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Sample records for cord-derived mesenchymal stem

  1. Immunomodulatory effects of umbilical cord-derived mesenchymal stem cells.

    PubMed

    Shawki, Shereen; Gaafar, Taghrid; Erfan, Hadeel; El Khateeb, Engy; El Sheikhah, Ahmad; El Hawary, Rabab

    2015-06-01

    Umbilical cord blood (UCB) is of great interest as a source of stem cells for use in cellular therapies. The immunomodulatory effect of mesenchymal stem cells (MSCs) originating from bone marrow, adipose tissue and amniotic membrane has previously been reported. In this study, MSCs were isolated from UCB with the aim of evaluating their immunomodulatory effects on proliferation of PB lymphocytes by two different techniques; namely, 5-bromo-2-deoxyuridine ELISA and a carboxy fluorescein diacetate succinimidyl ester flow cytometric technique. MSCs were isolated from UCB, propagated until Passage four, and then characterized for cell surface markers by flow cytometry and ability to differentiate towards osteocytes and adipocytes. Immunosuppressive effects on PB lymphocytes were examined by co-culturing mitomycin C-treated UCB MSCs with mitogen-stimulated lymphocytes for 72 hr. Thereafter, proliferation of lymphocytes was detected by CFSE flow cytometry and colorimetric ELISA. The titers of cytokines in cell culture supernatant were also assayed to clarify possible mechanisms of immunomodulation. UCB MSCs suppressed mitogen-stimulated lymphocyte proliferation, which occurs via both cell-cell contact and cytokine secretion. Titers of transforming growth factor beta and IL 10 increased, whereas that of IFN-γ decreased in the supernatants of co-cultures. Thus, UCB MSCs suppress the proliferation of mitogen-stimulated lymphocytes. However further in vivo studies are required to fully evaluate the immunomodulatory effects of UCB MSCs. PMID:25869421

  2. Effects of Hypoxia and Chitosan on Equine Umbilical Cord-Derived Mesenchymal Stem Cells

    PubMed Central

    Cho, J.; Wagoner Johnson, A.

    2016-01-01

    Chitosan opens new perspectives in regenerative medicine as it enhances the properties of mesenchymal stem cells (MSCs) through formation of spheroids. Hypoxia has also been proposed to enhance stemness and survival of MSCs after in vivo implantation. These characteristics are relevant to the development of an off-the-shelf source of allogenic cells for regenerative therapy of tendinopathies. Umbilical cord-derived MSCs (UCM-MSCs) offer an abundant source of immature and immunoprivileged stem cells. In this study, equine UCM-MSCs (eqUCM-MSCs) conditioned for 3 and 7 days on chitosan films at 5% oxygen were compared to eqUCM-MSCs under standard conditions. Equine UCM-MSCs formed spheroids on chitosan but yielded 72% less DNA than standard eqUCM-MSCs. Expression of Sox2, Oct4, and Nanog was 4 to 10 times greater in conditioned cells at day 7. Fluorescence-labeled cells cultured for 7 days under standard conditions or on chitosan films under hypoxia were compared in a bilateral patellar tendon defect model in rats. Fluorescence was present in all treated tendons, but the modulus of elasticity under tension was greater in tendons treated with conditioned cells. Chitosan and hypoxia affected cell yield but improved the stemness of eqUCM-MSCs and their contribution to the healing of tissues. Given the abundance of allogenic cells, these properties are highly relevant to clinical applications and outweigh the negative impact on cell proliferation. PMID:27379167

  3. Effect of HSA coated iron oxide labeling on human umbilical cord derived mesenchymal stem cells

    NASA Astrophysics Data System (ADS)

    Sanganeria, Purva; Chandra, Sudeshna; Bahadur, Dhirendra; Khanna, Aparna

    2015-03-01

    Human umbilical cord derived mesenchymal stem cells (hUC-MSCs) are known for self-renewal and differentiation into cells of various lineages like bone, cartilage and fat. They have been used in biomedical applications to treat degenerative disorders. However, to exploit the therapeutic potential of stem cells, there is a requirement of sensitive non-invasive imaging techniques which will offer the ability to track transplanted cells, bio-distribution, proliferation and differentiation. In this study, we have analyzed the efficacy of human serum albumin coated iron oxide nanoparticles (HSA-IONPs) on the differentiation of hUC-MSCs. The colloidal stability of the HSA-IONPs was tested over a long period of time (≥20 months) and the optimized concentration of HSA-IONPs for labeling the stem cells was 60 μg ml-1. Detailed in vitro assays have been performed to ascertain the effect of the nanoparticles (NPs) on stem cells. Lactate dehydrogenase (LDH) assay showed minimum release of LDH depicting the least disruptions in cellular membrane. At the same time, mitochondrial impairment of the cells was also not observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry analysis revealed lesser generation of reactive oxygen species in HSA-IONPs labeled hUC-MSCs in comparison to bare and commercial IONPs. Transmission electron microscopy showed endocytic engulfment of the NPs by the hUC-MSCs. During the process, the gross morphologies of the actin cytoskeleton were found to be intact as shown by immunofluorescence microscopy. Also, the engulfment of the HSA-IONