for bone regeneration in vitro and in vivo

PubMed Central

Wei, Xiaowei; Wang, Benjie; Wang, Wei; Kang, Kai; Xie, Hui; Liu, Baoyi; Zhang, Xiuzhi; Zhang, Jinsong; Yang, Zhenming

2016-01-01

Porous tantalum metal with low elastic modulus is similar to cancellous bone. Reticulated vitreous carbon (RVC) can provide three-dimensional pore structure and serves as the ideal scaffold of tantalum coating. In this study, the biocompatibility of domestic porous tantalum was first successfully tested with bone marrow stromal stem cells (BMSCs) in vitro and for bone tissue repair in vivo. We evaluated cytotoxicity of RVC scaffold and tantalum coating using BMSCs. The morphology, adhesion, and proliferation of BMSCs were observed via laser scanning confocal microscope and scanning electron microscopy. In addition, porous tantalum rods with or without autologous BMSCs were implanted on hind legs in dogs, respectively. The osteogenic potential was observed by hard tissue slice examination. At three weeks and six weeks following implantation, new osteoblasts and new bone were observed at the tantalum–host bone interface and pores. At 12 weeks postporous tantalum with autologous BMSCs implantation, regenerated trabecular equivalent to mature bone was found in the pore of tantalum rods. Our results suggested that domestic porous tantalum had excellent biocompatibility and could promote new bone formation in vivo. Meanwhile, the osteogenesis of porous tantalum associated with autologous BMSCs was more excellent than only tantalum implantation. Future clinical studies are warranted to verify the clinical efficacy of combined implantation of this domestic porous tantalum associated with autologous BMSCs implantation and compare their efficacy with conventional autologous bone grafting carrying blood vessel in patients needing bone repairing. PMID:26843518

Feasibility of autologous bone marrow mesenchymal stem cell-derived extracellular matrix scaffold for cartilage tissue engineering.

PubMed

Tang, Cheng; Xu, Yan; Jin, Chengzhe; Min, Byoung-Hyun; Li, Zhiyong; Pei, Xuan; Wang, Liming

2013-12-01

Extracellular matrix (ECM) materials are widely used in cartilage tissue engineering. However, the current ECM materials are unsatisfactory for clinical practice as most of them are derived from allogenous or xenogenous tissue. This study was designed to develop a novel autologous ECM scaffold for cartilage tissue engineering. The autologous bone marrow mesenchymal stem cell-derived ECM (aBMSC-dECM) membrane was collected and fabricated into a three-dimensional porous scaffold via cross-linking and freeze-drying techniques. Articular chondrocytes were seeded into the aBMSC-dECM scaffold and atelocollagen scaffold, respectively. An in vitro culture and an in vivo implantation in nude mice model were performed to evaluate the influence on engineered cartilage. The current results showed that the aBMSC-dECM scaffold had a good microstructure and biocompatibility. After 4 weeks in vitro culture, the engineered cartilage in the aBMSC-dECM scaffold group formed thicker cartilage tissue with more homogeneous structure and higher expressions of cartilaginous gene and protein compared with the atelocollagen scaffold group. Furthermore, the engineered cartilage based on the aBMSC-dECM scaffold showed better cartilage formation in terms of volume and homogeneity, cartilage matrix content, and compressive modulus after 3 weeks in vivo implantation. These results indicated that the aBMSC-dECM scaffold could be a successful novel candidate scaffold for cartilage tissue engineering. © 2013 Wiley Periodicals, Inc. and International Center for Artificial Organs and Transplantation.

Effects of different concentrations of Platelet-rich Plasma and Platelet-Poor Plasma on vitality and differentiation of autologous Adipose tissue-derived stem cells.

PubMed

Felthaus, Oliver; Prantl, Lukas; Skaff-Schwarze, Mona; Klein, Silvan; Anker, Alexandra; Ranieri, Marco; Kuehlmann, Britta

2017-01-01

Autologous fat grafts and adipose-derived stem cells (ASCs) can be used to treat soft tissue defects. However, the results are inconsistent and sometimes comprise tissue resorption and necrosis. This might be due to insufficient vascularization. Platelet-rich plasma (PRP) is a source of concentrated autologous platelets. The growth factors and cytokines released by platelets can facilitate angiogenesis. The simultaneous use of PRP might improve the regeneration potential of fat grafts. The optimal ratio has yet to be elucidated. A byproduct of PRP preparation is platelet-poor plasma (PPP). In this study we investigated the influence of different concentrations of PRP on the vitality and differentiation of ASCs. We processed whole blood with the Arthrex Angel centrifuge and isolated ASCs from the same donor. We tested the effects of different PRP and PPP concentrations on the vitality using resazurin assays and the differentiation of ASCs using oil-red staining. Both cell vitality and adipogenic differentiation increase to a concentration of 10% to 20% PRP. With a PRP concentration of 30% cell vitality and differentiation decrease. Both PRP and PPP can be used to expand ASCs without xenogeneic additives in cell culture. A PRP concentration above 20% has inhibitory effects.

Expression of intracellular reactive oxygen species (ROS) in haematopoietic stem cells (HSCs) correlates with time to neutrophil and platelet engraftment in patients undergoing autologous bone marrow transplantation.

PubMed

Bai, Lijun; Best, Giles; Xia, Wei; Peters, Lyndsay; Wong, Kelly; Ward, Christopher; Greenwood, Matthew

2018-06-19

Reactive oxygen species (ROS) play important roles in haematopoiesis and regulate the self-renewal, migration and myeloid differentiation of haemopoeitic stem cells (HSCs). This study was conducted to determine whether ROS levels in donor HSCs correlate with neutrophil and platelet engraftment in patients following bone marrow transplantation. Cryopreserved HSCs samples from 51 patients who underwent autologous transplantation were studied. Levels of intracellular ROS were assessed by flow cytometry using 2',7' dichlorodihydrofluorescein diacetate (H 2 DCFDA) in the CD45 + /CD34 + HSC population. Colony forming unit (CFU) assays were performed on HSCs isolated from the ROS high and ROS low populations to assess the differentiation potential of these two cell subsets. Distinct populations of ROS high and ROS low cells were evident in all patient samples. The median percentage of ROS high expressing HSCs in the study cohort was 75.8% (range 2% - 95.2%). A significant correlation was identified between the percentage of ROS high stem cells present in the HPC(A) product infused and the time to neutrophil engraftment (p < 0.001, R= - 0.54) as well as time to plt20, plt50 and plt100 (p < 0.001, R = - 0.55, - 0.59 and - 0.56 respectively). The dose of CD34 + / ROS high /kg infused also inversely correlated with a shorter time to neutrophil engraftment; time to engraftment for patients receiving > or ≤ 3 × 10 6 cells/kg was 11.5 (range 9 - 23) days vs. 14 (10 - 28) days respectively (p = 0.02). The dose of ROS high HSCs delivered did not correlate with platelet engraftment. Collectively, these data suggest that the dose of ROS high stem cells delivered to patients may predict time to neutrophil engraftment following autologous transplantation. Copyright © 2018. Published by Elsevier Inc.

Lymphomatoid hypersensitivity reaction to levofloxacin during autologous stem cell transplantation: a potential diagnostic pitfall in patients treated for lymphoma or leukemia.

PubMed

Esparza, Edward M; Takeshita, Junko; George, Evan

2011-01-01

Drug-associated cutaneous lymphomatoid hypersensitivity reactions are rare eruptions that can clinically and microscopically mimic a bona fide lymphomatous process. Clinically, the appearance ranges from papulosquamous to purpuric. Histopathologically, these reactions simulate a wide variety of lymphoma subtypes; the most frequently reported examples resemble mycosis fungoides. We report a 61-year-old female who developed a purpuric eruption prior to engraftment of an autologous hematopoietic stem cell transplant for stage IV mantle cell lymphoma. Skin biopsies showed a superficial perivascular and interstitial infiltrate of large, immature-appearing mononuclear cells associated with spongiosis, papillary dermal edema and erythrocyte extravasation. The cells were immunoreactive for T-cell markers and lacked B-cell marker expression, excluding recurrence of the underlying mantle cell lymphoma as a diagnostic possibility. The cutaneous eruption was temporally linked to levofloxacin administration and resolved after discontinuation of this medication. This is the first report of a lymphomatoid hypersensitivity reaction associated with fluoroquinolone use. The histopathologic features presented in this paper underscore the potential for misdiagnosis of such lesions as lymphoma or acute myeloid leukemia, particularly in the setting of hematopoietic stem cell transplantation for underlying lymphoma or leukemia. Clinical correlation, morphologic comparison to the original malignancy and immunohistochemical studies aid the dermatopathologist in rendering the correct diagnosis. Copyright © 2010 John Wiley & Sons A/S.

Living with Crohn’s disease: an exploratory cross-sectional qualitative study into decision-making and expectations in relation to autologous haematopoietic stem cell treatment (the DECIDES study)

PubMed Central

Cooper, Joanne; Blake, Iszara; Lindsay, James O; Hawkey, Christopher J

2017-01-01

Background/Objectives Severe Crohn’s disease impacts negatively on individual quality of life, with treatment options limited once conventional therapies have been exhausted. The aim of this study was to explore factors influencing decision-making and expectations of people considering or participating in the Autologous Haematopoietic Stem Cell Treatment trial. Methods An international, cross-sectional qualitative study, involving semistructured face to face interviews across five sites (four UK and one Spain). 38 participants were interviewed (13 men, 25 women; age range 23–67 years; mean age 37 years). The mean age at diagnosis was 20 years. Interviews were audio recorded and transcribed verbatim and transcripts were analysed using a framework approach. Results Four themes emerged from the analysis: (1) ‘making your mind up’—a determination to receive stem cell treatment despite potential risks; (2) communicating and understanding risks and benefits; (3) non-participation—your choice or mine? (4) recovery and reframing of personal expectations. Conclusions Decision-making and expectations of people with severe Crohn’s disease in relation to autologous haematopoietic stem cell treatment is a complex process influenced by participants’ histories of battling with their condition, a frequent willingness to consider novel treatment options despite potential risks and, in some cases, a raised level of expectation about the benefits of trial participation. Discussions with patients who are considering novel treatments should take into account potential ‘therapeutic misestimation’, thereby enhancing shared decision-making, informed consent and the communication with those deemed non-eligible. ASTIC trial EudraCT Number 2005-003337-40: results. PMID:28893742

Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually.

PubMed

Passweg, J R; Baldomero, H; Bader, P; Bonini, C; Cesaro, S; Dreger, P; Duarte, R F; Dufour, C; Kuball, J; Farge-Bancel, D; Gennery, A; Kröger, N; Lanza, F; Nagler, A; Sureda, A; Mohty, M

2016-06-01

A record number of 40 829 hematopoietic stem cell transplantation (HSCT) in 36 469 patients (15 765 allogeneic (43%), 20 704 autologous (57%)) were reported by 656 centers in 47 countries to the 2014 survey. Trends include: continued growth in transplant activity, more so in Eastern European countries than in the west; a continued increase in the use of haploidentical family donors (by 25%) and slower growth for unrelated donor HSCT. The use of cord blood as a stem cell source has decreased again in 2014. Main indications for HSCT were leukemias: 11 853 (33%; 96% allogeneic); lymphoid neoplasias; 20 802 (57%; 11% allogeneic); solid tumors; 1458 (4%; 3% allogeneic) and non-malignant disorders; 2203 (6%; 88% allogeneic). Changes in transplant activity include more allogeneic HSCT for AML in CR1, myeloproliferative neoplasm (MPN) and aplastic anemia and decreasing use in CLL; and more autologous HSCT for plasma cell disorders and in particular for amyloidosis. In addition, data on numbers of teams doing alternative donor transplants, allogeneic after autologous HSCT, autologous cord blood transplants are presented.

Does the preference of peripheral versus central venous access in peripheral blood stem cell collection/yield change stem cell kinetics in autologous stem cell transplantation?

PubMed

Dogu, Mehmet Hilmi; Kaya, Ali Hakan; Berber, Ilhami; Sari, İsmail; Tekgündüz, Emre; Erkurt, Mehmet Ali; Iskender, Dicle; Kayıkçı, Ömur; Kuku, Irfan; Kaya, Emin; Keskin, Ali; Altuntaş, Fevzi

2016-02-01

Central venous access is often used during apheresis procedure in stem cell collection. The aim of the present study was to evaluate whether central or peripheral venous access has an effect on stem cell yield and the kinetics of the procedure and the product in patients undergoing ASCT after high dose therapy. A total of 327 patients were retrospectively reviewed. The use of peripheral venous access for stem cell yield was significantly more frequent in males compared to females (p = 0.005). Total volume of the product was significantly lower in central venous access group (p = 0.046). As being a less invasive procedure, peripheral venous access can be used for stem cell yield in eligible selected patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Next Generation Mesenchymal Stem Cell (MSC)–Based Cartilage Repair Using Scaffold-Free Tissue Engineered Constructs Generated with Synovial Mesenchymal Stem Cells

PubMed Central

Shimomura, Kazunori; Ando, Wataru; Moriguchi, Yu; Sugita, Norihiko; Yasui, Yukihiko; Koizumi, Kota; Fujie, Hiromichi; Hart, David A.; Yoshikawa, Hideki

2015-01-01

Because of its limited healing capacity, treatments for articular cartilage injuries are still challenging. Since the first report by Brittberg, autologous chondrocyte implantation has been extensively studied. Recently, as an alternative for chondrocyte-based therapy, mesenchymal stem cell–based therapy has received considerable research attention because of the relative ease in handling for tissue harvest, and subsequent cell expansion and differentiation. This review summarizes latest development of stem cell therapies in cartilage repair with special attention to scaffold-free approaches. PMID:27340513

Ebselen Preserves Tissue-Engineered Cell Sheets and their Stem Cells in Hypothermic Conditions

PubMed Central

Katori, Ryosuke; Hayashi, Ryuhei; Kobayashi, Yuki; Kobayashi, Eiji; Nishida, Kohji

2016-01-01

Clinical trials have been performed using autologous tissue-engineered epithelial cell sheets for corneal regenerative medicine. To improve stem cell-based therapy for convenient clinical practice, new techniques are required for preserving reconstructed tissues and their stem/progenitor cells until they are ready for use. In the present study, we screened potential preservative agents and developed a novel medium for preserving the cell sheets and their stem/progenitor cells; the effects were evaluated with a luciferase-based viability assay. Nrf2 activators, specifically ebselen, could maintain high ATP levels during preservation. Ebselen also showed a strong influence on maintenance of the viability, morphology, and stem cell function of the cell sheets preserved under hypothermia by protecting them from reactive oxygen species-induced damage. Furthermore, ebselen drastically improved the preservation performance of human cornea tissues and their stem cells. Therefore, ebselen shows good potential as a useful preservation agent in regenerative medicine as well as in cornea transplantation. PMID:27966584

Ebselen Preserves Tissue-Engineered Cell Sheets and their Stem Cells in Hypothermic Conditions.

PubMed

Katori, Ryosuke; Hayashi, Ryuhei; Kobayashi, Yuki; Kobayashi, Eiji; Nishida, Kohji

2016-12-14

Clinical trials have been performed using autologous tissue-engineered epithelial cell sheets for corneal regenerative medicine. To improve stem cell-based therapy for convenient clinical practice, new techniques are required for preserving reconstructed tissues and their stem/progenitor cells until they are ready for use. In the present study, we screened potential preservative agents and developed a novel medium for preserving the cell sheets and their stem/progenitor cells; the effects were evaluated with a luciferase-based viability assay. Nrf2 activators, specifically ebselen, could maintain high ATP levels during preservation. Ebselen also showed a strong influence on maintenance of the viability, morphology, and stem cell function of the cell sheets preserved under hypothermia by protecting them from reactive oxygen species-induced damage. Furthermore, ebselen drastically improved the preservation performance of human cornea tissues and their stem cells. Therefore, ebselen shows good potential as a useful preservation agent in regenerative medicine as well as in cornea transplantation.

[G-CSF administration following autologous peripheral blood stem cell transplantation--the effect of G-CSF level on neutrophil recovery].

PubMed

Saigo, K; Sugimoto, T; Matsuo, M; Narita, H; Ryo, R; Kumagai, S

2000-03-01

We studied the usefulness of rhG-CSF (filgrastim) administration in patients who received autologous peripheral blood stem cell transplantation (PBSCT) combined with super-high dose chemotherapy. Twenty patients received 0-8.3 micrograms/kg/day filgrastim after PBSCT. There was a significant relationship between G-CSF dose and the neutrophil recovery rate, and the highest levels of serum G-CSF tended to correlate with neutrophil recovery rate. The highest G-CSF level after 75 micrograms injection in normal volunteers is reported to be 1,500 pg/ml. On the other hand, as one patient in our series exhibited extremely high endogenous G-CSF of 11,500 pg/ml, measurements of G-CSF might reduce the over-administration of rhG-CSF.

Living with Crohn's disease: an exploratory cross-sectional qualitative study into decision-making and expectations in relation to autologous haematopoietic stem cell treatment (the DECIDES study).

PubMed

Cooper, Joanne; Blake, Iszara; Lindsay, James O; Hawkey, Christopher J

2017-09-11

Severe Crohn's disease impacts negatively on individual quality of life, with treatment options limited once conventional therapies have been exhausted. The aim of this study was to explore factors influencing decision-making and expectations of people considering or participating in the Autologous Haematopoietic Stem Cell Treatment trial. An international, cross-sectional qualitative study, involving semistructured face to face interviews across five sites (four UK and one Spain). 38 participants were interviewed (13 men, 25 women; age range 23-67 years; mean age 37 years). The mean age at diagnosis was 20 years. Interviews were audio recorded and transcribed verbatim and transcripts were analysed using a framework approach. Four themes emerged from the analysis: (1) 'making your mind up'-a determination to receive stem cell treatment despite potential risks; (2) communicating and understanding risks and benefits; (3) non-participation-your choice or mine? (4) recovery and reframing of personal expectations. Decision-making and expectations of people with severe Crohn's disease in relation to autologous haematopoietic stem cell treatment is a complex process influenced by participants' histories of battling with their condition, a frequent willingness to consider novel treatment options despite potential risks and, in some cases, a raised level of expectation about the benefits of trial participation. Discussions with patients who are considering novel treatments should take into account potential 'therapeutic misestimation', thereby enhancing shared decision-making, informed consent and the communication with those deemed non-eligible. 2005-003337-40: results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Cord blood stem cell banking: a snapshot of the Italian situation.

PubMed

Capone, Francesca; Lombardini, Letizia; Pupella, Simonetta; Grazzini, Giuliano; Costa, Alessandro Nanni; Migliaccio, Giovanni

2011-09-01

In Italy, the law does not permit the setting up of private banks to preserve cord blood (CB) stem cells for personal use. However, since 2007 the right to export and preserve them in private laboratories located outside Italy has existed, and an increasing number of women are requesting this collection of umbilical CB at delivery to enable storage of stem cells for autologous use. Since private banks recruit clients mainly via the Internet, we examined the content of 24 Italian-language websites that offer stem cells storage (from CB or amniotic fluid), to assess what information is available. We found that the majority of private banks give no clear information about the procedures of collection, processing, and banking of CB units and that the standards offered by private CB banks strongly differ in terms of exclusion or acceptance criteria from the public banks. These factors may well influence the overall quality of the CB units stored in private CB banks. Of note, during the period 2007 to 2009, the number collected for autologous use did not create a downward trend on the number of units stored in public CB banks for allogeneic use. CB is a valuable community resource but expectant parents should be better informed as to the quality variables necessary for its storage, both by institutions and by professionals. Currently, most of the advertising is insufficient to justify the expense and the hopes pinned on autologous use of CB stem cells. © 2011 American Association of Blood Banks.

Safeguarding Stem Cell-Based Regenerative Therapy against Iatrogenic Cancerogenesis: Transgenic Expression of DNASE1, DNASE1L3, DNASE2, DFFB Controlled By POLA1 Promoter in Proliferating and Directed Differentiation Resisting Human Autologous Pluripotent Induced Stem Cells Leads to their Death

PubMed Central

Malecki, Marek; LaVanne, Christine; Alhambra, Dominique; Dodivenaka, Chaitanya; Nagel, Sarah; Malecki, Raf

2014-01-01

Introduction The worst possible complication of using stem cells for regenerative therapy is iatrogenic cancerogenesis. The ultimate goal of our work is to develop a self-triggering feedback mechanism aimed at causing death of all stem cells, which resist directed differentiation, keep proliferating, and can grow into tumors. Specific aim The specific aim was threefold: (1) to genetically engineer the DNA constructs for the human, recombinant DNASE1, DNASE1L3, DNASE2, DFFB controlled by POLA promoter; (2) to bioengineer anti-SSEA-4 antibody guided vectors delivering transgenes to human undifferentiated and proliferating pluripotent stem cells; (3) to cause death of proliferating and directed differentiation resisting stem cells by transgenic expression of the human recombinant the DNases (hrDNases). Methods The DNA constructs for the human, recombinant DNASE1, DNASE1L3, DNASE2, DFFB controlled by POLA promoter were genetically engineered. The vectors targeting specifically SSEA-4 expressing stem cells were bioengineered. The healthy volunteers’ bone marrow mononuclear cells (BMMCs) were induced into human, autologous, pluripotent stem cells with non-integrating plasmids. Directed differentiation of the induced stem cells into endothelial cells was accomplished with EGF and BMP. The anti-SSEA 4 antibodies’ guided DNA vectors delivered the transgenes for the human recombinant DNases’ into proliferating stem cells. Results Differentiation of the pluripotent induced stem cells into the endothelial cells was verified by highlighting formation of tight and adherens junctions through transgenic expression of recombinant fluorescent fusion proteins: VE cadherin, claudin, zona occludens 1, and catenin. Proliferation of the stem cells was determined through highlighting transgenic expression of recombinant fluorescent proteins controlled by POLA promoter, while also reporting expression of the transgenes for the hrDNases. Expression of the transgenes for the DNases

Tantalum coating of porous carbon scaffold supplemented with autologous bone marrow stromal stem cells for bone regeneration in vitro and in vivo.

PubMed

Wei, Xiaowei; Zhao, Dewei; Wang, Benjie; Wang, Wei; Kang, Kai; Xie, Hui; Liu, Baoyi; Zhang, Xiuzhi; Zhang, Jinsong; Yang, Zhenming

2016-03-01

Porous tantalum metal with low elastic modulus is similar to cancellous bone. Reticulated vitreous carbon (RVC) can provide three-dimensional pore structure and serves as the ideal scaffold of tantalum coating. In this study, the biocompatibility of domestic porous tantalum was first successfully tested with bone marrow stromal stem cells (BMSCs) in vitro and for bone tissue repair in vivo. We evaluated cytotoxicity of RVC scaffold and tantalum coating using BMSCs. The morphology, adhesion, and proliferation of BMSCs were observed via laser scanning confocal microscope and scanning electron microscopy. In addition, porous tantalum rods with or without autologous BMSCs were implanted on hind legs in dogs, respectively. The osteogenic potential was observed by hard tissue slice examination. At three weeks and six weeks following implantation, new osteoblasts and new bone were observed at the tantalum-host bone interface and pores. At 12 weeks postporous tantalum with autologous BMSCs implantation, regenerated trabecular equivalent to mature bone was found in the pore of tantalum rods. Our results suggested that domestic porous tantalum had excellent biocompatibility and could promote new bone formation in vivo. Meanwhile, the osteogenesis of porous tantalum associated with autologous BMSCs was more excellent than only tantalum implantation. Future clinical studies are warranted to verify the clinical efficacy of combined implantation of this domestic porous tantalum associated with autologous BMSCs implantation and compare their efficacy with conventional autologous bone grafting carrying blood vessel in patients needing bone repairing. © 2016 by the Society for Experimental Biology and Medicine.

Autologous c-Kit+ Mesenchymal Stem Cell Injections Provide Superior Therapeutic Benefit as Compared to c-Kit+ Cardiac-Derived Stem Cells in a Feline Model of Isoproterenol-Induced Cardiomyopathy.

PubMed

Taghavi, Sharven; Sharp, Thomas E; Duran, Jason M; Makarewich, Catherine A; Berretta, Remus M; Starosta, Tim; Kubo, Hajime; Barbe, Mary; Houser, Steven R

2015-10-01

Cardiac- (CSC) and mesenchymal-derived (MSC) CD117+ isolated stem cells improve cardiac function after injury. However, no study has compared the therapeutic benefit of these cells when used autologously. MSCs and CSCs were isolated on day 0. Cardiomyopathy was induced (day 28) by infusion of L-isoproterenol (1,100 ug/kg/hour) from Alzet minipumps for 10 days. Bromodeoxyuridine (BrdU) was infused via minipumps (50 mg/mL) to identify proliferative cells during the injury phase. Following injury (day 38), autologous CSC (n = 7) and MSC (n = 4) were delivered by intracoronary injection. These animals were compared to those receiving sham injections by echocardiography, invasive hemodynamics, and immunohistochemistry. Fractional shortening improved with CSC (26.9 ± 1.1% vs. 16.1 ± 0.2%, p = 0.01) and MSC (25.1 ± 0.2% vs. 12.1 ± 0.5%, p = 0.01) as compared to shams. MSC were superior to CSC in improving left ventricle end-diastolic (LVED) volume (37.7 ± 3.1% vs. 19.9 ± 9.4%, p = 0.03) and ejection fraction (27.7 ± 0.1% vs. 19.9 ± 0.4%, p = 0.02). LVED pressure was less in MSC (6.3 ± 1.3 mmHg) as compared to CSC (9.3 ± 0.7 mmHg) and sham (13.3 ± 0.7); p = 0.01. LV BrdU+ myocytes were higher in MSC (0.17 ± 0.03%) than CSC (0.09 ± 0.01%) and sham (0.06 ± 01%); p < 0.001. Both CD117+ isolated CSC and MSC therapy improve cardiac function and attenuate pathological remodeling. However, MSC appear to confer additional benefit. © 2015 Wiley Periodicals, Inc.

Long-term follow up of high-dose chemotherapy with autologous stem cell rescue in adults with Ewing tumor.

PubMed

Laurence, Valérie; Pierga, Jean-Yves; Barthier, Sophie; Babinet, Antoine; Alapetite, Claire; Palangié, Thao; de Pinieux, Gonzagues; Anract, Philippe; Pouillart, Pierre

2005-06-01

Ewing tumors remain of poor prognosis, with 5-year overall survival of 55% to 65% in localized patients and not exceeding 25% in primarily metastatic disease. Several reports, mainly in children, have reported that some patients with poor-risk Ewing tumors may benefit from high-dose chemotherapy (HDCT) with autologous stem cell rescue. This retrospective study analyzed 46 patients treated in our institution between 1987 and 2000 for localized or primary metastatic Ewing tumors by HDCT followed by stem cell rescue. Median follow up was 7.1 years. Median age was 21 years (range, 15-46 years). Twenty-two percent of patients had metastases at diagnosis. The tumor site was axial in 56% of patients. Median tumor size was 9.5 cm. The treatment regimen consisted of induction chemotherapy, local treatment, maintenance chemotherapy, and consolidation HDCT based on alkylating agents. No toxic death was observed in the intensive therapy phase. Five-year overall survival and progression-free survival were 63 +/- 7.7% and 47 +/- 7.6%, respectively. Pejorative prognostic factors in this population were metastases at diagnosis (5-year overall survival 34% vs.71%, P = 0.017) and poor pathologic response (5-year overall survival 44% vs.77%, P = 0.03). This retrospective study shows a high long-term survival rate with high-dose chemotherapy in adults.

Concise Review: Adult Mesenchymal Stem Cells, Adult Neural Crest Stem Cells, and Therapy of Neurological Pathologies: A State of Play

PubMed Central

Neirinckx, Virginie; Coste, Cécile; Rogister, Bernard

2013-01-01

Adult stem cells are endowed with in vitro multilineage differentiation abilities and constitute an attractive autologous source of material for cell therapy in neurological disorders. With regard to lately published results, the ability of adult mesenchymal stem cells (MSCs) and neural crest stem cells (NCSCs) to integrate and differentiate into neurons once inside the central nervous system (CNS) is currently questioned. For this review, we collected exhaustive data on MSC/NCSC neural differentiation in vitro. We then analyzed preclinical cell therapy experiments in different models for neurological diseases and concluded that neural differentiation is probably not the leading property of adult MSCs and NCSCs concerning neurological pathology management. A fine analysis of the molecules that are secreted by MSCs and NCSCs would definitely be of significant interest regarding their important contribution to the clinical and pathological recovery after CNS lesions. PMID:23486833

Stem Cell Genetic Therapy for Fanconi Anemia - A New Hope.

PubMed

Hanenberg, Helmut; Roellecke, Katharina; Wiek, Constanze

2017-01-01

Fanconi anemia (FA) is a rare inherited DNA disorder clinically characterized by congenital malformations, progressive bone marrow failure, and cancer susceptibility. Due to a strong survival advantage of spontaneously corrected 'normal' hematopoietic stem cells (HSCs) in a few patients, FA is considered a model disorder for genetic correction of autologous stem cells, where genetically corrected stem cells and their progeny have a strong in vivo selective advantage, ultimately leading to normal hematopoiesis. Despite these apparently ideal circumstances, three HSC gene therapy trials with gammaretroviral vectors (stage I) designed to cure the hematological manifestation of FA completely failed to provide long-term clinical benefits for patients, predominantly due to the combination of insufficient gene transfer technologies and incompletely understood FA HSC pathobiology. Currently, FA gene therapy is in stage II where, based on an improved understanding of the cellular defects in FA HSCs, consequently adapted transduction protocols are being used in two phase I/II trials for in vitro genetic correction of FANCA-deficient hematopoietic stem cells. These results are eagerly awaited. Independent from the outcome of these studies, technologies are already available that seem highly attractive for testing in FA. In stage III, this would ultimately include targeted in vivo correction of autologous HSCs by overexpression of nonintegrating lentiviral vectors with scaffold/matrix attachment region elements using specific envelopes as pseudotypes. Although currently still challenging, in a few years in vivo genome editing approaches will be readily available in stage IV, in which the delivery of the editing machinery/ complex is targeted to the autologous FA HSCs by the nonintegrating lentiviral vectors established in stage III. Even low levels of corrected stem cells will then quickly repopulate the entire hematopoiesis of the patient. We therefore are sanguine that in

Stem Cells as a Tool for Breast Imaging

PubMed Central

Padín-Iruegas, Maria Elena; López López, Rafael

2012-01-01

Stem cells are a scientific field of interest due to their therapeutic potential. There are different groups, depending on the differentiation state. We can find lonely stem cells, but generally they distribute in niches. Stem cells don't survive forever. They are affected for senescence. Cancer stem cells are best defined functionally, as a subpopulation of tumor cells that can enrich for tumorigenic property and can regenerate heterogeneity of the original tumor. Circulating tumor cells are cells that have detached from a primary tumor and circulate in the bloodstream. They may constitute seeds for subsequent growth of additional tumors (metastasis) in different tissues. Advances in molecular imaging have allowed a deeper understanding of the in vivo behavior of stem cells and have proven to be indispensable in preclinical and clinical studies. One of the first imaging modalities for monitoring pluripotent stem cells in vivo, magnetic resonance imaging (MRI) offers high spatial and temporal resolution to obtain detailed morphological and functional information. Advantages of radioscintigraphic techniques include their picomolar sensitivity, good tissue penetration, and translation to clinical applications. Radionuclide imaging is the sole direct labeling technique used thus far in human studies, involving both autologous bone marrow derived and peripheral stem cells. PMID:22848220

Hurdles to clinical translation of human induced pluripotent stem cells

PubMed Central

Neofytou, Evgenios; O’Brien, Connor Galen; Couture, Larry A.; Wu, Joseph C.

2015-01-01

Human pluripotent stem cells are known to have the capacity to renew indefinitely, being intrinsically able to differentiate into many different cell types. These characteristics have generated tremendous enthusiasm about the potential applications of these cells in regenerative medicine. However, major challenges remain with the development and testing of novel experimental stem cell therapeutics in the field. In this Review, we focus on the nature of the preclinical challenges and discuss potential solutions that could help overcome them. Furthermore, we discuss the use of allogeneic versus autologous stem cell products, including a review of their respective advantages and disadvantages, major clinical requirements, quality standards, time lines, and costs of clinical grade development. PMID:26132109

Hurdles to clinical translation of human induced pluripotent stem cells.

PubMed

Neofytou, Evgenios; O'Brien, Connor Galen; Couture, Larry A; Wu, Joseph C

2015-07-01

Human pluripotent stem cells are known to have the capacity to renew indefinitely, being intrinsically able to differentiate into many different cell types. These characteristics have generated tremendous enthusiasm about the potential applications of these cells in regenerative medicine. However, major challenges remain with the development and testing of novel experimental stem cell therapeutics in the field. In this Review, we focus on the nature of the preclinical challenges and discuss potential solutions that could help overcome them. Furthermore, we discuss the use of allogeneic versus autologous stem cell products, including a review of their respective advantages and disadvantages, major clinical requirements, quality standards, time lines, and costs of clinical grade development.

Stem Cell Therapy to Treat Diabetes Mellitus

PubMed Central

Liew, Chee Gee; Andrews, Peter W.

2008-01-01

Transplantation of pancreatic islets offers a direct treatment for type 1 diabetes and in some cases, insulin-dependent type 2 diabetes. However, its widespread use is hampered by a shortage of donor organs. Many extant studies have focused on deriving β-cell progenitors from pancreas and pluripotent stem cells. Efforts to generate β-cells in vitro will help elucidate the mechanisms of β-cell formation and thus provide a versatile in vivo system to evaluate the therapeutic potential of these cells to treat diabetes. Various successful experiments using β-cells in animal models have generated extensive interest in using human embryonic stem cells to restore normoglycemia in diabetic patients. While new techniques are continually unveiled, the success of β-cell generation rests upon successful manipulation of culture conditions and the induction of key regulatory genes implicated in pancreas development. In this review, we compare successfully conducted protocols, highlight essential steps and identify some of the remarkable shortfalls common to these methods. In addition, we discuss recent advancements in the derivation of patient-specific pluripotent stem cells that may facilitate the use of autologous β-cells in stem cell therapy. PMID:19290381

The emergence and popularisation of autologous somatic cellular therapies in Australia: therapeutic innovation or regulatory failure?

PubMed

McLean, Alison K; Stewart, Cameron; Kerridge, Ian

2014-09-01

Private stem cell clinics throughout Australia are providing autologous stem cell therapies for a range of chronic and debilitating illnesses despite the lack of published literature to support the clinical application of these therapies. The Therapeutic Goods Administration has excluded autologous stem cell therapies from its regulatory domain leaving such therapies to be regulated by the same mechanisms that regulate research, such as the National Health and Medical Research Council Research Ethics Guidelines, and clinical practice, such as the Australian Health Practitioner Regulation Agency. However, the provision of these stem cell therapies does not follow the established pathways for legitimate medical advance--therapeutic innovation or research. The current regulatory framework is failing to achieve its aims of protecting vulnerable patients and ensuring the proper conduct of medical practitioners in the private stem cell industry.

Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via PD-L1

PubMed Central

Fiorina, Paolo; Jurewicz, Mollie; Vergani, Andrea; Petrelli, Alessandra; Carvello, Michele; D’Addio, Francesca; Godwin, Jonathan G.; Law, Kenneth; Wu, Erxi; Tian, Ze; Thoma, Gebhard; Kovarik, Jiri; La Rosa, Stefano; Capella, Carlo; Rodig, Scott; Zerwes, Hans-Guenter; Sayegh, Mohamed H.; Abdi, Reza

2012-01-01

Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on HSCs and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of hematopoietic stem cells (HSCs) to the periphery. Due to their profound immunomodulatory effects, HSCs have emerged as a promising therapeutic strategy for autoimmune disorders. We sought to investigate the immunomodulatory role of mobilized autologous HSCs, via target of the CXCR4-CXL12 axis, to promote engraftment of islet cell transplantation. Islets from BALB/c mice were transplanted beneath the kidney capsule of hyperglycemic C57BL/6 mice, and treatment of recipients with CXCR4 antagonist resulted in mobilization of HSCs and in prolongation of islet graft survival. Addition of Rapamycin to anti-CXCR4 therapy further promoted HSC mobilization and islet allograft survival, inducing a robust and transferable host hyporesponsiveness, while administration of an ACK2 (anti-CD117) mAb halted CXCR4 antagonist-mediated HSC release and restored allograft rejection. Mobilized HSCs were shown to express high levels of the negative co-stimulatory molecule PD-L1, and HSCs extracted from WT mice, but not from PD-L1 KO, suppressed the in vitro alloimmune response. Moreover, HSC mobilization in PD-L1 KO mice failed to prolong islet allograft survival. Targeting the CXCR4-CXCL12 axis thus mobilizes autologous HSCs and promotes long-term survival of islet allografts via a PD-L1-mediated mechanism. PMID:21131428

Selection and expansion of peripheral blood CD34+ cells in autologous stem cell transplantation for breast cancer.

PubMed

Williams, S F; Lee, W J; Bender, J G; Zimmerman, T; Swinney, P; Blake, M; Carreon, J; Schilling, M; Smith, S; Williams, D E; Oldham, F; Van Epps, D

1996-03-01

Cytopenia after high-dose chemotherapy and autologous stem cell reinfusion is a major cause of morbidity. Ex vivo cultured expansion and differentiation of CD34+ peripheral blood progenitor cells (PBPC) to neutrophil precursors may shorten the neutropenic period further. We explored the use of these ex vivo cultured PBPCs in nine patients with metastatic breast cancer. All underwent PBPC mobilization with cyclophosphamide, VP-16, and G-CSF. Subsequently, they underwent four to five apheresis procedures. One apheresis product from each patient was prepared using the Isolex 300 Magnetic Cell Separation System (Baxter Immunotherapy, Irvine, CA) to obtain CD34+ cells. These cells were then cultured in gas permeable bags containing serum-free X-VIVO 10 (BioWhittaker, Walkersville, MD) medium supplemented with 1% human serum albumin and 100 ng/mL PIXY321. At day 12 of culture the mean fold expansion was 26x with a range of 6 to 64x. One patient's cells did not expand because of a technical difficulty. The final cell product contained an average of 29.3% CD15+ neutrophil precursors with a range of 18.5% to 48.1%. The patients underwent high-dose chemotherapy with cyclophosphamide, carboplatin, and thiotepa. On day 0, the cryopreserved PBPCs were reinfused and on day +1 the 12-day cultured cells were washed, resuspended, and reinfused into eight of nine patients. One patient was not infused with cultured cells. The mean number of cultured cells reinfused was 44.6 x 10(6) cells/kg with a range of 0.8 to 156.6 x 10(6) cells/kg. No toxicity was observed after reinfusion. The eight patients have recovered absolute neutrophil counts > 500/microL on a median of 8 days (range 8 to 10 days); the median platelet transfusion independence occurred on day 10 (range 8 to 12 days) and platelet counts > 50,000/microL were achieved by day 12 (range 9 to 14) for the seven patients whose platelet counts could be determined. Expanded CD34+ selected PBPC can be obtained and safely reinfused

Application of Stem Cell Technology in Dental Regenerative Medicine.

PubMed

Feng, Ruoxue; Lengner, Chistopher

2013-07-01

In this review, we summarize the current literature regarding the isolation and characterization of dental tissue-derived stem cells and address the potential of these cell types for use in regenerative cell transplantation therapy. Looking forward, platforms for the delivery of stem cells via scaffolds and the use of growth factors and cytokines for enhancing dental stem cell self-renewal and differentiation are discussed. We aim to understand the developmental origins of dental tissues in an effort to elucidate the molecular pathways governing the genesis of somatic dental stem cells. The advantages and disadvantages of several dental stem cells are discussed, including the developmental stage and specific locations from which these cells can be purified. In particular, stem cells from human exfoliated deciduous teeth may act as a very practical and easily accessibly reservoir for autologous stem cells and hold the most value in stem cell therapy. Dental pulp stem cells and periodontal ligament stem cells should also be considered for their triple lineage differentiation ability and relative ease of isolation. Further, we address the potentials and limitations of induced pluripotent stem cells as a cell source in dental regenerative. From an economical and a practical standpoint, dental stem cell therapy would be most easily applied in the prevention of periodontal ligament detachment and bone atrophy, as well as in the regeneration of dentin-pulp complex. In contrast, cell-based tooth replacement due to decay or other oral pathology seems, at the current time, an untenable approach.

Advising patients seeking stem cell interventions for multiple sclerosis.

PubMed

von Wunster, Beatrice; Bailey, Steven; Wilkins, Alastair; Marks, David I; Scolding, Neil J; Rice, Claire M

2018-05-30

Given the intuitive potential of stem cell therapy and limitations of current treatment options for progressive multiple sclerosis (MS), it is not surprising that patients consider undertaking significant clinical and financial risks to access stem cell transplantation. However, while increasing evidence supports autologous haematopoietic stem cell transplantation (AHSCT) in aggressive relapsing-remitting MS, interventions employing haematopoietic or other stem cells should otherwise be considered experimental and recommended only in the context of a properly regulated clinical study. Understandably, most neurologists are unfamiliar with AHSCT procedures and the specific requirements for quality assurance and safety standards, as well as post-procedure precautions and follow-up. Consequently they may feel ill-equipped to advise patients. Here, we highlight important points for discussion in consultations with patients considering stem cell 'tourism' for MS. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Platelet-Rich Blood Derivatives for Stem Cell-Based Tissue Engineering and Regeneration

PubMed Central

Kaushik, Gaurav; Leijten, Jeroen; Khademhosseini, Ali

2016-01-01

Platelet rich blood derivatives have been widely used in different fields of medicine and stem cell based tissue engineering. They represent natural cocktails of autologous growth factor, which could provide an alternative for recombinant protein based approaches. Platelet rich blood derivatives, such as platelet rich plasma, have consistently shown to potentiate stem cell proliferation, migration, and differentiation. Here, we review the spectrum of platelet rich blood derivatives, discuss their current applications in tissue engineering and regenerative medicine, reflect on their effect on stem cells, and highlight current translational challenges. PMID:27047733

Injectable gellan gum hydrogels with autologous cells for the treatment of rabbit articular cartilage defects.

PubMed

Oliveira, João T; Gardel, Leandro S; Rada, Tommaso; Martins, Luís; Gomes, Manuela E; Reis, Rui L

2010-09-01

In this work, the ability of gellan gum hydrogels coupled with autologous cells to regenerate rabbit full-thickness articular cartilage defects was tested. Five study groups were defined: (a) gellan gum with encapsulated chondrogenic predifferentiated rabbit adipose stem cells (ASC + GF); (b) gellan gum with encapsulated nonchondrogenic predifferentiated rabbit adipose stem cells (ASC); (c) gellan gum with encapsulated rabbit articular chondrocytes (AC) (standard control); (d) gellan gum alone (control); (e) empty defect (control). Full-thickness articular cartilage defects were created and the gellan gum constructs were injected and left for 8 weeks. The macroscopic aspect of the explants showed a progressive increase of similarity with the lateral native cartilage, stable integration at the defect site, more pronouncedly in the cell-loaded constructs. Tissue scoring showed that ASC + GF exhibited the best results regarding tissue quality progression. Alcian blue retrieved similar results with a better outcome for the cell-loaded constructs. Regarding real-time PCR analyses, ASC + GF had the best progression with an upregulation of collagen type II and aggrecan, and a downregulation of collagen type I. Gellan gum hydrogels combined with autologous cells constitute a promising approach for the treatment of articular cartilage defects, and adipose derived cells may constitute a valid alternative to currently used articular chondrocytes. (c) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Differentiation of Human Dental Pulp Stem Cells into Dopaminergic Neuron-like Cells in Vitro.

PubMed

Chun, So Young; Soker, Shay; Jang, Yu-Jin; Kwon, Tae Gyun; Yoo, Eun Sang

2016-02-01

We investigated the potential of human dental pulp stem cells (hDPSCs) to differentiate into dopaminergic neurons in vitro as an autologous stem cell source for Parkinson's disease treatment. The hDPSCs were expanded in knockout-embryonic stem cell (KO-ES) medium containing leukemia inhibitory factor (LIF) on gelatin-coated plates for 3-4 days. Then, the medium was replaced with KO-ES medium without LIF to allow the formation of the neurosphere for 4 days. The neurosphere was transferred into ITS medium, containing ITS (human insulin-transferrin-sodium) and fibronectin, to select for Nestin-positive cells for 6-8 days. The cells were then cultured in N-2 medium containing basic fibroblast growth factor (FGF), FGF-8b, sonic hedgehog-N, and ascorbic acid on poly-l-ornithine/fibronectin-coated plates to expand the Nestin-positive cells for up to 2 weeks. Finally, the cells were transferred into N-2/ascorbic acid medium to allow for their differentiation into dopaminergic neurons for 10-15 days. The differentiation stages were confirmed by morphological, immunocytochemical, flow cytometric, real-time PCR, and ELISA analyses. The expressions of mesenchymal stem cell markers were observed at the early stages. The expressions of early neuronal markers were maintained throughout the differentiation stages. The mature neural markers showed increased expression from stage 3 onwards. The percentage of cells positive for tyrosine hydroxylase was 14.49%, and the amount was 0.526 ± 0.033 ng/mL at the last stage. hDPSCs can differentiate into dopaminergic neural cells under experimental cell differentiation conditions, showing potential as an autologous cell source for the treatment of Parkinson's disease.

Generation of male differentiated germ cells from various types of stem cells.

PubMed

Hou, Jingmei; Yang, Shi; Yang, Hao; Liu, Yang; Liu, Yun; Hai, Yanan; Chen, Zheng; Guo, Ying; Gong, Yuehua; Gao, Wei-Qiang; Li, Zheng; He, Zuping

2014-06-01

Infertility is a major and largely incurable disease caused by disruption and loss of germ cells. It affects 10-15% of couples, and male factor accounts for half of the cases. To obtain human male germ cells 'especially functional spermatids' is essential for treating male infertility. Currently, much progress has been made on generating male germ cells, including spermatogonia, spermatocytes, and spermatids, from various types of stem cells. These germ cells can also be used in investigation of the pathology of male infertility. In this review, we focused on advances on obtaining male differentiated germ cells from different kinds of stem cells, with an emphasis on the embryonic stem (ES) cells, the induced pluripotent stem (iPS) cells, and spermatogonial stem cells (SSCs). We illustrated the generation of male differentiated germ cells from ES cells, iPS cells and SSCs, and we summarized the phenotype for these stem cells, spermatocytes and spermatids. Moreover, we address the differentiation potentials of ES cells, iPS cells and SSCs. We also highlight the advantages, disadvantages and concerns on derivation of the differentiated male germ cells from several types of stem cells. The ability of generating mature and functional male gametes from stem cells could enable us to understand the precise etiology of male infertility and offer an invaluable source of autologous male gametes for treating male infertility of azoospermia patients. © 2014 Society for Reproduction and Fertility.

Regeneration of articular cartilage by adipose tissue derived mesenchymal stem cells: perspectives from stem cell biology and molecular medicine.

PubMed

Wu, Ling; Cai, Xiaoxiao; Zhang, Shu; Karperien, Marcel; Lin, Yunfeng

2013-05-01

Adipose-derived stem cells (ASCs) have been discovered for more than a decade. Due to the large numbers of cells that can be harvested with relatively little donor morbidity, they are considered to be an attractive alternative to bone marrow derived mesenchymal stem cells. Consequently, isolation and differentiation of ASCs draw great attention in the research of tissue engineering and regenerative medicine. Cartilage defects cause big therapeutic problems because of their low self-repair capacity. Application of ASCs in cartilage regeneration gives hope to treat cartilage defects with autologous stem cells. In recent years, a lot of studies have been performed to test the possibility of using ASCs to re-construct damaged cartilage tissue. In this article, we have reviewed the most up-to-date articles utilizing ASCs for cartilage regeneration in basic and translational research. Our topic covers differentiation of adipose tissue derived mesenchymal stem cells into chondrocytes, increased cartilage formation by co-culture of ASCs with chondrocytes and enhancing chondrogenic differentiation of ASCs by gene manipulation. Copyright © 2012 Wiley Periodicals, Inc.

A Role for SHIP in Stem Cell Biology and Transplantation

PubMed Central

Kerr, William G.

2008-01-01

Inositol phospholipid signaling pathways have begun to emerge as important players in stem cell biology and bone marrow transplantation [1–4]. The SH2-containing Inositol Phosphatase (SHIP) is among the enzymes that can modify endogenous mammalian phosphoinositides. SHIP encodes an isoform specific to pluripotent stem (PS) cells [5,6] plays a role in hematopoietic stem (HS) cell biology [7,8] and allogeneic bone marrow (BM) transplantation [1,2,9,10]. Here I discuss our current understanding of the cell and molecular pathways that SHIP regulates that influence PS/HS cell biology and BM transplantation. Genetic models of SHIP-deficiency indicate this enzyme is a potential molecular target to enhance both autologous and allogeneic BM transplantation. Thus, strategies to reversibly target SHIP expression and their potential application to stem cell therapies and allogeneic BMT are also discussed. PMID:18473876

21st Nantes Actualités Transplantation: "When Stem Cells Meet Immunology".

PubMed

Anegon, Ignacio; Nguyen, Tuan Huy

2017-01-01

"When Stem Cells Meet Immunology" has been the topic of the 21st annual "Nantes Actualités en Transplantation" meeting (June 9-10, 2016, Nantes, France). This meeting brought together pioneers and leading experts in the fields of stem cells, biomaterials and immunoregulation. Presentations covered multipotent (mesenchymal and hematopoietic) and pluripotent stem cells (embryonic and induced) for regenerative medicine of incurable diseases, immunotherapy and blood transfusions. An additional focus had been immune rejections and responses of allogeneic or autologous stem cells. Conversely, stem cells are also able to directly modulate the immune response through the production of immunoregulatory molecules. Moreover, stem cells may also provide an unlimited source of immune cells (DCs, NK cells, B cells, and T cells) that can operate as "super" immune cells, for example, through genetic engineering with chimeric antigen receptors.This meeting report puts presentations into an overall context highlighting new potential biomarkers for potency prediction of mesenchymal stem cell-derived and pluripotent stem cell-derived multicellular organoids. Finally, we propose future directions arising from the flourishing encounter of stem cell and immune biology.

Pluripotent Stem Cells in Research and Treatment of Hemoglobinopathies

PubMed Central

Arora, Natasha; Daley, George Q.

2012-01-01

Pluripotent stem cells (PSCs) hold great promise for research and treatment of hemoglobinopathies. In principle, patient-specific induced pluripotent stem cells could be derived from a blood sample, genetically corrected to repair the disease-causing mutation, differentiated into hematopoietic stem cells (HSCs), and returned to the patient to provide a cure through autologous gene and cell therapy. However, there are many challenges at each step of this complex treatment paradigm. Gene repair is currently inefficient in stem cells, but use of zinc finger nucleases and transcription activator-like effector nucleases appear to be a major advance. To date, no successful protocol exists for differentiating PSCs into definitive HSCs. PSCs can be directly differentiated into primitive red blood cells, but not yet in sufficient numbers to enable treating patients, and the cost of clinical scale differentiation is prohibitively expensive with current differentiation methods and efficiencies. Here we review the progress, promise, and remaining hurdles in realizing the potential of PSCs for cell therapy. PMID:22474618

Technologies enabling autologous neural stem cell-based therapies for neurodegenerative disease and injury

NASA Astrophysics Data System (ADS)

Bakhru, Sasha H.

The intrinsic abilities of mammalian neural stem cells (NSCs) to self-renew, migrate over large distances, and give rise to all primary neural cell types of the brain offer unprecedented opportunity for cell-based treatment of neurodegenerative diseases and injuries. This thesis discusses development of technologies in support of autologous NSC-based therapies, encompassing harvest of brain tissue biopsies from living human patients; isolation of NSCs from harvested tissue; efficient culture and expansion of NSCs in 3D polymeric microcapsule culture systems; optimization of microcapsules as carriers for efficient in vivo delivery of NSCs; genetic engineering of NSCs for drug-induced, enzymatic release of transplanted NSCs from microcapsules; genetic engineering for drug-induced differentiation of NSCs into specific therapeutic cell types; and synthesis of chitosan/iron-oxide nanoparticles for labeling of NSCs and in vivo tracking by cellular MRI. Sub-millimeter scale tissue samples were harvested endoscopically from subventricular zone regions of living patient brains, secondary to neurosurgical procedures including endoscopic third ventriculostomy and ventriculoperitoneal shunt placement. On average, 12,000 +/- 3,000 NSCs were isolated per mm 3 of subventricular zone tissue, successfully demonstrated in 26 of 28 patients, ranging in age from one month to 68 years. In order to achieve efficient expansion of isolated NSCs to clinically relevant numbers (e.g. hundreds of thousands of cells in Parkinson's disease and tens of millions of cells in multiple sclerosis), an extracellular matrix-inspired, microcapsule-based culture platform was developed. Initial culture experiments with murine NSCs yielded unprecedented expansion folds of 30x in 5 days, from initially minute NSC populations (154 +/- 15 NSCs per 450 mum diameter capsule). Within 7 days, NSCs expanded as almost perfectly homogenous populations, with 94.9% +/- 4.1% of cultured cells staining positive for

Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial.

PubMed

van Laar, Jacob M; Farge, Dominique; Sont, Jacob K; Naraghi, Kamran; Marjanovic, Zora; Larghero, Jérôme; Schuerwegh, Annemie J; Marijt, Erik W A; Vonk, Madelon C; Schattenberg, Anton V; Matucci-Cerinic, Marco; Voskuyl, Alexandre E; van de Loosdrecht, Arjan A; Daikeler, Thomas; Kötter, Ina; Schmalzing, Marc; Martin, Thierry; Lioure, Bruno; Weiner, Stefan M; Kreuter, Alexander; Deligny, Christophe; Durand, Jean-Marc; Emery, Paul; Machold, Klaus P; Sarrot-Reynauld, Francoise; Warnatz, Klaus; Adoue, Daniel F P; Constans, Joël; Tony, Hans-Peter; Del Papa, Nicoletta; Fassas, Athanasios; Himsel, Andrea; Launay, David; Lo Monaco, Andrea; Philippe, Pierre; Quéré, Isabelle; Rich, Éric; Westhovens, Rene; Griffiths, Bridget; Saccardi, Riccardo; van den Hoogen, Frank H; Fibbe, Willem E; Socié, Gérard; Gratwohl, Alois; Tyndall, Alan

2014-06-25

High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. HSCT vs intravenous pulse cyclophosphamide. The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year

Comparison of clinical outcome after autologous stem cell transplantation between patients with peripheral T-cell lymphomas and diffuse large B-cell lymphoma.

PubMed

Sohn, B S; Park, I; Kim, E K; Yoon, D H; Lee, S S; Kang, B W; Jang, G; Choi, Y H; Kim, C; Lee, D H; Kim, S; Huh, J; Suh, C

2009-09-01

Although patients with T-cell phenotype lymphomas are generally accepted to have worse prognosis than B-cell phenotype lymphomas, the studies comparing outcomes after autologous stem cell transplantation (ASCT) between peripheral T-cell lymphomas (PTCLs) and with diffuse large B-cell lymphoma (DLBCL) are few. In this study, we compared outcomes after ASCT between 23 patients with PTCLs and 54 patients with DLBCL. Univariate analysis showed that the timing of ASCT, complete response (CR) at ASCT, favorable lactate dehydrogenase/performance/stage, low/low-intermediate (L-LI) International Prognostic Index (IPI) and L-LI age-adjusted IPI (aaIPI) at ASCT were significant predictors of both OS and EFS. Multivariate analysis showed that CR and L-LI aaIPI at ASCT were favorable for both OS (hazard ratio (HR), 0.34; 95% CI, 0.14-0.81; P=0.016 and HR, 0.27; 95% CI, 0.12-0.57; P=0.001) and EFS (HR, 0.38; 95% CI, 0.17-0.85; P=0.020 and HR, 0.36; 95% CI, 0.17-0.77; P=0.008). B-cell or T-cell phenotype, however, had no impact on OS (HR, 0.56; 95% CI, 0.27-1.18; P=0.126) or EFS (HR, 0.62; 95% CI, 0.30-1.30; P=0.206). In conclusion, when compared to patients with DLBCL, patients with PTCLs did not have inferior outcomes after ASCT. T-cell phenotype itself may not have an effect on outcomes of PTCL patients who underwent ASCT.

[Autologous stem cell transplantation in the treatment of multiple myeloma--single center experience].

PubMed

Marjanović, Slobodan; Stamatović, Dragana; Tukić, Ljiljana; Tarabar, Olivera; Elez, Marija; Madjaru, Lavinika; Balint, Bela; Tatomirović, Zeljka; Kuljić-Kapulica, Nada; Andjelković, Nebojsa

2011-05-01

In comparison to standard therapy autologous stem cell transplant (ASCT) with high doses mel-phalane has improved treatment of multiple myeloma (MM) patients. The aim of this study was to evaluate the results of treatment of MM patients in our center with ASCTconditioning with melphalane or combining busulphane, cyclophosphamide and melphalane. We performed 62 ASCT procedures in 47 patients from 1998 till 2008. Single ASCT were performed in 32 patients (68%), after 3-6 cycles of (26% patients. Median engraftment was on 12th day. In a 50-month follow-up period 64% patients were alive. The overall response rate (ORR), wich was reached in 38 (80%) patients, was better in the group of patients treated in the early phase of MM. Totally 25 (53%) patients were without progression in a 25-month follow-up period. Twenty patients met criteria for CR + VGPR (very good partial remission), that was 5 patients more than in the period before ASCT. Fourteen (30%) patients died and median time till death was 17 months. The ASCT perfomed in early phase of MM after V A D induction had a significant influence onthe treatment of MM patients. Reaching CR + VGPR before and after the ASCT is predictive factor for overall survival (OS) or prolongation of period till recidive appears, progression, therapy withdrowal or death.

Autologous bone marrow purging with LAK cells.

PubMed

Giuliodori, L; Moretti, L; Stramigioli, S; Luchetti, F; Annibali, G M; Baldi, A

1993-12-01

In this study we will demonstrate that LAK cells, in vitro, can lyse hematologic neoplastic cells with a minor toxicity of the staminal autologous marrow cells. In fact, after bone marrow and LAK co-culture at a ratio of 1/1 for 8 hours, the inhibition on the GEMM colonies resulted to be 20% less compared to the untreated marrow. These data made LAK an inviting agent for marrow purging in autologous bone marrow transplantation.

Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis.

PubMed

Casanova, Bonaventura; Jarque, Isidro; Gascón, Francisco; Hernández-Boluda, Juan Carlos; Pérez-Miralles, Francisco; de la Rubia, Javier; Alcalá, Carmen; Sanz, Jaime; Mallada, Javier; Cervelló, Angeles; Navarré, Arantxa; Carcelén-Gadea, María; Boscá, Isabel; Gil-Perotin, Sara; Solano, Carlos; Sanz, Miguel Angel; Coret, Francisco

2017-07-01

The main objective of our work is to describe the long-term results of myeloablative autologous hematopoietic stem cell transplant (AHSCT) in multiple sclerosis patients. Patients that failed to conventional therapies for multiple sclerosis (MS) underwent an approved protocol for AHSCT, which consisted of peripheral blood stem cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), followed by a conditioning regimen of BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit Thymoglobulin. Thirty-eight MS patients have been transplanted since 1999. Thirty-one patients have been followed for more than 2 years (mean 8.4 years). There were 22 relapsing-remitting multiple sclerosis (RRMS) patients and 9 secondary progressive multiple sclerosis (SPMS) patients. No death related to AHSCT. A total of 10 patients (32.3%) had at least one relapse during post-AHSCT evolution, 6 patients in the RRMS group (27.2%) and 4 in the SPMS group (44.4%). After AHSCT, 7 patients (22.6%) experienced progression of disability, all within SP form. By contrast, no patients with RRMS experienced worsening of disability after a median follow-up of 5.4 years, 60% of them showed a sustained reduction in disability (SRD), defined as the improvement of 1.0 point in the expanded disability status scale (EDSS) sustains for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical variable that predicted a poor response to AHSCT was a high EDSS in the year before transplant. AHSCT using the BEAM-ATG scheme is safe and efficacious to control the aggressive forms of RRMS.

Combination therapy with carfilzomib, lenalidomide and dexamethasone (KRd) results in an unprecedented purity of the stem cell graft in newly diagnosed patients with myeloma.

PubMed

Tageja, Nishant; Korde, Neha; Kazandjian, Dickran; Panch, Sandhya; Manasanch, Elisabet; Bhutani, Manisha; Kwok, Mary; Mailankody, Sham; Yuan, Constance; Stetler-Stevenson, Maryalice; Leitman, Susan F; Sportes, Claude; Landgren, Ola

2018-05-04

Still, many physicians give 4 cycles of combination therapy to multiple myeloma patients prior to collection of stem cells for autologous bone marrow transplant. This tradition originates from older doxorubicin-containing regiments which limited the number of cycles due to cumulative cardiotoxicity. Using older regiments, most patients had residual myeloma cells in their autologous stem-cell grafts during collection. Emerging data show that newly diagnosed multiple myeloma patients treated with modern carfilzomib/lenalidomide/dexamethasone (KRd) therapy, on average, take 6 cycles until reaching minimal residual disease (MRD) negativity. We assessed newly diagnosed patients treated with KRd focusing MRD status both in the individual patient's bone marrow, and the corresponding autologous hematopoietic progenitor cell grafts during collection. Per protocol, stem-cell collection was allowed after 4 to 8 cycles of KRd. We found similar stem-cell yield independent of the number of cycles of KRd. At stem-cell collection, 11/30 patients (36.6%) were MRD negative in their bone marrow; all 11 patients had MRD negative hematopoietic progenitor cell grafts. Furthermore, 18/19 patients who were MRD positive in their bone marrows also had MRD negative hematopoietic progenitor cell grafts. These observations support 6 cycles of KRd as an efficacious and safe induction strategy prior to stem-cell collection.

Assessing commercial opportunities for autologous and allogeneic cell-based products.

PubMed

Smith, Devyn M

2012-09-01

The two primary cell sources used to produce cell-based therapies are autologous (self-derived) and allogeneic (derived from a donor). This analysis attempts to compare and contrast the two approaches in order to understand whether there is an emerging preference in the market. While the current clinical trials underway are slightly biased to autologous approaches, it is clear that both cell-based approaches are being aggressively pursued. This analysis also breaks down the commercial advantages of each cell-based approach, comparing both cost of goods and the ideal indication type for each. While allogeneic therapies have considerable advantages over autologous therapies, they do have a distinct disadvantage regarding potential immunogenicity. The introduction of the hybrid autologous business model provides the ability for autologous-based therapies to mitigate some of the advantages that allogeneic cell-based therapies enjoy, including cost of goods. Finally, two case studies are presented that demonstrate that there is sufficient space for both autologous and allogeneic cell-based therapies within a single disease area.

Addition of doxycycline to ciprofloxacin for infection prophylaxis during autologous stem cell transplants for multiple myeloma.

PubMed

Sivik, J M; Davidson, J; Hale, C M; Drabick, J J; Talamo, G

2018-03-21

The most commonly used antibacterial prophylaxis during autologous stem cell transplants (ASCT) for multiple myeloma (MM) involves a fluoroquinolone, such as ciprofloxacin or levofloxacin. We assessed the impact of adding doxycycline to ciprofloxacin as routine antibacterial prophylaxis in these patients. We retrospectively reviewed electronic medical records and our ASCT database to analyze rates and types of bacterial infections in MM patients who underwent ASCT in our institution. Among 419 patients, 118 received ciprofloxacin alone (cipro group), and 301 ciprofloxacin and doxycycline (cipro-doxy group). Neutropenic fever (NF) developed in 63 (53%) and 108 (36%) patients of the cipro and cipro-doxy groups, respectively (p = 0.010). The number of documented bacteremic episodes was 13 (11%) and 14 (4.7%) in the two groups, respectively (p = 0.017). Antimicrobial resistance and Clostridium difficile infections were uncommon. Transplant-related mortality was 1% in both groups. The addition of doxycycline to standard prophylaxis with ciprofloxacin seems to reduce the number of NF episodes and documented bacterial infections in patients with MM undergoing ASCT, without increasing rate of serious complications.

Recovery of polyclonal immunoglobulins one year after autologous stem cell transplantation as a long-term predictor marker of progression and survival in multiple myeloma.

PubMed

González-Calle, Verónica; Cerdá, Seila; Labrador, Jorge; Sobejano, Eduardo; González-Mena, Beatriz; Aguilera, Carmen; Ocio, Enrique María; Vidriales, María Belén; Puig, Noemí; Gutiérrez, Norma Carmen; García-Sanz, Ramón; Alonso, José María; López, Rosa; Aguilar, Carlos; de Coca, Alfonso García; Hernández, Roberto; Hernández, José Mariano; Escalante, Fernando; Mateos, María-Victoria

2017-05-01

Immunoparesis or suppression of polyclonal immunoglobulins is a very common condition in newly diagnosed myeloma patients. However, the recovery of polyclonal immunoglobulins in the setting of immune reconstitution after autologous stem cell transplantation and its effect on outcome has not yet been explored. We conducted this study in a cohort of 295 patients who had undergone autologous transplantation. In order to explore the potential role of immunoglubulin recovery as a dynamic predictor of progression or survival after transplantation, conditional probabilities of progression-free survival and overall survival were estimated according to immunoglobulin recovery at different time points using a landmark approach. One year after transplant, when B-cell reconstitution is expected to be completed, among 169 patients alive and progression free, 88 patients (52%) showed immunoglobulin recovery and 81 (48%) did not. Interestingly, the group with immunoglobulin recovery had a significantly longer median progression-free survival than the group with persistent immunoparesis (median 60.4 vs. 27.9 months, respectively; Hazard Ratio: 0.45, 95%Confidence Interval: 0.31-0.66; P <0.001), and improved overall survival (11.3 vs. 7.3 years; Hazard Ratio: 0.45, 95%Confidence Interval: 0.27-0.74; P =0.002). Furthermore, the percentage of normal plasma cells detected by flow cytometry in the bone marrow assessed at day 100 after transplantation was associated with the immunoglobulin recovery at that time and may predict immunoglobulin recovery in the subsequent months: nine months and one year. In conclusion, the recovery of polyclonal immunoglobulins one year after autologous transplantation in myeloma patients is an independent long-term predictor marker for progression and survival. Copyright© Ferrata Storti Foundation.

High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Transplantation in Metastatic Breast Cancer: Overview of Six Randomized Trials

PubMed Central

Berry, Donald A.; Ueno, Naoto T.; Johnson, Marcella M.; Lei, Xiudong; Caputo, Jean; Smith, Dori A.; Yancey, Linda J.; Crump, Michael; Stadtmauer, Edward A.; Biron, Pierre; Crown, John P.; Schmid, Peter; Lotz, Jean-Pierre; Rosti, Giovanni; Bregni, Marco; Demirer, Taner

2011-01-01

Purpose High doses of effective chemotherapy are compelling if they can be delivered safely. Substantial interest in supporting high-dose chemotherapy with bone marrow or autologous hematopoietic stem-cell transplantation in the 1980s and 1990s led to the initiation of randomized trials to evaluate its effect in the treatment of metastatic breast cancer. Methods We identified six randomized trials in metastatic breast cancer that evaluated high doses of chemotherapy with transplant support versus a control regimen without stem-cell support. We assembled a single database containing individual patient information from these trials. The primary analysis of overall survival was a log-rank test comparing high dose versus control. We also used Cox proportional hazards regression, adjusting for known covariates. We addressed potential treatment differences within subsets of patients. Results The effect of high-dose chemotherapy on overall survival was not statistically different (median, 2.16 v 2.02 years; P = .08). A statistically significant advantage in progression-free survival (median, 0.91 v 0.69 years) did not translate into survival benefit. Subset analyses found little evidence that there are groups of patients who might benefit from high-dose chemotherapy with hematopoietic support. Conclusion Overall survival of patients with metastatic breast cancer in the six randomized trials was not significantly improved by high-dose chemotherapy; any benefit from high doses was small. No identifiable subset of patients seems to benefit from high-dose chemotherapy. PMID:21768454

Stem cell research in cell transplantation: sources, geopolitical influence, and transplantation.

PubMed

Eve, David J; Fillmore, Randolph W; Borlongan, Cesar V; Sanberg, Paul R

2010-01-01

If the rapidly progressing field of stem cell research reaches its full potential, successful treatments and enhanced understanding of many diseases are the likely results. However, the full potential of stem cell science will only be reached if all possible avenues can be explored and on a worldwide scale. Until 2009, the US had a highly restrictive policy on obtaining cells from human embryos and fetal tissue, a policy that pushed research toward the use of adult-derived cells. Currently, US policy is still in flux, and retrospective analysis does show the US lagging behind the rest of the world in the proportional increase in embryonic/fetal stem cell research. The majority of US studies being on either a limited number of cell lines, or on cells derived elsewhere (or funded by other sources than Federal) rather than on freshly isolated embryonic or fetal material. Neural, mesenchymal, and the mixed stem cell mononuclear fraction are the most commonly investigated types, which can generally be classified as adult-derived stem cells, although roughly half of the neural stem cells are fetal derived. Other types, such as embryonic and fat-derived stem cells, are increasing in their prominence, suggesting that new types of stem cells are still being pursued. Sixty percent of the reported stem cell studies involved transplantation, of which over three quarters were allogeneic transplants. A high proportion of the cardiovascular systems articles were on allogeneic transplants in a number of different species, including several autologous studies. A number of pharmaceutical grade stem cell products have also recently been tested and reported on. Stem cell research shows considerable promise for the treatment of a number of disorders, some of which have entered clinical trials; over the next few years it will be interesting to see how these treatments progress in the clinic.

Autologous Hematopoietic Stem Cells transplantation and genetic modification of CCR5 m303/m303 mutant patient for HIV/AIDS.

PubMed

Esmaeilzadeh, Abdolreza; Farshbaf, Alieh; Erfanmanesh, Maryam

2015-03-01

HIV and AIDS is one of the biggest challenges all over the world. There are an approximately 34 million people living with the virus, and a large number of them become infected each year. Although there are some antiviral drugs for HIV viral load reduction, they are not sufficient. There is no cure for AIDS. Nowadays natural resistance or immunity has absorbed attentions. Because in some HIV positive patients progression trend is slow or even they indicate resistance to AIDS. One of the most interesting approaches in this category is CCR5 gene. CCR5 is a main cc-chemokine co-receptor that facilitates HIV-1 entry to macrophage and CD4(+) T cells. To now, many polymorphisms have been known by CCR5 gene that produces a truncated protein with no function. So, HIV-1 could not entry to immune-cells and the body resistant to HIV/AIDS. Δ32/Δ32 and m303/m303 homozygotes are example of mutations that could create this resistance mechanism. There is a new treatment, such as Hematopoietic Stem Cell transplantation (HSCT) in Berlin and Boston patients for Δ32/Δ32 mutation. It could eliminate co-receptor antagonist and highly-active-anti retroviral therapy (HAART) drugs problems such as toxicity, low safety and side-effects. Now there, the aim of this hypothesis will be evaluation of a new mutation CCR5 m303/m303 as autologous HSCT. This novel hypothesis indicates that autologous HSCT for m303/m303 could be effective treatment for anyone HIV/AIDS affected patient worldwide. Copyright © 2015 Elsevier Ltd. All rights reserved.

Challenges and opportunities for stem cell therapy in patients with chronic kidney disease

PubMed Central

Hickson, LaTonya J.; Eirin, Alfonso; Lerman, Lilach O.

2016-01-01

Chronic kidney disease (CKD) is a global healthcare burden affecting billions of individuals worldwide. The kidney has limited regenerative capacity from chronic insults, and for the most common causes of CKD, no effective treatment exists to prevent progression to end-stage kidney failure. Therefore, novel interventions, such as regenerative cell-based therapies, need to be developed for CKD. Given the risk of allosensitization, autologous transplantation of cells to boost regenerative potential is preferred. Therefore, verification of cell function and vitality in CKD patients is imperative. Two cell types have been most commonly applied in regenerative medicine. Endothelial progenitor cells contribute to neovasculogenesis primarily through paracrine angiogenic activity and partly by differentiation into mature endothelial cells in situ. Mesenchymal stem cells also exert paracrine effects, including pro-angiogenic, anti-inflammatory, and anti-fibrotic activity. However, in CKD, multiple factors may contribute to reduced cell function, including older age, coexisting cardiovascular disease, diabetes, chronic inflammatory states, and uremia, which may limit the effectiveness of an autologous cell-based therapy approach. This review highlights current knowledge on stem and progenitor cell function and vitality, aspects of the uremic milieu that may serve as a barrier to therapy, and novel methods to improve stem cell function for potential transplantation. PMID:26924058

Long-term in-vivo tumorigenic assessment of human culture-expanded adipose stromal/stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

MacIsaac, Zoe Marie, E-mail: zmm4a@virgina.edu; Shang, Hulan, E-mail: shanghulan@gmail.com; Agrawal, Hitesh, E-mail: hiteshdos@hotmail.com

2012-02-15

After more than a decade of extensive experimentation, the promise of stem cells to revolutionize the field of medicine has negotiated their entry into clinical trial. Adipose tissue specifically holds potential as an attainable and abundant source of stem cells. Currently undergoing investigation are adipose stem cell (ASC) therapies for diabetes and critical limb ischemia, among others. In the enthusiastic pursuit of regenerative therapies, however, questions remain regarding ASC persistence and migration, and, importantly, their safety and potential for neoplasia. To date, assays of in vivo ASC activity have been limited by early end points. We hypothesized that with time,more » ASCs injected subcutaneously undergo removal by normal tissue turnover and homeostasis, and by the host's immune system. In this study, a high dose of culture expanded ASCs was formulated and implanted as multicellular aggregates into immunocompromised mice, which were maintained for over one year. Animals were monitored for toxicity, and surviving cells quantified at study endpoint. No difference in growth/weight or lifespan was found between cell-treated and vehicle treated animals, and no malignancies were detected in treated animals. Moreover, real-time PCR for a human specific sequence, ERV-3, detected no persistent ASCs. With the advent of clinical application, clarification of currently enigmatic stem cell properties has become imperative. Our study represents the longest duration determination of stem cell activity in vivo, and contributes strong evidence in support of the safety of adipose derived stem cell applications. -- Highlights: Black-Right-Pointing-Pointer Adipose stem cells promise novel clinical therapies. Black-Right-Pointing-Pointer Before clinical translation, safety profiles must be further elucidated. Black-Right-Pointing-Pointer Subcutaneously injected non-autologous adipose stem cells do not form tumors. Black-Right-Pointing-Pointer Subcutaneously injected non-autologous

Hematopoietic stem cell transplantation for HIV cure.

PubMed

Kuritzkes, Daniel R

2016-02-01

The apparent cure of an HIV-infected person following hematopoietic stem cell transplantation (HSCT) from an allogeneic donor homozygous for the ccr5Δ32 mutation has stimulated the search for strategies to eradicate HIV or to induce long-term remission without requiring ongoing antiretroviral therapy. A variety of approaches, including allogeneic HSCT from CCR5-deficient donors and autologous transplantation of genetically modified hematopoietic stem cells, are currently under investigation. This Review covers the experience with HSCT in HIV infection to date and provides a survey of ongoing work in the field. The challenges of developing HSCT for HIV cure in the context of safe, effective, and convenient once-daily antiretroviral therapy are also discussed.

Parasitic Infections in Hematopoietic Stem Cell Transplantation

PubMed Central

Jarque, Isidro; Salavert, Miguel; Pemán, Javier

2016-01-01

Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients. PMID:27413527

Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial.

PubMed

Younes, Anas; Santoro, Armando; Shipp, Margaret; Zinzani, Pier Luigi; Timmerman, John M; Ansell, Stephen; Armand, Philippe; Fanale, Michelle; Ratanatharathorn, Voravit; Kuruvilla, John; Cohen, Jonathon B; Collins, Graham; Savage, Kerry J; Trneny, Marek; Kato, Kazunobu; Farsaci, Benedetto; Parker, Susan M; Rodig, Scott; Roemer, Margaretha G M; Ligon, Azra H; Engert, Andreas

2016-09-01

Malignant cells of classical Hodgkin's lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkin's lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin. In this ongoing, single-arm phase 2 study, adult patients (aged ≥18 years) with recurrent classical Hodgkin's lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02181738. Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4-7). At a median follow-up of 8·9 months (IQR 7·8-9·9), 53 (66·3%, 95% CI 54·8-76·4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in ≥15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most

Directed induction of functional motor neuron-like cells from genetically engineered human mesenchymal stem cells.

PubMed

Park, Hwan-Woo; Cho, Jung-Sun; Park, Chul-Kyu; Jung, Sung Jun; Park, Chang-Hwan; Lee, Shin-Jae; Oh, Seog Bae; Park, Young-Seok; Chang, Mi-Sook

2012-01-01

Cell replacement using stem cells is a promising therapeutic approach to treat degenerative motor neuron (MN) disorders, such as amyotrophic lateral sclerosis and spinal cord injury. Human bone marrow-derived mesenchymal stem cells (hMSCs) are a desirable cell source for autologous cell replacement therapy to treat nervous system injury due to their plasticity, low immunogenicity, and a lower risk of tumor formation than embryonic stem cells. However, hMSCs are inefficient with regards to differentiating into MN-like cells. To solve this limitation, we genetically engineered hMSCs to express MN-associated transcription factors, Olig2 and Hb9, and then treat the hMSCs expressing Olig2 and Hb9 with optimal MN induction medium (MNIM). This method of induction led to higher expression (>30% of total cells) of MN markers. Electrophysiological data revealed that the induced hMSCs had the excitable properties of neurons and were able to form functional connections with muscle fibers in vitro. Furthermore, when the induced hMSCs were transplanted into an injured organotypic rat spinal cord slice culture, an ex vivo model of spinal cord injury, they exhibited characteristics of MNs. The data strongly suggest that induced Olig2/Hb9-expressing hMSCs were clearly reprogrammed and directed toward a MN-like lineage. We propose that methods to induce Olig2 and Hb9, followed by further induction with MNIM have therapeutic potential for autologous cell replacement therapy to treat degenerative MN disorders.

Validation of a novel animal model for sciatic nerve repair with an adipose-derived stem cell loaded fibrin conduit.

PubMed

Saller, Maximilian M; Huettl, Rosa-Eva; Mayer, Julius M; Feuchtinger, Annette; Krug, Christian; Holzbach, Thomas; Volkmer, Elias

2018-05-01

Despite the regenerative capabilities of peripheral nerves, severe injuries or neuronal trauma of critical size impose immense hurdles for proper restoration of neuro-muscular circuitry. Autologous nerve grafts improve re-establishment of connectivity, but also comprise substantial donor site morbidity. We developed a rat model which allows the testing of different cell applications, i.e., mesenchymal stem cells, to improve nerve regeneration in vivo. To mimic inaccurate alignment of autologous nerve grafts with the injured nerve, a 20 mm portion of the sciatic nerve was excised, and sutured back in place in reversed direction. To validate the feasibility of our novel model, a fibrin gel conduit containing autologous undifferentiated adipose-derived stem cells was applied around the coaptation sites and compared to autologous nerve grafts. After evaluating sciatic nerve function for 16 weeks postoperatively, animals were sacrificed, and gastrocnemius muscle weight was determined along with morphological parameters (g-ratio, axon density & diameter) of regenerating axons. Interestingly, the addition of undifferentiated adipose-derived stem cells resulted in a significantly improved re-myelination, axon ingrowth and functional outcome, when compared to animals without a cell seeded conduit. The presented model thus displays several intriguing features: it imitates a certain mismatch in size, distribution and orientation of axons within the nerve coaptation site. The fibrin conduit itself allows for an easy application of cells and, as a true critical-size defect model, any observed improvement relates directly to the performed intervention. Since fibrin and adipose-derived stem cells have been approved for human applications, the technique can theoretically be performed on humans. Thus, we suggest that the model is a powerful tool to investigate cell mediated assistance of peripheral nerve regeneration.

Integration of immunological aspects in the European Human Embryonic Stem Cell Registry.

PubMed

Borstlap, Joeri; Kurtz, Andreas

2008-05-01

The immunological properties of stem cells are of increasing importance in regenerative medicine. Immunomodulatory mechanisms seem to play an important role not only with respect to the understanding of underlying mechanisms of autologous versus allogenic therapeutic approaches, but also for endogeneous tissue regeneration. The newly established European human embryonic stem cell registry (hESCreg) offers an international database for the registration, documentation and characterisation of human embryonic stem cells (hESC) and their use. By doing so, hESCreg aims to develop a model procedure for further standardisation efforts in the field of stem cell research and regenerative medicine, and eventually the registry may lead to a repository of therapy-related information. Currently the stem cell characterisation data acquired by the registry are divided into several categories such as cell derivation, culture conditions, genetic constitution, stem cell marker expression and degree of modification. This article describes immunological aspects of stem cell characterisation and explores the layout and relevance of a possible additional section to the hESCreg repository to include immunological characteristics of human embryonic stem cells.

Induced Pluripotent Stem Cell Therapies for Degenerative Disease of the Outer Retina: Disease Modeling and Cell Replacement.

PubMed

Di Foggia, Valentina; Makwana, Priyanka; Ali, Robin R; Sowden, Jane C

2016-06-01

Stem cell therapies are being explored as potential treatments for retinal disease. How to replace neurons in a degenerated retina presents a continued challenge for the regenerative medicine field that, if achieved, could restore sight. The major issues are: (i) the source and availability of donor cells for transplantation; (ii) the differentiation of stem cells into the required retinal cells; and (iii) the delivery, integration, functionality, and survival of new cells in the host neural network. This review considers the use of induced pluripotent stem cells (iPSC), currently under intense investigation, as a platform for cell transplantation therapy. Moreover, patient-specific iPSC are being developed for autologous cell transplantation and as a tool for modeling specific retinal diseases, testing gene therapies, and drug screening.

Current Therapeutic Strategies for Stem Cell-Based Cartilage Regeneration

PubMed Central

Nam, Yoojun; Lee, Jennifer

2018-01-01

The process of cartilage destruction in the diarthrodial joint is progressive and irreversible. This destruction is extremely difficult to manage and frustrates researchers, clinicians, and patients. Patients often take medication to control their pain. Surgery is usually performed when pain becomes uncontrollable or joint function completely fails. There is an unmet clinical need for a regenerative strategy to treat cartilage defect without surgery due to the lack of a suitable regenerative strategy. Clinicians and scientists have tried to address this using stem cells, which have a regenerative potential in various tissues. Cartilage may be an ideal target for stem cell treatment because it has a notoriously poor regenerative potential. In this review, we describe past, present, and future strategies to regenerate cartilage in patients. Specifically, this review compares a surgical regenerative technique (microfracture) and cell therapy, cell therapy with and without a scaffold, and therapy with nonaggregated and aggregated cells. We also review the chondrogenic potential of cells according to their origin, including autologous chondrocytes, mesenchymal stem cells, and induced pluripotent stem cells. PMID:29765426

Infusion of autologous adipose tissue derived neuronal differentiated mesenchymal stem cells and hematopoietic stem cells in post-traumatic paraplegia offers a viable therapeutic approach.

PubMed

Thakkar, Umang G; Vanikar, Aruna V; Trivedi, Hargovind L; Shah, Veena R; Dave, Shruti D; Dixit, Satyajit B; Tiwari, Bharat B; Shah, Harda H

2016-01-01

Spinal cord injury (SCI) is not likely to recover by current therapeutic modalities. Stem cell (SC) therapy (SCT) has promising results in regenerative medicine. We present our experience of co-infusion of autologous adipose tissue derived mesenchymal SC differentiated neuronal cells (N-Ad-MSC) and hematopoietic SCs (HSCs) in a set of patients with posttraumatic paraplegia. Ten patients with posttraumatic paraplegia of mean age 3.42 years were volunteered for SCT. Their mean age was 28 years, and they had variable associated complications. They were subjected to adipose tissue resection for in vitro generation of N-Ad-MSC and bone marrow aspiration for generation of HSC. Generated SCs were infused into the cerebrospinal fluid (CSF) below injury site in all patients. Total mean quantum of SC infused was 4.04 ml with a mean nucleated cell count of 4.5 × 10(4)/μL and mean CD34+ of 0.35%, CD45-/90+ and CD45-/73+ of 41.4%, and 10.04%, respectively. All of them expressed transcription factors beta-3 tubulin and glial fibrillary acid protein. No untoward effect of SCT was noted. Variable and sustained improvement in Hauser's index and American Spinal Injury Association score was noted in all patients over a mean follow-up of 2.95 years. Mean injury duration was 3.42 years against the period of approximately 1-year required for natural recovery, suggesting a positive role of SCs. Co-infusion of N-Ad-MSC and HSC in CSF is safe and viable therapeutic approach for SCIs.

Comparison of the Fenwal Amicus and Fresenius Com.Tec cell separators for autologous peripheral blood progenitor cell collection.

PubMed

Altuntas, Fevzi; Kocyigit, Ismail; Ozturk, Ahmet; Kaynar, Leylagul; Sari, Ismail; Oztekin, Mehmet; Solmaz, Musa; Eser, Bulent; Cetin, Mustafa; Unal, Ali

2007-04-01

Peripheral blood progenitor cells (PBPC) are commonly used as a stem cell source for autologous transplantation. This study was undertaken to evaluate blood cell separators with respect to separation results and content of the harvest. Forty autologous PBPC collections in patients with hematological malignancies were performed with either the Amicus or the COM.TEC cell separators. The median product volume was lower with the Amicus compared to the COM.TEC (125 mL vs. 300 mL; p < 0.001). There was no statistically significant difference in the median number of CD34+ cell/kg in product between the Amicus and the COM.TEC (3.0 x 10(6) vs. 4.1 x 10(6); p = 0.129). There was a statistically higher mean volume of ACD used in collections on the Amicus compared to the COM.TEC (1040 +/- 241 mL vs. 868 +/- 176 mL; p = 0.019). There was a statistical difference in platelet (PLT) contamination of the products between the Amicus and the COM.TEC (0.3 x 10(11) vs. 1.1 x 10(11); p < 0.001). The median % decrease in PB PLT count was statistically higher in the COM.TEC compared to the Amicus instruments (18.5% vs. 9.5%; p = 0.028). In conclusion, both instruments collected PBPCs efficiently. However, Amicus has the advantage of lower PLT contamination in the product, and less decrease in PB platelet count with lower product volume in autologous setting.

Towards Standardized Stem Cell Therapy in Type 2 Diabetes Mellitus: A Systematic Review.

PubMed

Pawitan, Jeanne Adiwinata; Yang, Zheng; Wu, Ying Nan; Leed, Eng Hin

2018-05-02

To compile and analyze the published studies on cell therapy for type 2 diabetes mellitus (T2DM) to obtain a better insight into management of T2DM that involved stem cell therapy. We searched all published studies in Pubmed/Medline, and Cochrane library, using keywords: 'stem cell' AND 'therapy' AND 'diabetes type 2'. original articles on the use of stem cells in humans with T2DM. articles in the non-English literature, studies on T2DM complications that did not assess both adverse events and any of the common diabetes study outcomes. type of study, number of cases, and all data that were related to outcome and adverse events. Data were analyzed descriptively to conclude the possible cause of adverse reactions, and which protocols gave a satisfactory outcome. We collected 26 original articles, out of which 17 studies did not have controls and were classified as case reports, while there were 8 studies that were controlled clinical trials. Most studies used autologous bone marrow mononuclear cells (BM-MNCs) or autologous or allogeneic mesenchymal stem cells (MSCs) from various sources. Adverse events were mild and mostly intervention related. Efficacy of autologous BM-MNCs that were given via interventional route was comparable to Wharton jelly or umbilical cord MSCs that were given via intravenous (IV), Intra muscular (IM), or subcutaneous (SC) route. Further controlled studies that compare BM-MNCs to BM-MSCs or WJ-MSCs or UCSCs are recommended to prove their comparable efficacy. In addition, studies that compare various routes of administration (IV, IM or SC) versus the more invasive interventional routes are needed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Diagnostic value of sTREM-1, IL-8, PCT, and CRP in febrile neutropenia after autologous stem cell transplantation.

PubMed

Michel, C S; Teschner, D; Wagner, E M; Theobald, M; Radsak, Markus P

2017-12-01

Infections and infectious complications are the major cause of morbidity and mortality in febrile neutropenic patients after autologous stem cell transplantation. Laboratory biomarkers are helpful for early identification of critically ill patients and optimal therapy management. Several studies in adult non-neutropenic patients proposed sTREM-1 as a superior biomarker for identification of septic patients as well as a predictor for survival in these patients compared with procalcitonin (PCT), C-reactive protein (CRP), or interleukin-8 (IL-8). Here, to assess the utility of PCT, CRP, IL-8, and sTREM-1 in febrile neutropenia, 44 patients presenting with febrile neutropenia after autologous stem cell transplantation were recruited in a single-center prospective pilot study. We analyzed PCT and CRP as well as IL-8 and sTREM-1 levels pre- and post-transplantation at defined time points. In 20 of 44 patients, concentration of sTREM-1 was under the detection level at appearance of febrile neutropenia. Mean levels of PCT, IL-8, and CRP were significantly increased in infections of critically ill patients who by dysfunction or failure of one or more organs/system depend on survival from advanced instruments of monitoring and therapy. However, all tested biomarkers could not distinguish between presence and absence of bloodstream infection. The combination of the biomarkers PCT and IL-8 achieved a high sensitivity of 90% and specificity of 74% for the identification of serious complications in febrile neutropenia, whereas the combination of CRP and PCT or IL-8 achieved a high sensitivity of 100%, but with the addition of a low specificity of 47or 41%. In conclusion, we found that the measurement of sTREM-1 concentration at presentation of febrile neutropenia is not useful to identify bacterial bloodstream infections and critically ill patients. PCT and IL-8 are useful biomarkers for the early identification of critically ill patients, compared to CRP and sTREM-1 in febrile

Treatment of pressure ulcers with autologous bone marrow nuclear cells in patients with spinal cord injury

PubMed Central

Sarasúa, J González; López, S Pérez; Viejo, M Álvarez; Basterrechea, M Pérez; Rodríguez, A Fernández; Gutiérrez, A Ferrero; Gala, J García; Menéndez, Y Menéndez; Augusto, D Escudero; Arias, A Pérez; Hernández, J Otero

2011-01-01

Context Pressure ulcers are especially difficult to treat in patients with spinal cord injury (SCI) and recurrence rates are high. Prompted by encouraging results obtained using bone marrow stem cells to treat several diseases including chronic wounds, this study examines the use of autologous stem cells from bone marrow to promote the healing of pressure ulcers in patients with SCI. Objective To obtain preliminary data on the use of bone marrow mononuclear cells (BM-MNCs) to treat pressure ulcers in terms of clinical outcome, procedure safety, and treatment time. Participants Twenty-two patients with SCI (19 men, 3 women; mean age 56.41 years) with single type IV pressure ulcers of more than 4 months duration. Interventions By minimally invasive surgery, the ulcers were debrided and treated with BM-MNCs obtained by Ficoll density gradient separation of autologous bone marrow aspirates drawn from the iliac crest. Results In 19 patients (86.36%), the pressure ulcers treated with BM-MNCs had fully healed after a mean time of 21 days. The number of MNCs isolated was patient dependent, although similar clinical outcomes were observed in each case. Compared to conventional surgical treatment, mean intra-hospital stay was reduced from 85.16 to 43.06 days. Following treatment, 5 minutes of daily wound care was required per patient compared to 20 minutes for conventional surgery. During a mean follow-up of 19 months, none of the resolved ulcers recurred. Conclusions Our data indicate that cell therapy using autologous BM-MNCs could be an option to treat type IV pressure ulcers in patients with SCI, avoiding major surgical intervention. PMID:21756569

IMPACT OF PRE-TRANSPLANT RITUXIMAB ON SURVIVAL AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR DIFFUSE LARGE B-CELL LYMPHOMA

PubMed Central

Fenske, Timothy S.; Hari, Parameswaran N.; Carreras, Jeanette; Zhang, Mei-Jie; Kamble, Rammurti T.; Bolwell, Brian J.; Cairo, Mitchell S.; Champlin, Richard E.; Chen, Yi-Bin; Freytes, César O.; Gale, Robert Peter; Hale, Gregory A.; Ilhan, Osman; Khoury, H. Jean; Lister, John; Maharaj, Dipnarine; Marks, David I.; Munker, Reinhold; Pecora, Andrew L.; Rowlings, Philip A.; Shea, Thomas C.; Stiff, Patrick; Wiernik, Peter H.; Winter, Jane N.; Rizzo, J. Douglas; van Besien, Koen; Lazarus, Hillard M.; Vose, Julie M.

2010-01-01

Incorporation of the anti-CD20 monoclonal antibody rituximab into front-line regimens for diffuse large B-cell lymphoma (DLBCL) has resulted in improved survival. Despite this progress, many patients develop refractory or recurrent DLBCL and then receive autologous hematopoietic stem cell transplantation (AuHCT). It is unclear to what extent pre-transplant exposure to rituximab affects outcomes following AuHCT. Outcomes of 994 patients receiving AuHCT for DLBCL between 1996 and 2003 were analyzed according to whether rituximab was (n=176, “+R” group) or was not (n=818, “ −R” group) administered with front-line or salvage therapy prior to AuHCT. The +R group had superior progression-free survival (50% versus 38%, p=0.008) and overall survival (57% versus 45%, p=0.006) at 3 years. Platelet and neutrophil engraftment were not affected by exposure to rituximab. Non-relapse mortality (NRM) did not differ significantly between the +R and −R groups. In multivariate analysis, the +R group had improved progression-free survival (relative risk of relapse/progression or death 0.64, p<0.001) and improved overall survival (relative risk of death of 0.74, p=0.039). We conclude that pre-transplant rituximab is associated with a lower rate of progression and improved survival following AuHCT for DLBCL, with no evidence of impaired engraftment or increased NRM. PMID:19822306

Double versus single high-dose melphalan 200 mg/m2 and autologous stem cell transplantation for multiple myeloma: a region-based study in 484 patients from the Nordic area

PubMed Central

Björkstrand, Bo; Klausen, Tobias W.; Remes, Kari; Gruber, Astrid; Knudsen, Lene M.; Bergmann, Olav J.; Lenhoff, Stig; Johnsen, Hans E.

2009-01-01

Autologous stem cell transplantation is still considered the standard of care in young patients with multiple myeloma (MM). This disease is the most common indication for high-dose therapy (HDT) supported by hematopoietic stem cell transplantation and much data support the benefit of this procedure. Results of randomized studies are in favor of tandem autologous transplantation although the effect on overall survival is unclear. Based on sequential registration trials in the Nordic area, we aimed to evaluate the outcome of conventional single or double HDT. During 1994–2000 we registered a total of 484 previously untreated patients under the age of 60 years at diagnosis who on a regional basis initially were treated with single [Trial NMSG #5/94 and #7/98 (N=383)] or double [Trial Huddinge Karolinska Turku Herlev (N=101)] high-dose melphalan (200 mg/m2) therapy supported by autologous stem cell transplantation. A complete or very good partial response was achieved by 40% of patients in the single transplant group and 60% of patients in the double transplant group (p=0.0006). The probability of surviving progression free for five years after the diagnosis was 25% (95% CL 18–32%) in the singletransplant group and 46% (95% CL 33–55%) in the double transplant group (p=0.0014). The estimated overall five-year survival rate was 60% in the single transplant group and 64% in the doubletransplant (p=0.9). In a multivariate analysis of variables, including single versus double transplantation, β2 microglobulin level, age, sex and disease stage, only β2 microglobulin level was predictive for overall survival (p>0.0001) and progression free survival (p=0.001). In accordance with these results, a 1:1 case-control matched comparison between double and single transplantation did not identify significant differences in overall and progression free survival. In this retrospective analysis up front double transplantation with melphalan (200 mg/m2) as compared to single

Technological progress and challenges towards cGMP manufacturing of human pluripotent stem cells based therapeutic products for allogeneic and autologous cell therapies.

PubMed

Abbasalizadeh, Saeed; Baharvand, Hossein

2013-12-01

Recent technological advances in the generation, characterization, and bioprocessing of human pluripotent stem cells (hPSCs) have created new hope for their use as a source for production of cell-based therapeutic products. To date, a few clinical trials that have used therapeutic cells derived from hESCs have been approved by the Food and Drug Administration (FDA), but numerous new hPSC-based cell therapy products are under various stages of development in cell therapy-specialized companies and their future market is estimated to be very promising. However, the multitude of critical challenges regarding different aspects of hPSC-based therapeutic product manufacturing and their therapies have made progress for the introduction of new products and clinical applications very slow. These challenges include scientific, technological, clinical, policy, and financial aspects. The technological aspects of manufacturing hPSC-based therapeutic products for allogeneic and autologous cell therapies according to good manufacturing practice (cGMP) quality requirements is one of the most important challenging and emerging topics in the development of new hPSCs for clinical use. In this review, we describe main critical challenges and highlight a series of technological advances in all aspects of hPSC-based therapeutic product manufacturing including clinical grade cell line development, large-scale banking, upstream processing, downstream processing, and quality assessment of final cell therapeutic products that have brought hPSCs closer to clinical application and commercial cGMP manufacturing. © 2013.

Characterization of insulin-producing cells derived from PDX-1-transfected neural stem cells.

PubMed

Wang, Hailan; Jiang, Zesheng; Li, Aihui; Gao, Yi

2012-12-01

Islet cell transplantation is a promising treatment strategy for type-1 diabetes. However, functional islet cells are hard to obtain for transplantation and are in short supply. Directing the differentiation of stem cells into insulin‑producing cells, which serve as islet cells, would overcome this shortage. Bone marrow contains hematopoietic stem cells and mesenchymal stem cells. The present study used bone marrow cells isolated from rats and neural stem cells (NSCs) that were derived from bone marrow cells in culture. Strong nestin staining was detected in NSCs, but not in bone marrow stromal cells (BMSCs). In vitro transfection of the pancreatic duodenal homeobox-1 (PDX-1) gene into NSCs generated insulin‑producing cells. Reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analysis confirmed that PDX-1-transfected NSCs expressed insulin mRNA and released insulin protein. However, insulin release from PDX-1-transfected NSCs did not respond to the challenge of glucose and glucagon-like peptide-1. These results support the use of bone marrow-derived NSCs as a renewable source of insulin-producing cells for autologous transplantation to treat type-1 diabetes.

Juvenile Swine Surgical Alveolar Cleft Model to Test Novel Autologous Stem Cell Therapies

PubMed Central

Caballero, Montserrat; Morse, Justin C.; Halevi, Alexandra E.; Emodi, Omri; Pharaon, Michael R.; Wood, Jeyhan S.

2015-01-01

Reconstruction of craniofacial congenital bone defects has historically relied on autologous bone grafts. Engineered bone using mesenchymal stem cells from the umbilical cord on electrospun nanomicrofiber scaffolds offers an alternative to current treatments. This preclinical study presents the development of a juvenile swine model with a surgically created maxillary cleft defect for future testing of tissue-engineered implants for bone generation. Five-week-old pigs (n=6) underwent surgically created maxillary (alveolar) defects to determine critical-sized defect and the quality of treatment outcomes with rib, iliac crest cancellous bone, and tissue-engineered scaffolds. Pigs were sacrificed at 1 month. Computed tomography scans were obtained at days 0 and 30, at the time of euthanasia. Histological evaluation was performed on newly formed bone within the surgical defect. A 1 cm surgically created defect healed with no treatment, the 2 cm defect did not heal. A subsequently created 1.7 cm defect, physiologically similar to a congenitally occurring alveolar cleft in humans, from the central incisor to the canine, similarly did not heal. Rib graft treatment did not incorporate into adjacent normal bone; cancellous bone and the tissue-engineered graft healed the critical-sized defect. This work establishes a juvenile swine alveolar cleft model with critical-sized defect approaching 1.7 cm. Both cancellous bone and tissue engineered graft generated bridging bone formation in the surgically created alveolar cleft defect. PMID:25837453

Serologic response to a 23-valent pneumococcal vaccine administered prior to autologous stem cell transplantation in patients with multiple myeloma.

PubMed

Hinge, Maja; Ingels, Helene A S; Slotved, Hans-Christian; Mølle, Ingolf

2012-11-01

Patients with multiple myeloma are known to have an increased risk of infections with Streptococcus pneumoniae and vaccination is recommended. We retrospectively investigated the response of a 23-valent polysaccharide-based pneumococcal vaccine in 60 patients with multiple myeloma administered prior to autologous stem cell transplantation (ASCT). Specific antibody titers were measured before and after vaccination. Disease stage was evaluated and associated to the response. We found that 33% of the patients responded to the vaccine. There was a statistic significant association between response to the vaccine and disease stage (p = 0.01). We conclude that vaccination against S. pneumoniae prior to ASCT is reasonable at least in patients responding well to induction therapy, but still it is important to be aware that the response is frequently poor and the duration of it is unknown. © 2012 The Authors APMIS © 2012 APMIS.

Cell-mediated remodeling of biomimetic encapsulating hydrogels triggered by adipogenic differentiation of adipose stem cells.

PubMed

Clevenger, Tracy N; Luna, Gabriel; Boctor, Daniel; Fisher, Steven K; Clegg, Dennis O

2016-01-01

One of the most common regenerative therapies is autologous fat grafting, which frequently suffers from unexpected volume loss. One approach is to deliver adipose stem cells encapsulated in the engineered hydrogels supportive of cell survival, differentiation, and integration after transplant. We describe an encapsulating, biomimetic poly(ethylene)-glycol hydrogel, with embedded peptides for attachment and biodegradation. Poly(ethylene)-glycol hydrogels containing an Arg-Gly-Asp attachment sequence and a matrix metalloprotease 3/10 cleavage site supported adipose stem cell survival and showed remodeling initiated by adipogenic differentiation. Arg-Gly-Asp-matrix metalloprotease 3/10 cleavage site hydrogels showed an increased number and area of lacunae or holes after adipose stem cell differentiation. Image analysis of adipose stem cells in Arg-Gly-Asp-matrix metalloprotease 3/10 cleavage site hydrogels showed larger Voronoi domains, while cell density remained unchanged. The differentiated adipocytes residing within these newly remodeled spaces express proteins and messenger RNAs indicative of adipocytic differentiation. These engineered scaffolds may provide niches for stem cell differentiation and could prove useful in soft tissue regeneration.

Cell-mediated remodeling of biomimetic encapsulating hydrogels triggered by adipogenic differentiation of adipose stem cells

PubMed Central

Clevenger, Tracy N; Luna, Gabriel; Boctor, Daniel; Fisher, Steven K; Clegg, Dennis O

2016-01-01

One of the most common regenerative therapies is autologous fat grafting, which frequently suffers from unexpected volume loss. One approach is to deliver adipose stem cells encapsulated in the engineered hydrogels supportive of cell survival, differentiation, and integration after transplant. We describe an encapsulating, biomimetic poly(ethylene)-glycol hydrogel, with embedded peptides for attachment and biodegradation. Poly(ethylene)-glycol hydrogels containing an Arg–Gly–Asp attachment sequence and a matrix metalloprotease 3/10 cleavage site supported adipose stem cell survival and showed remodeling initiated by adipogenic differentiation. Arg–Gly–Asp–matrix metalloprotease 3/10 cleavage site hydrogels showed an increased number and area of lacunae or holes after adipose stem cell differentiation. Image analysis of adipose stem cells in Arg–Gly–Asp–matrix metalloprotease 3/10 cleavage site hydrogels showed larger Voronoi domains, while cell density remained unchanged. The differentiated adipocytes residing within these newly remodeled spaces express proteins and messenger RNAs indicative of adipocytic differentiation. These engineered scaffolds may provide niches for stem cell differentiation and could prove useful in soft tissue regeneration. PMID:27733898

Improved targeting and enhanced retention of the human, autologous, fibroblast-derived, induced, pluripotent stem cells to the sarcomeres of the infarcted myocardium with the aid of the bioengineered, heterospecific, tetravalent antibodies**

PubMed Central

Malecki, Marek

2013-01-01

Clinical trials, to regenerate the human heart injured by myocardial infarction, involve the delivery of stem cells to the site of the injury. However, only a small fraction of the introduced stem cells are detected at the site of the injury, merely two weeks after this therapeutic intervention. This significantly hampers the effectiveness of the stem cell therapy. To resolve the aforementioned problem, we genetically and molecularly bioengineered heterospecific, tetravalent antibodies (htAbs), which have both exquisite specificity and high affinity towards human, pluripotent, stem cells through the htAbs’ domains binding SSEA-4, SSEA-3, TRA-1-60, and TRA-1-81, as well as towards the injured cardiac muscle through the htAbs’ domains binding human cardiac myosin, α-actinin, actin, and titin. The cardiac tissue was acquired from the patients, who were receiving heart transplants. The autologous, human, induced, pluripotent stem cells (hiPSCs) were generated from the patients’ fibroblasts by non-viral delivery and transient expression of the DNA constructs for: Oct4, Nanog, Sox2, Lin28, Klf4, c-Myc. In the trials involving the htAbs, the human, induced, pluripotent stem cells anchored to the myocardial sarcomeres with the efficiency, statistically, significantly higher, than in the trials with non-specific or without antibodies (p < 0.0003). Moreover, application of the htAbs resulted in cross-linking of the sarcomeric proteins to create the stable scaffolds for anchoring of the stem cells. Thereafter, these human, induced pluripotent stem cells differentiated into cardiomyocytes at their anchorage sites. By bioengineering of these novel heterospecific, tetravalent antibodies and using them to guide and to anchor the stem cells specifically to the stabilized sarcomeric scaffolds, we demonstrated the proof of concept in vitro for improving effectiveness of regenerative therapy of myocardial infarction and created the foundations for the trials in vivo. PMID

Febrile neutropenic infection occurred in cancer patients undergoing autologous peripheral blood stem cell transplantation.

PubMed

Zhang, W-X; Zhao, Q-Y; Huang, H-Q

2015-03-01

The objective of this study was to investigate the incidence, risk factors, and clinical and prognostic characteristics of febrile infection that occurred during the neutropenic period in cancer patients who underwent autologous peripheral blood stem cell transplantation (APBSCT). Clinical data of all the APBSCT cases from 2007 to 2009 in Sun Yat-sen University Cancer Center were collected and retrospectively analyzed. Eighty-nine APBSCT subjects were investigated. Neutropenia usually occurred on the 4th day (range, 0-15) after transplantation and lasted 6 (range, 3-27) days. Febrile neutropenia occurred in 78.7% patients and lasted around 3 (range, 1-20) days and no infection-related deaths were observed. For febrile episodes, 12 patients (17.1%) were diagnosed as having microbiologically documented infections (MDI). Initial empirical antimicrobial therapy was given to all cases of post-APBSCT febrile neutropenia, of which 44 cases (62.9%) were effective. Febrile neutropenia occurred in 25/34 (73.5%) patients who were given antifungal drugs for prophylaxis. Neutropenic infection is still the major complication in APBSCT patients and duration of neutropenia is one of the major risk factors. Prophylactic administration of antifungal drugs seems to be invalid to reduce post-APBSCT infection. Sufficient doses of broad-spectrum antibiotics at the early stage lead to better results of initial antimicrobial treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.

PubMed

Nash, Richard A; Dansey, Roger; Storek, Jan; Georges, George E; Bowen, James D; Holmberg, Leona A; Kraft, George H; Mayes, Maureen D; McDonagh, Kevin T; Chen, Chien-Shing; Dipersio, John; Lemaistre, C Fred; Pavletic, Steven; Sullivan, Keith M; Sunderhaus, Julie; Furst, Daniel E; McSweeney, Peter A

2003-09-01

High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated for the control of severe autoimmune diseases. The addition of antithymocyte globulin (ATG) to high-dose chemoradiotherapy in the high-dose immunosuppressive therapy regimen and CD34 selection of the autologous graft may induce a higher degree of immunosuppression compared with conventional autologous HSCT for malignant diseases. Patients may be at higher risk of transplant-related complications secondary to the immunosuppressed state, including Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD), but this is an unusual complication after autologous HSCT. Fifty-six patients (median age, 42 years; range, 23-61 years) with either multiple sclerosis (n = 26) or systemic sclerosis (n = 30) have been treated. The median follow-up has been 24 months (range, 2-60 months). Two patients (multiple sclerosis, n = 1; systemic sclerosis, n = 1) had significant reactivations of herpesvirus infections early after HSCT and then developed aggressive EBV-PTLD and died on days +53 and +64. Multiorgan clonal B-cell infiltrates that were EBV positive by molecular studies or immunohistology were identified at both autopsies. Both patients had positive screening skin tests for equine ATG (Atgam) and had been converted to rabbit ATG (Thymoglobulin) from the first dose. Of the other 54 patients, 2 of whom had partial courses of rabbit ATG because of a reaction to the intravenous infusion of equine ATG, only 1 patient had a significant clinical reactivation of a herpesvirus infection (herpes simplex virus 2) early after HSCT, and none developed EBV-PTLD. The T-cell count in the peripheral blood on day 28 was 0/microL in all 4 patients who received rabbit ATG; this was significantly less than in patients who received equine ATG (median, 174/microL; P =.001; Mann-Whitney ranked sum test). Although the numbers are limited

Human embryonic stem cell therapies for neurodegenerative diseases.

PubMed

Tomaskovic-Crook, Eva; Crook, Jeremy M

2011-06-01

There is a renewed enthusiasm for the clinical translation of human embryonic stem (hES) cells. This is abetted by putative clinically-compliant strategies for hES cell maintenance and directed differentiation, greater understanding of and accessibility to cells through formal cell registries and centralized cell banking for distribution, the revised US government policy on funding hES cell research, and paradoxically the discovery of induced pluripotent stem (iPS) cells. Additionally, as we consider the constraints (practical and fiscal) of delivering cell therapies for global healthcare, the more efficient and economical application of allogeneic vs autologous treatments will bolster the clinical entry of hES cell derivatives. Neurodegenerative disorders such as Parkinson's disease are primary candidates for hES cell therapy, although there are significant hurdles to be overcome. The present review considers key advances and challenges to translating hES cells into novel therapies for neurodegenerative diseases, with special consideration given to Parkinson's disease and Alzheimer's disease. Importantly, despite the focus on degenerative brain disorders and hES cells, many of the issues canvassed by this review are relevant to systemic application of hES cells and other pluripotent stem cells such as iPS cells.

Evaluation of Hematopoietic Stem Cell Mobilization Rates with Early Plerixafor Administration for Adult Stem Cell Transplantation.

PubMed

Stover, Jessica T; Shaw, J Ryan; Kuchibhatla, Maragatha; Horwitz, Mitchell E; Engemann, Ashley M

2017-08-01

The addition of plerixafor to high-dose colony-stimulating growth factor has been shown to improve stem cell mobilization rates in autologous transplant patients with multiple myeloma and non-Hodgkin lymphoma. This study evaluates the change in administration time of plerixafor to determine if cell mobilization rates are similar between the US Food and Drug Administration-approved administration time of 11 hours before apheresis and an earlier administration time of 16 hours before apheresis. Medical records of patients age ≥ 18 years undergoing autologous stem cell transplantation requiring the use of plerixafor after at least 4 days of granulocyte colony-stimulating factor therapy to complete stem cell mobilization from January 1, 2010 through September 30, 2014 were retrospectively reviewed. The primary outcome was CD34 + cell mobilization success rates when plerixafor was administered 11 ± 2 hours (standard administration group) compared with 16 ± 2 hours before cell apheresis (early administration group), as defined as collection of  ≥2 × 10 6 CD34 + cells/kg. Secondary outcomes included the number of plerixafor therapy days required to collect a total of ≥2 × 10 6 CD34 + cells/kg, the number of apheresis cycles required to achieve ≥2 × 10 6 CD34 + cells/kg, the median CD34 + cells/kg collected in each apheresis session, and the rates of reported adverse events that occurred in the standard administration time group compared with the early administration time group. Of the 197 patients included, 114 patients received plerixafor 11 ± 2 hours before apheresis and 83 patients received plerixafor 16 hours ± 2 hours before apheresis. Ninety-four percent of patients in the early administration group achieved successful stem cell mobilization compared with 81.6% in the standard administration group (P = .0111). The median number of plerixafor days to reach the collection goal of  ≥2 × 10 6 CD34 + cells/kg was 1 day for

Challenges and opportunities for stem cell therapy in patients with chronic kidney disease.

PubMed

Hickson, LaTonya J; Eirin, Alfonso; Lerman, Lilach O

2016-04-01

Chronic kidney disease (CKD) is a global health care burden affecting billions of individuals worldwide. The kidney has limited regenerative capacity from chronic insults, and for the most common causes of CKD, no effective treatment exists to prevent progression to end-stage kidney failure. Therefore, novel interventions, such as regenerative cell-based therapies, need to be developed for CKD. Given the risk of allosensitization, autologous transplantation of cells to boost regenerative potential is preferred. Therefore, verification of cell function and vitality in CKD patients is imperative. Two cell types have been most commonly applied in regenerative medicine. Endothelial progenitor cells contribute to neovasculogenesis primarily through paracrine angiogenic activity and partly by differentiation into mature endothelial cells in situ. Mesenchymal stem cells also exert paracrine effects, including proangiogenic, anti-inflammatory, and antifibrotic activity. However, in CKD, multiple factors may contribute to reduced cell function, including older age, coexisting cardiovascular disease, diabetes, chronic inflammatory states, and uremia, which may limit the effectiveness of an autologous cell-based therapy approach. This Review highlights current knowledge on stem and progenitor cell function and vitality, aspects of the uremic milieu that may serve as a barrier to therapy, and novel methods to improve stem cell function for potential transplantation. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Granulocyte Colony-Stimulating Factor Use after Autologous Peripheral Blood Stem Cell Transplantation: Comparison of Two Practices.

PubMed

Singh, Amrita D; Parmar, Sapna; Patel, Khilna; Shah, Shreya; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; Phillips, Adrienne; Hsu, Jing-Mei; Niesvizky, Ruben; Mark, Tomer M; Pearse, Roger; Rossi, Adriana; van Besien, Koen

2018-02-01

Administration of granulocyte colony-stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (PBSCT) is generally recommended to reduce the duration of severe neutropenia; however, data regarding the optimal timing of G-CSFs post-transplantation are limited and conflicting. This retrospective study was performed at NewYork-Presbyterian/Weill Cornell Medical Center between November 5, 2013, and August 9, 2016, of adult inpatient autologous PBSCT recipients who received G-CSF empirically starting on day +5 (early) versus on those who received G-CSF on day +12 only if absolute neutrophil count (ANC) was <0.5 × 10 9 /L (ANC-driven). G-CSF was dosed at 300 µg in patients weighing <75 kg and 480 µg in those weighing ≥75 kg. One hundred consecutive patients underwent autologous PBSCT using either the early (n = 50) or ANC-driven (n = 50) G-CSF regimen. Patient and transplantation characteristics were comparable in the 2 groups. In the ANC-driven group, 24% (n = 12) received G-CSF on day +12 and 60% (n = 30) started G-CSF earlier due to febrile neutropenia or at the physician's discretion, 6% (n = 3) started after day +12 at the physician's discretion, and 10% (n = 5) did not receive any G-CSF. The median start day of G-CSF therapy was day +10 in the ANC-driven group versus day +5 in the early group (P < .0001). For the primary outcome, the median time to neutrophil engraftment was 12 days (interquartile range [IQR] 11-13 days) in the early group versus 13 days (IQR, 12-14 days) in the ANC-driven group (P = .07). There were no significant between-group differences in time to platelet engraftment, 1-year relapse rate, or 1-year overall survival. The incidence of febrile neutropenia was 74% in the early group versus 90% in the ANC-driven group (P = .04); however, there was no significant between-group difference in the incidence of positive bacterial cultures or transfer to the intensive care

Storage Duration of Autologous Stem Cell Preparations Has No Impact on Hematopoietic Recovery after Transplantation.

PubMed

Lisenko, Katharina; Pavel, Petra; Kriegsmann, Mark; Bruckner, Thomas; Hillengass, Jens; Goldschmidt, Hartmut; Witzens-Harig, Mathias; Ho, Anthony D; Wuchter, Patrick

2017-04-01

Peripheral blood stem cells (PBSCs) are widely used for autologous blood stem cell transplantation (ABSCT). These cells must be stored for months or even years, usually at temperatures ≤-140°C, until their use. Although several in vitro studies on CD34 + viability and clonogenic assays of PBSCs after long-term storage have been reported, only a few publications have investigated the influence of long-term storage on in vivo hematopoietic reconstitution. In this study, we retrospectively analyzed hematopoietic recovery after storage of PBSCs via controlled-rate freezing (CRF) and cryostorage in 10% DMSO at ≤-140°C in 105 patients with multiple myeloma who received high-dose melphalan before ABSCT. Three groups of PBSC transplantation (n = 247) were delineated based on the storage period: short-term (≤12 months, n = 143), medium-term (>12 and ≤60 months, n = 75), and long-term storage (>60 months, n = 29). A neutrophil increase of ≥.5 × 10 9 /L in medium-term or long-term PBSC cryopreservation groups was observed at day 14 after ABSCT; this increase was comparable to patients who received briefly stored PBSCs (day 15). No negative effect of PBSC storage duration was observed on leucocyte or neutrophil reconstitution. Platelet reconstitutions of ≥20  × 10 9 /L and 50 × 10 9 /L were observed after median times of 10 to 11 and 13 to 14 days after ABSCT, respectively. No influence of PBSC storage duration on platelet recovery of ≥20  × 10 9 /L and ≥50 × 10 9 /L was observed in the 3 storage groups (P = .07, P = .32). The number of previous ABSCTs also had no significant impact upon hematopoietic reconstitution. In conclusion, these results indicate that long-term cryopreservation of PBSC products at vapor nitrogen temperature after CRF does not have a negative effect on hematopoietic recovery even after prolonged storage. Copyright © 2017 The American Society for Blood and Marrow Transplantation

Concise Review: The Potential Use of Intestinal Stem Cells to Treat Patients with Intestinal Failure.

PubMed

Hong, Sung Noh; Dunn, James C Y; Stelzner, Matthias; Martín, Martín G

2017-02-01

Intestinal failure is a rare life-threatening condition that results in the inability to maintain normal growth and hydration status by enteral nutrition alone. Although parenteral nutrition and whole organ allogeneic transplantation have improved the survival of these patients, current therapies are associated with a high risk for morbidity and mortality. Development of methods to propagate adult human intestinal stem cells (ISCs) and pluripotent stem cells raises the possibility of using stem cell-based therapy for patients with monogenic and polygenic forms of intestinal failure. Organoids have demonstrated the capacity to proliferate indefinitely and differentiate into the various cellular lineages of the gut. Genome-editing techniques, including the overexpression of the corrected form of the defective gene, or the use of CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to selectively correct the monogenic disease-causing variant within the stem cell, make autologous ISC transplantation a feasible approach. However, numerous techniques still need to be further optimized, including more robust ex vivo ISC expansion, native ISC ablation, and engraftment protocols. Large-animal models can to be used to develop such techniques and protocols and to establish the safety of autologous ISC transplantation because outcomes in such models can be extrapolated more readily to humans. Stem Cells Translational Medicine 2017;6:666-676. © 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Can mammalian cloning combined with embryonic stem cell technologies be used to treat human diseases?

PubMed Central

Hadjantonakis, Anna-Katerina; Papaioannou, Virginia E

2002-01-01

Cloning is commonly perceived as a means of generating genetically identical individuals, but it can also be used to obtain genetically matched embryo-derived stem cells, which could potentially be used in the treatment of patients. A recent report offers the first 'proof of principle' of such cloning for therapeutic purposes, referred to as nuclear transplantation to produce stem cells for autologous transplantation. PMID:12186652

[Ethical aspects of human embryonic stem cell use and commercial umbilical cord blood stem cell banking. Ethical reflections on the occasion of the regulation of the European Council and Parliament on advanced therapy medicinal products].

PubMed

Virt, G

2010-01-01

The regulation of the European Council and Parliament on advanced therapy medicinal products also includes therapies with human embryonic stem cells. The use of these stem cells is controversially and heavily discussed. Contrary to the use of adult stem cells, medical and ethical problems concerning the use of human embryonic stem cells persists, because this use is based on the destruction of human life at the very beginning. The regulation foresees, therefore, subsidiarity within the European Member States. Although there are no ethical problems in principle with the use of stem cells from the umbilical cord blood, there are social ethical doubts with the banking of these stem cells for autologous use without any currently foreseeable medical advantage by commercial blood banks. Also in this case subsidiarity is valid.

Regeneration of dental pulp by stem cells.

PubMed

Nakashima, M; Iohara, K

2011-07-01

Angiogenesis/vasculogenesis and neurogenesis are essential for pulp regeneration. Two subfractions of side-population (SP) cells, CD31(-)/CD146(-) SP cells and CD105(+) cells with angiogenic and neurogenic potential, were isolated by flow cytometry from canine dental pulp. In an experimental model of mouse hindlimb ischemia, transplantation of these cell populations resulted in an increase in blood flow, including high-density capillary formation. In a model of rat cerebral ischemia, stem cell transplantations enhanced neuronal regeneration and recovery from motor disability. Autologous transplantation of the CD31(-)/CD146(-) SP cells into an in vivo model of amputated pulp resulted in complete regeneration of pulp tissue with vascular and neuronal processes within 14 days. The transplanted cells expressed pro-angiogenic factors, implying trophic action on endothelial cells. Autologous transplantation of CD31(-)/CD146(-) SP cells or CD105(+) cells with stromal-cell-derived factor-1 (SDF-1) into root canals after whole pulp removal of mature teeth resulted in complete regeneration of pulp replete with nerves and vasculature by day 14, followed by dentin formation along the dentinal wall by day 35. Therefore, the potential utility of fractionated SP cells and CD105(+) cells in angiogenesis and neurogenesis was demonstrated by treatment of limb and cerebral ischemia following pulpotomy and pulpectomy.

Periodontal Ligament Stem Cell-Mediated Treatment for Periodontitis in Miniature Swine

PubMed Central

Liu, Yi; Zheng, Ying; Ding, Gang; Fang, Dianji; Zhang, Chunmei; Bartold, Peter Mark; Gronthos, Stan; Shi, Songtao; Wang, Songlin

2009-01-01

Periodontitis is a periodontal tissue infectious disease and the most common cause for tooth loss in adults. It has been linked to many systemic disorders, such as coronary artery disease, stroke, and diabetes. At present, there is no ideal therapeutic approach to cure periodontitis and achieve optimal periodontal tissue regeneration. In this study, we explored the potential of using autologous periodontal ligament stem cells (PDLSCs) to treat periodontal defects in a porcine model of periodontitis. The periodontal lesion was generated in the first molars area of miniature pigs by the surgical removal of bone and subsequent silk ligament suture around the cervical portion of the tooth. Autologous PDLSCs were obtained from extracted teeth of the miniature pigs and then expanded ex vivo to enrich PDLSC numbers. When transplanted into the surgically created periodontal defect areas, PDLSCs were capable of regenerating periodontal tissues, leading to a favorable treatment for periodontitis. This study demonstrates the feasibility of using stem cell-mediated tissue engineering to treat periodontal diseases. PMID:18238856

Concise Review: Bioprinting of Stem Cells for Transplantable Tissue Fabrication.

PubMed

Leberfinger, Ashley N; Ravnic, Dino J; Dhawan, Aman; Ozbolat, Ibrahim T

2017-10-01

Bioprinting is a quickly progressing technology, which holds the potential to generate replacement tissues and organs. Stem cells offer several advantages over differentiated cells for use as starting materials, including the potential for autologous tissue and differentiation into multiple cell lines. The three most commonly used stem cells are embryonic, induced pluripotent, and adult stem cells. Cells are combined with various natural and synthetic materials to form bioinks, which are used to fabricate scaffold-based or scaffold-free constructs. Computer aided design technology is combined with various bioprinting modalities including droplet-, extrusion-, or laser-based bioprinting to create tissue constructs. Each bioink and modality has its own advantages and disadvantages. Various materials and techniques are combined to maximize the benefits. Researchers have been successful in bioprinting cartilage, bone, cardiac, nervous, liver, and vascular tissues. However, a major limitation to clinical translation is building large-scale vascularized constructs. Many challenges must be overcome before this technology is used routinely in a clinical setting. Stem Cells Translational Medicine 2017;6:1940-1948. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

A Contact-Based Method for Differentiation of Human Mesenchymal Stem Cells into an Endothelial Cell-Phenotype.

PubMed

Joddar, Binata; Kumar, Shweta Anil; Kumar, Alok

2018-06-01

Adult stem cells such as mesenchymal stem cells (MSC) are known to possess the ability to augment neovascularization processes and are thus widely popular as an autologous source of progenitor cells. However there is a huge gap in our current knowledge of mechanisms involved in differentiating MSC into endothelial cells (EC), essential for lining engineered blood vessels. To fill up this gap, we attempted to differentiate human MSC into EC, by culturing the former onto chemically fixed layers of EC or its ECM, respectively. We expected direct contact of MSC when cultured atop fixed EC or its ECM, would coax the former to differentiate into EC. Results showed that human MSC cultured atop chemically fixed EC or its ECM using EC-medium showed enhanced expression of CD31, a marker for EC, compared to other cases. Further in all human MSC cultured using EC-medium, typically characteristic cobble stone shaped morphologies were noted in comparison to cells cultured using MSC medium, implying that the differentiated cells were sensitive to soluble VEGF supplementation present in the EC-medium. Results will enhance and affect therapies utilizing autologous MSC as a cell source for generating vascular cells to be used in a variety of tissue engineering applications.

Tissue-engineered composite scaffold of poly(lactide-co-glycolide) and hydroxyapatite nanoparticles seeded with autologous mesenchymal stem cells for bone regeneration.

PubMed

Zhang, Bing; Zhang, Pei-Biao; Wang, Zong-Liang; Lyu, Zhong-Wen; Wu, Han

A new therapeutic strategy using nanocomposite scaffolds of grafted hydroxyapatite (g-HA)/ poly(lactide-co-glycolide) (PLGA) carried with autologous mesenchymal stem cells (MSCs) and bone morphogenetic protein-2 (BMP-2) was assessed for the therapy of critical bone defects. At the same time, tissue response and in vivo mineralization of tissue-engineered implants were investigated. A composite scaffold of PLGA and g-HA was fabricated by the solvent casting and particulate-leaching method. The tissue-engineered implants were prepared by seeding the scaffolds with autologous bone marrow MSCs in vitro. Then, mineralization and osteogenesis were observed by intramuscular implantation, as well as the repair of the critical radius defects in rabbits. After eight weeks post-surgery, scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) revealed that g-HA/PLGA had a better interface of tissue response and higher mineralization than PLGA. Apatite particles were formed and varied both in macropores and micropores of g-HA/PLGA. Computer radiographs and histological analysis revealed that there were more and more quickly formed new bone formations and better fusion in the bone defect areas of g-HA/PLGA at 2-8 weeks post-surgery. Typical bone synostosis between the implant and bone tissue was found in g-HA/PLGA, while only fibrous tissues formed in PLGA. The incorporation of g-HA mainly improved mineralization and bone formation compared with PLGA. The application of MSCs can enhance bone formation and mineralization in PLGA scaffolds compared with cell-free scaffolds. Furthermore, it can accelerate the absorption of scaffolds compared with composite scaffolds.

Allogeneic MSCs and Recycled Autologous Chondrons Mixed in a One-Stage Cartilage Cell Transplantion: A First-in-Man Trial in 35 Patients.

PubMed

de Windt, Tommy S; Vonk, Lucienne A; Slaper-Cortenbach, Ineke C M; Nizak, Razmara; van Rijen, Mattie H P; Saris, Daniel B F

2017-08-01

MSCs are known as multipotent mesenchymal stem cells that have been found capable of differentiating into various lineages including cartilage. However, recent studies suggest MSCs are pericytes that stimulate tissue repair through trophic signaling. Aimed at articular cartilage repair in a one-stage cell transplantation, this study provides first clinical evidence that MSCs stimulate autologous cartilage repair in the knee without engrafting in the host tissue. A phase I (first-in-man) clinical trial studied the one-stage application of allogeneic MSCs mixed with 10% or 20% recycled defect derived autologous chondrons for the treatment of cartilage defects in 35 patients. No treatment-related serious adverse events were found and statistically significant improvement in clinical outcome shown. Magnetic resonance imaging and second-look arthroscopies showed consistent newly formed cartilage tissue. A biopsy taken from the center of the repair tissue was found to have hyaline-like features with a high concentration of proteoglycans and type II collagen. DNA short tandem repeat analysis delivered unique proof that the regenerated tissue contained patient-DNA only. These findings support the hypothesis that allogeneic MSCs stimulate a regenerative host response. This first-in-man trial supports a paradigm shift in which MSCs are applied as augmentations or "signaling cells" rather than differentiating stem cells and opens doors for other applications. Stem Cells 2017;35:1984-1993. © 2017 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

The Role of Mesenchymal Stem Cells in the Regenerative Wound Healing Phenotype.

PubMed

Balaji, Swathi; Keswani, Sundeep G; Crombleholme, Timothy M

2012-08-01

Mesenchymal stem cells (MSCs) are key to regenerative wound healing. MSCs have spatial memory and respond to local environment. MSCs orchestrate wound repair by: (1) structural repair via cellular differentiation; (2) immune-modulation; (3) secretion of growth factors that drive neovascularization and re-epithelialization; and (4) mobilization of resident stem cells. Autologous bone-marrow-derived cells and MSCs demonstrate improved healing and tissue-integrity in animal models and clinical trials. However, the effects are variable and the mechanisms of MSC-mediated wound healing are not fully understood. The mammalian MSC niche and signaling sequences and factors affecting their homing, differentiation, viability, and safety need to be characterized to get full benefits of MSC cellular therapy. MSCs can be isolated from bone-marrow, and less-invasive tissues such as adipose, gingiva, muscle, and umbilical cord, with similar functional effects. However, isolation, culture conditions, and markers used to identify and trace the lineage of these MSCs have not been standardized, which is crucial to determine the extent to which MSCs act as multipotent stem cells or sources of secreted factors in wounds. In chronic nonhealing wounds, where efficacy of conventional therapies is unsatisfactory, autotransplantation of MSCs could accelerate wound healing, promote regeneration and restoration of tissue integrity, and reduce recurrence of wounds at characteristically predisposed sites. Regenerative medicine and novel wound therapies using autologous stem cells holds great promise for clinical management of difficult wounds. The ideal candidate stem cells can be used to repopulate the wound bed to mediate appropriate epidermal and dermal regeneration and promote efficient wound repair, while modulating the immune system to prevent infection.

Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: Subset analysis of randomized trial intergroup SWOG S9704

PubMed Central

Puvvada, Soham D.; Stiff, Patrick J.; Leblanc, Michael; Cook, James R.; Couban, Stephen; Leonard, John P.; Kahl, Brad; Marcellus, Deborah; Shea, Thomas C.; Winter, Jane N.; Li, Hongli; Rimsza, Lisa M.; Friedberg, Jonathan W.; Smith, Sonali M.

2016-01-01

Summary Double hit lymphoma (DHL) and double protein-expressing (MYC and BCL2) lymphomas (DPL) fare poorly with R-CHOP; consolidative autologous stem cell transplant (ASCT) may improve outcomes. S9704, a phase III randomized study of CHOP +/−R with or without ASCT allows evaluation of intensive consolidation. Immunohistochemical analysis identified 27 of 198 patients (13.6%) with MYC IHC overexpression and 20 (74%) harboring concurrent BCL2 overexpression. Four had DHL and 16 had DPL only. With median follow-up 127 months, there is a trend favoring outcomes after consolidative ASCT in DPL and MYC protein overexpressing patients, whereas all DHL patients have died irrespective of ASCT. PMID:27072903

Generation of functional hepatocyte-like cells from human deciduous periodontal ligament stem cells.

PubMed

Vasanthan, Punitha; Jayaraman, Pukana; Kunasekaran, Wijenthiran; Lawrence, Anthony; Gnanasegaran, Nareshwaran; Govindasamy, Vijayendran; Musa, Sabri; Kasim, Noor Hayaty Abu

2016-08-01

Human deciduous periodontal ligament stem cells have been introduced for as an easily accessible source of stem cells from dental origin. Although recent studies have revealed the ability of these stem cells in multipotential attribute, their efficiency of hepatic lineage differentiation has not been addressed so far. The aim of this study is to investigate hepatic lineage fate competence of periodontal ligament stem cells through direct media induction. Differentiation of periodontal ligament stem cells into hepatocyte-like cells was conducted by the exposure of two phase media induction. First phase was performed in the presence of hepatocyte growth factors to induce a definitive endoderm formation. In the subsequent phase, the cells were treated with oncostatin M and dexamethosone followed by insulin and transferrin to generate hepatocyte-like cells. Hepatic-related characters of the generated hepatocyte-like cells were determined at both mRNA and protein level followed by functional assays. Foremost changes observed in the generation of hepatocyte-like cells were the morphological features in which these cells were transformed from fibroblastic shape to polygonal shape. Temporal expression of hepatic markers ranging from early endodermal up to late markers were detected in the hepatocyte-like cells. Crucial hepatic markers such as glycogen storage, albumin, and urea secretion were also shown. These findings exhibited the ability of periodontal ligament stem cells of dental origin to be directed into hepatic lineage fate. These cells can be regarded as an alternative autologous source in the usage of stem cell-based treatment for liver diseases.

Generation of functional hepatocyte-like cells from human deciduous periodontal ligament stem cells

NASA Astrophysics Data System (ADS)

Vasanthan, Punitha; Jayaraman, Pukana; Kunasekaran, Wijenthiran; Lawrence, Anthony; Gnanasegaran, Nareshwaran; Govindasamy, Vijayendran; Musa, Sabri; Kasim, Noor Hayaty Abu

2016-08-01

Human deciduous periodontal ligament stem cells have been introduced for as an easily accessible source of stem cells from dental origin. Although recent studies have revealed the ability of these stem cells in multipotential attribute, their efficiency of hepatic lineage differentiation has not been addressed so far. The aim of this study is to investigate hepatic lineage fate competence of periodontal ligament stem cells through direct media induction. Differentiation of periodontal ligament stem cells into hepatocyte-like cells was conducted by the exposure of two phase media induction. First phase was performed in the presence of hepatocyte growth factors to induce a definitive endoderm formation. In the subsequent phase, the cells were treated with oncostatin M and dexamethosone followed by insulin and transferrin to generate hepatocyte-like cells. Hepatic-related characters of the generated hepatocyte-like cells were determined at both mRNA and protein level followed by functional assays. Foremost changes observed in the generation of hepatocyte-like cells were the morphological features in which these cells were transformed from fibroblastic shape to polygonal shape. Temporal expression of hepatic markers ranging from early endodermal up to late markers were detected in the hepatocyte-like cells. Crucial hepatic markers such as glycogen storage, albumin, and urea secretion were also shown. These findings exhibited the ability of periodontal ligament stem cells of dental origin to be directed into hepatic lineage fate. These cells can be regarded as an alternative autologous source in the usage of stem cell-based treatment for liver diseases.

Haemopoietic stem cell transplantation in Australia and New Zealand, 1992-2001: progress report from the Australasian Bone Marrow Transplant Recipient Registry.

PubMed

Nivison-Smith, I; Bradstock, K F; Dodds, A J; Hawkins, P A; Szer, J

2005-01-01

Bone marrow and blood stem cell transplantation is now used as curative therapy for a range of haematological malignancies and other conditions. The Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) has recorded transplant activity in Australia since 1992; transplant centres in New Zealand have corresponded with the Registry since 1998. To describe allogeneic and autologous bone marrow and blood stem cell transplantation activity and outcomes in Australia and New Zealand from 1992 to 2001. Each haemopoietic stem cell transplant centre in Australia and New Zealand contributes information to the Registry via a single information form compiled when a transplant is performed. An annual follow-up request is then sent from the Registry to the contributing centre at the anniversary of each individual transplant. Haemopoietic stem cell transplants in Australia have increased in number from 478 in 1992 to 937 in 2001, whereas in New Zealand the number has grown from 91 in 1998 to 105 in 2001, mainly as a result of an increase in autologous blood stem cell transplants. The number of hospitals contributing to the ABMTRR has grown from 20 in 1992 to 37 in 2001. The most common indication for autologous transplantation in 2001 was non-Hodgkin's lymphoma, whereas for allogeneic transplants it was acute myeloid leukaemia. The 9-year actuarial disease-free survival probability for patients aged 16 and above between 1992 and 2000 was 37% for autologous, 39% for allogeneic related donor and 30% for allogeneic unrelated donor transplants. Recurrence of the underlying disease was the main cause of death post-transplant after both allogeneic (26.3% of deaths in the first year and 68.0% of deaths in the second year) and autologous transplants (59.0% and 86.2%). Treatment-related mortality was 16.9% after allogeneic transplantation and 2.1% after autologous transplantation in 2000. The ABMTRR provides a comprehensive source of information on the use of bone marrow

Genome Modification Leads to Phenotype Reversal in Human Myotonic Dystrophy type 1 iPS-cell Derived Neural Stem Cells

PubMed Central

Xia, Guangbin; Gao, Yuanzheng; Jin, Shouguang; Subramony, SH.; Terada, Naohiro; Ranum, Laura P.W.; Swanson, Maurice S.; Ashizawa, Tetsuo

2015-01-01

Objective Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the 3'-untranslated region (3’ UTR) of the DMPK gene. Correcting the mutation in DM1 stem cells would be an important step towards autologous stem cell therapy. The objective of this study is to demonstrate in vitro genome editing to prevent production of toxic mutant transcripts and reverse phenotypes in DM1 stem cells. Methods Genome editing was performed in DM1 neural stem cells (NSCs) derived from human DM1 iPS cells. An editing cassette containing SV40/bGH polyA signals was integrated upstream of the CTG repeats by TALEN-mediated homologous recombination (HR). The expression of mutant CUG repeats transcript was monitored by nuclear RNA foci, the molecular hallmarks of DM1, using RNA fluorescence in situ hybridization (RNA-FISH). Alternative splicing of microtubule-associated protein tau (MAPT) and muscleblind-like (MBNL) proteins were analyzed to further monitor the phenotype reversal after genome modification. Results The cassette was successfully inserted into DMPK intron 9 and this genomic modification led to complete disappearance of nuclear RNA foci. MAPT and MBNL 1, 2 aberrant splicing in DM1 NSCs was reversed to normal pattern in genome-modified NSCs. Interpretation Genome modification by integration of exogenous polyA signals upstream of the DMPK CTG repeat expansion prevents the production of toxic RNA and leads to phenotype reversal in human DM1 iPS-cells derived stem cells. Our data provide proof-of-principle evidence that genome modification may be used to generate genetically modified progenitor cells as a first step toward autologous cell transfer therapy for DM1. PMID:25702800

Infused autograft lymphocyte-to-monocyte ratio and survival in T-cell lymphoma post-autologous peripheral blood hematopoietic stem cell transplantation.

PubMed

Porrata, Luis F; Inwards, David J; Ansell, Stephen M; Micallef, Ivana N; Johnston, Patrick B; Hogan, William J; Markovic, Svetomir N

2015-07-03

The infused autograft lymphocyte-to-monocyte ratio (A-LMR) is a prognostic factor for survival in B-cell lymphomas post-autologous peripheral hematopoietic stem cell transplantation (APHSCT). Thus, we set out to investigate if the A-LMR is also a prognostic factor for survival post-APHSCT in T-cell lymphomas. From 1998 to 2014, 109 T-cell lymphoma patients that underwent APHSCT were studied. Receiver operating characteristic (ROC) and area under the curve (AUC) were used to identify the optimal cut-off value of A-LMR for survival analysis and k-fold cross-validation model to validate the A-LMR cut-off value. Univariate and multivariate Cox proportional hazard models were used to assess the prognostic discriminator power of A-LMR. ROC and AUC identified an A-LMR ≥ 1 as the best cut-off value and was validated by k-fold cross-validation. Multivariate analysis showed A-LMR to be an independent prognostic factor for overall survival (OS) and progression-free survival (PFS). Patients with an A-LMR ≥ 1.0 experienced a superior OS and PFS versus patients with an A-LMR < 1.0 [median OS was not reached vs 17.9 months, 5-year OS rates of 87% (95% confidence interval (CI), 75-94%) vs 26% (95% CI, 13-42%), p < 0.0001; median PFS was not reached vs 11.9 months, 5-year PFS rates of 72% (95% CI, 58-83%) vs 16% (95% CI, 6-32%), p < 0.0001]. A-LMR is also a prognostic factor for clinical outcomes in patients with T-cell lymphomas undergoing APHSCT.

Comparison of Nutrition-Related Adverse Events and Clinical Outcomes Between ICE (Ifosfamide, Carboplatin, and Etoposide) and MCEC (Ranimustine, Carboplatin, Etoposide, and Cyclophosphamide) Therapies as Pretreatment for Autologous Peripheral Blood Stem Cell Transplantation in Patients with Malignant Lymphoma

PubMed Central

Imataki, Osamu; Arai, Hidekazu; Kume, Tetsuo; Shiozaki, Hitomi; Katsumata, Naomi; Mori, Mariko; Ishide, Keiko; Ikeda, Takashi

2018-01-01

Background The aim of this study was to compare nutrition-related adverse events and clinical outcomes of ifosfamide, carboplatin, and etoposide regimen (ICE therapy) and ranimustine, carboplatin, etoposide, and cyclophosphamide regimen (MCEC therapy) instituted as pretreatment for autologous peripheral blood stem cell transplantation. Material/Methods We enrolled patients who underwent autologous peripheral blood stem cell transplantation between 2007 and 2012. Outcomes were compared between ICE therapy (n=14) and MCEC therapy (n=14) in relation to nutrient balance, engraftment day, and length of hospital stay. In both groups, we compared the timing of nutrition-related adverse events with oral caloric intake, analyzed the correlation between length of hospital stay and duration of parenteral nutrition, and investigated the association between oral caloric intake and the proportion of parenteral nutrition energy in total calorie supply. Five-year survival was compared between the groups. Results Compared with the MCEC group, the ICE group showed significant improvement in oral caloric intake, length of hospital stay, and timing of nutrition-related adverse events and oral calorie intake, but a delay in engraftment. Both groups showed a correlation between duration of parenteral nutrition and length of hospital stay (P=0.0001) and between oral caloric intake (P=0.0017) and parenteral nutrition energy sufficiency rate (r=−0.73, P=0.003; r=−0.76, P=0.002). Five-year survival was not significantly different between the groups (P=0.1355). Conclusions Our findings suggest that compared with MCEC therapy, ICE therapy improves nutrition-related adverse events and reduces hospital stay, conserving medical resources, with no significant improvement in long-term survival. The nutritional pathway may serve as a tool for objective evaluation of pretreatment for autologous peripheral blood stem cell transplantation. PMID:29398693

Is it feasible to conduct a randomised controlled trial of pretransplant exercise (prehabilitation) for patients with multiple myeloma awaiting autologous haematopoietic stem cell transplantation? Protocol for the PREeMPT study.

PubMed

Keen, Carol; Skilbeck, Julie; Ross, Helen; Smith, Lauren; Collins, Karen; Dixey, Joanne; Walters, Stephen; Greenfield, Diana M; Snowden, John A; Mawson, Susan

2018-03-09

While myeloma is an incurable malignancy, developments in disease management have led to increased life expectancy in recent years. Treatment typically involves stem-cell transplantation. Increased survival rates equate to more patients living with the burden of both the disease and its treatment for increasing number of years, rendering myeloma a long-term condition.Evidence exists to demonstrate the benefits of exercise for patients recovering from stem-cell transplantation, and prehabilitation-exercise before treatment-has been shown to be effective in other disease areas. To date there has been no research into prehabilitation in patients with myeloma awaiting transplantation treatment.Our objective is to determine whether it is feasible to conduct a randomised controlled trial into pretransplant exercise for patients with multiple myeloma who are awaiting autologous stem-cell transplantation. This mixed methods study identifies patients with diagnosis of multiple myeloma who have been assigned to the autologous transplantation list and invites them to participate in six weekly sessions of individualised, supervised exercise while awaiting transplantation.Quantitative data to determine feasibility targets include rates of recruitment, adherence and adverse events, and outcome measures including 6 min walking distance test and quality of life.Qualitative interviews are undertaken with a purposive sample of patients to capture their experiences of the study and the intervention. Ethics committee approval has been obtained. Dissemination will be through open-access publications and presentations and will seek to reach multiprofessional bases as well as patients and carer groups, addressing the widespread interest in this area of research. NCT03135925; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Research Advancements in Porcine Derived Mesenchymal Stem Cells

PubMed Central

Bharti, Dinesh; Shivakumar, Sharath Belame; Subbarao, Raghavendra Baregundi; Rho, Gyu-Jin

2016-01-01

In the present era of stem cell biology, various animals such as Mouse, Bovine, Rabbit and Porcine have been tested for the efficiency of their mesenchymal stem cells (MSCs) before their actual use for stem cell based application in humans. Among them pigs have many similarities to humans in the form of organ size, physiology and their functioning, therefore they have been considered as a valuable model system for in vitro studies and preclinical assessments. Easy assessability, few ethical issues, successful MSC isolation from different origins like bone marrow, skin, umbilical cord blood, Wharton’s jelly, endometrium, amniotic fluid and peripheral blood make porcine a good model for stem cell therapy. Porcine derived MSCs (pMSCs) have shown greater in vitro differentiation and transdifferention potential towards mesenchymal lineages and specialized lineages such as cardiomyocytes, neurons, hepatocytes and pancreatic beta cells. Immunomodulatory and low immunogenic profiles as shown by autologous and heterologous MSCs proves them safe and appropriate models for xenotransplantation purposes. Furthermore, tissue engineered stem cell constructs can be of immense importance in relation to various osteochondral defects which are difficult to treat otherwise. Using pMSCs successful treatment of various disorders like Parkinson’s disease, cardiac ischemia, hepatic failure, has been reported by many studies. Here, in this review we highlight current research findings in the area of porcine mesenchymal stem cells dealing with their isolation methods, differentiation ability, transplantation applications and their therapeutic potential towards various diseases. PMID:26201864

Human Herpesvirus-6 cytopathic inclusions: an exceptional and recognizable finding on skin biopsy during HHV6 reactivation after autologous stem-cell transplantation.

PubMed

Roux, Jennifer; Battistella, Maxime; Fornecker, Luc; Legoff, Jérôme; Deau, Bénédicte; Houhou, Nadira; Bouaziz, Jean-David; Thieblemont, Catherine; Janin, Anne

2012-08-01

Skin rash are common in immunocompromised patients, particularly after bone marrow transplantation. Human herpes virus 6 (HHV6) reactivation is often suspected, but its clinical presentation and the routine laboratory tests may be unspecific, thus leading to late diagnosis. In this case, we report specific intralymphocytic cytopathic inclusions on skin biopsy as a sign of systemic HHV6 reactivation. A 56-year-old patient presented progressive erythroderma and fever occurring after autologous hematopoietic stem-cell transplantation for mantle cell lymphoma. The skin biopsy showed a perivascular infiltrate of medium-to-large lymphocytes with irregular nuclei containing a large central basophilic inclusion surrounded by a clear halo. High levels of HHV-6 genomic in skin biopsy confirm HHV-6-induced cytopathic effect. The clinical course improved with intravenous foscavir. The specific histopathological findings encountered in this case are exceptional but recognizable, and along with HHV-6 DNA detection allow a prompt recognition of HHV6 skin rash.

Antibody responses to tetanus toxoid and Haemophilus influenzae type b conjugate vaccines following autologous peripheral blood stem cell transplantation (PBSCT).

PubMed

Chan, C Y; Molrine, D C; Antin, J H; Wheeler, C; Guinan, E C; Weinstein, H J; Phillips, N R; McGarigle, C; Harvey, S; Schnipper, C; Ambrosino, D M

1997-07-01

Accelerated granulocyte and platelet recovery following peripheral blood stem cell transplantation (PBSCT) are well documented. We hypothesize that functional immunity may also be enhanced in PBSCT and performed a phase II trial of immunizations in patients with lymphoma undergoing autologous transplantation with peripheral blood stem cells or bone marrow. Seventeen BMT and 10 PBSCT recipients were immunized at 3, 6, 12, and 24-months post-transplantation with Haemophilus influenzae type b (HIB)-conjugate and tetanus toxoid (TT) vaccines. IgG anti-HIB and anti-TT antibody concentrations were measured and compared between the two groups. Geometric mean IgG anti-HIB antibody concentrations were significantly higher for PBSCT recipients compared to BMT recipients at 24 months post-transplantation (11.3 micrograms/ml vs 0.93 microgram/ml, P = 0.051) and following the 24 month immunization (66.2 micrograms/ml vs 1.30 micrograms/ml, P = 0.006). Similar results were noted for IgG anti-TT antibody with significantly higher geometric mean antibody concentrations in the PBSCT group at 24 months post-transplantation (182 micrograms/ml vs 21.6 micrograms/ml, P = 0.039). Protective levels of total anti-HIB antibody were achieved earlier in PBSCT recipients compared with those of BMT recipients. PBSCT recipients had higher antigen-specific antibody concentrations following HIB and TT immunizations. These results suggest enhanced recovery of humoral immunity in PBSCT recipients and earlier protection against HIB with immunization.

Dendrimer-driven neurotrophin expression differs in temporal patterns between rodent and human stem cells.

PubMed

Shakhbazau, Antos; Shcharbin, Dzmitry; Seviaryn, Ihar; Goncharova, Natalya; Kosmacheva, Svetlana; Potapnev, Mihail; Bryszewska, Maria; Kumar, Ranjan; Biernaskie, Jeffrey; Midha, Rajiv

2012-05-07

This study reports the use of a nonviral expression system based on polyamidoamine dendrimers for time-restricted neurotrophin overproduction in mesenchymal stem cells and skin precursor-derived Schwann cells. The dendrimers were used to deliver plasmids for brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) expression in both rodent and human stem cells, and the timelines of expression were studied. We have found that, despite the fact that transfection efficiencies and protein expression levels were comparable, dendrimer-driven expression in human mesenchymal stem cells was characterized by a more rapid decline compared to rodent cells. Transient expression systems can be beneficial for some neurotrophins, which were earlier reported to cause unwanted side effects in virus-based long-term expression models. Nonviral neurotrophin expression is a biologically safe and accessible alternative to increase the therapeutic potential of autologous adult stem cells and stem cell-derived functional differentiated cells.

Genetic modification of hematopoietic stem cells: recent advances in the gene therapy of inherited diseases.

PubMed

Bueren, Juan A; Guenechea, Guillermo; Casado, José A; Lamana, María Luisa; Segovia, José C

2003-01-01

Hematopoietic stem cells constitute a rare population of precursor cells with remarkable properties for being used as targets in gene therapy protocols. The last years have been particularly productive both in the fields of gene therapy and stem cell biology. Results from ongoing clinical trials have shown the first unquestionable clinical benefits of immunodeficient patients transplanted with genetically modified autologous stem cells. On the other hand, severe side effects in a few patients treated with gene therapy have also been reported, indicating the usefulness of further improving the vectors currently used in gene therapy clinical trials. In the field of stem cell biology, evidence showing the plastic potential of adult hematopoietic stem cells and data indicating the multipotency of adult mesenchymal precursor cells have been presented. Also, the generation of embryonic stem cells by means of nuclear transfer techniques has appeared as a new methodology with direct implications in gene therapy.

[Multiple organ failure presumably due to alkylating agents used as preconditioning drugs for autologous peripheral blood stem cell transplantation in an acute promyelocytic leukemia].

PubMed

Ida, Tori; Hashimoto, Shigeo; Suzuki, Nobuaki; Ebe, Yusuke; Yano, Toshio; Sato, Naoko; Koike, Tadashi

2016-01-01

A 52-year-old male was diagnosed as having acute promyelocytic leukemia (APL) in 2006. He received induction chemotherapy including all-trans retinoic acid and initially achieved a complete remission (CR). After several courses of consolidation therapy combining anthracyclines and cytarabine, he maintained CR. In 2009, an APL relapse was diagnosed, and he was treated with arsenic trioxide. Since he achieved a second CR, he underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) with a conditioning regimen consisting of busulfan and melphalan. At four months after auto-PBSCT, he developed a pneumothorax and acute respiratory failure. He died despite intensive therapy. Autopsy findings included various atypical and apoptotic cells in his pulmonary tissue. These changes were confirmed in multiple organs throughout the body, suggesting them to be drug-induced. The findings in this case suggested multiple organ failure due to alkylating agents.

Mesenchymal Stem Cells: New Players in Retinopathy Therapy

PubMed Central

Rajashekhar, Gangaraju

2014-01-01

Retinopathies in human and animal models have shown to occur through loss of pericytes resulting in edema formation, excessive immature retinal angiogenesis, and neuronal apoptosis eventually leading to blindness. In recent years, the concept of regenerating terminally differentiated organs with a cell-based therapy has evolved. The cells used in these approaches are diverse and include tissue-specific endogenous stem cells, endothelial progenitor (EPC), embryonic stem cells, induced pluripotent stem cells (iPSC) and mesenchymal stem cells (MSC). Recently, MSC derived from the stromal fraction of adipose tissue have been shown to possess pluripotent differentiation potential in vitro. These adipose stromal cells (ASC) have been differentiated in a number of laboratories to osteogenic, myogenic, vascular, and adipocytic cell phenotypes. In vivo, ASC have been shown to have functional and phenotypic overlap with pericytes lining microvessels in adipose tissues. Furthermore, these cells either in paracrine mode or physical proximity with endothelial cells, promoted angiogenesis, improved ischemia–reperfusion, protected from myocardial infarction, and were neuroprotective. Owing to the easy isolation procedure and abundant supply, fat-derived ASC are a more preferred source of autologous mesenchymal cells compared to bone marrow MSC. In this review, we present evidence that these readily available ASC from minimally invasive liposuction will facilitate translation of ASC research into patients with retinal diseases in the near future. PMID:24795699

Banking on cord blood stem cells.

PubMed

Sullivan, Michael J

2008-07-01

Umbilical cord blood gifted to non-profit public cord blood banks is now routinely used as an alternative source of haematopoietic stem cells for allogeneic transplantation for children and adults with cancer, bone marrow failure syndromes, haemoglobinopathies and many genetic metabolic disorders. Because of the success and outcomes of public cord banking, many companies now provide private cord banking services. However, in the absence of any published transplant evidence to support autologous and non-directed family banking, commercial cord banks currently offer a superfluous service.

The lived experience of autologous stem cell-transplanted patients: Post-transplantation and before discharge.

PubMed

Alnasser, Qasem; Abu Kharmah, Salahel Deen; Attia, Manal; Aljafari, Akram; Agyekum, Felicia; Ahmed, Falak Aftab

2018-04-01

To explore the lived experience of the patients post-haematopoietic stem cell transplantation and specifically after engraftment and before discharge. Patients post-stem cell transplantation experience significant changes in all life aspects. Previous studies carried out by other researchers focused mainly on the postdischarge experience, where patients reported their perceptions that have always been affected by the life post-transplantation and influenced by their surroundings. The lived experience of patients, specifically after engraftment and prior to discharge (the "transition" phase), has not been adequately explored in the literature. Doing so might provide greater insight into the cause of change post-haematopoietic stem cell transplantation. This study is a phenomenological description of the participants' perception about their lived experience post-haematopoietic stem cell transplantation. The study used Giorgi's method of analysis. Through purposive sampling, 15 post-haematopoietic stem cell transplantation patients were recruited. Data were collected by individual interviews. Data were then analysed based on Giorgi's method of analysis to reveal the meaning of a phenomenon as experienced through the identification of essential themes. The analysis process revealed 12 core themes covered by four categories that detailed patients lived experience post-haematopoietic stem cell transplantation. The four categories were general transplant experience, effects of transplantation, factors of stress alleviation and finally life post-transplantation. This study showed how the haematopoietic stem cell transplantation affected the patients' physical, psychological and spiritual well-being. Transplantation also impacted on the patients' way of thinking and perception of life. Attending to patients' needs during transplantation might help to alleviate the severity of the effects and therefore improve experience. Comprehensive information about transplantation needs

Comparison of the glycosphingolipids of human-induced pluripotent stem cells and human embryonic stem cells.

PubMed

Säljö, Karin; Barone, Angela; Vizlin-Hodzic, Dzeneta; Johansson, Bengt R; Breimer, Michael E; Funa, Keiko; Teneberg, Susann

2017-04-01

High expectations are held for human-induced pluripotent stem cells (hiPSC) since they are established from autologous tissues thus overcoming the risk of allogeneic immune rejection when used in regenerative medicine. However, little is known regarding the cell-surface carbohydrate antigen profile of hiPSC compared with human embryonic stem cells (hESC). Here, glycosphingolipids were isolated from an adipocyte-derived hiPSC line, and hiPSC and hESC glycosphingolipids were compared by concurrent characterization by binding assays with carbohydrate-recognizing ligands and mass spectrometry. A high similarity between the nonacid glycosphingolipids of hiPSC and hESC was found. The nonacid glycosphingolipids P1 pentaosylceramide, x2 pentaosylceramide and H type 1 heptaosylceramide, not previously described in human pluripotent stem cells (hPSC), were characterized in both hiPSC and hESC. The composition of acid glycosphingolipids differed, with increased levels of GM3 ganglioside, and reduced levels of GD1a/GD1b in hiPSC when compared with hESC. In addition, the hESC glycosphingolipids sulf-globopentaosylceramide and sialyl-globotetraosylceramide were lacking in hiPSC. Neural stem cells differentiating from hiPSC had a reduced expression of sialyl-lactotetra, whereas expression of the GD1a ganglioside was significantly increased. Thus, while sialyl-lactotetra is a marker of undifferentiated hPSC, GD1a is a novel marker of neural differentiation. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Disease and Stem Cell-Based Analysis of the 2014 ASNTR Meeting

PubMed Central

Eve, David J.

2015-01-01

A wide variety of subjects are presented at the annual American Society of Neural Therapy and Repair meeting every year, as typified by this summary of the 2014 meeting. Parkinson’s disease-related presentations were again the most popular topic, with traumatic brain injury, spinal cord injury, and stroke being close behind. Other disorders included Huntington’s disease, brain cancer, and bipolar disorders. Several studies were related to multiple diseases, and many studies attempted to reveal more about the disease process. The use of scaffolds, drugs, and gene therapy as disease models and/or potential therapies were also featured. An increasing proportion of presentations related to stem cells, with the study of multiple stem cell types being the most common. Induced pluripotent stem cells were increasingly popular, including two presentations each on a muscle-derived dedifferentiated cell type and cells derived from bipolar patients. Other stem cells, including neural stem cells, mesenchymal stem cells, umbilical cord blood cells, and embryonic stem cells, were featured. More than 55% of the stem cell studies involved transplantation, with human-derived cells being the most frequently transplanted, while rats were the most common recipient. Two human autologous studies for spinal cord injury and hypoxia-derived encephalopathy, while a further three allogenic studies for stroke and spinal cord injury, were also featured. This year’s meeting highlights the increasing promise of stem cells and other therapies for the treatment of neurodegenerative disorders. PMID:26858901

Music therapy for mood disturbance during hospitalization for autologous stem cell transplantation: a randomized controlled trial.

PubMed

Cassileth, Barrie R; Vickers, Andrew J; Magill, Lucanne A

2003-12-15

High-dose therapy with autologous stem cell transplantation (HDT/ASCT) is a commonly used treatment for hematologic malignancies. The procedure causes significant psychological distress and no interventions have been demonstrated to improve mood in these patients. Music therapy has been shown to improve anxiety in a variety of acute medical settings. In the current study, the authors determined the effects of music therapy compared with standard care on mood during inpatient stays for HDT/ASCT. Patients with hematologic malignancy admitted for HDT/ASCT at two sites (Memorial Sloan-Kettering Cancer Center and Ireland Cancer Center in Cleveland, Ohio) were randomized to receive music therapy given by trained music therapists or standard care. Outcome was assessed at baseline and every 3 days after randomization using the Profile of Mood States. Of 69 patients registered in the study, follow-up data were available for 62 (90%). During their inpatient stay, patients in the music therapy group scored 28% lower on the combined Anxiety/Depression scale (P = 0.065) and 37% lower (P = 0.01) on the total mood disturbance score compared with controls. Music therapy is a noninvasive and inexpensive intervention that appears to reduce mood disturbance in patients undergoing HDT/ASCT. Copyright 2003 American Cancer Society.

[Tissue engineering with mesenchymal stem cells for cartilage and bone regeneration].

PubMed

Schaefer, D J; Klemt, C; Zhang, X H; Stark, G B

2000-09-01

Tissue engineering offers the possibility to fabricate living substitutes for tissues and organs by combining histogenic cells and biocompatible carrier materials. Pluripotent mesenchymal stem cells are isolated and subcultured ex vivo and then their histogenic differentiation is induced by external factors. The fabrication of bone and cartilage constructs, their combinations and gene therapeutic approaches are demonstrated. Advantages and disadvantages of these methods are described by in vitro and in vitro testing. The proof of histotypical function after implantation in vivo is essential. The use of autologous cells and tissue engineering methods offers the possibility to overcome the disadvantages of classical tissue reconstruction--donor site morbidity of autologous grafts, immunogenicity of allogenic grafts and loosening of alloplastic implants. Furthermore, tissue engineering widens the spectrum of surgical indications in bone and cartilage reconstruction.

High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone

PubMed Central

O'Sullivan, J M; McCready, V R; Flux, G; Norman, A R; Buffa, F M; Chittenden, S; Guy, M; Pomeroy, K; Cook, G; Gadd, J; Treleaven, J; Al-Deen, A; Horwich, A; Huddart, R A; Dearnaley, D P

2002-01-01

We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates. British Journal of Cancer (2002) 86, 1715–1720. doi:10.1038/sj.bjc.6600348 www.bjcancer.com © 2002 Cancer Research UK PMID:12087455

Adipose-derived stem cells and periodontal tissue engineering.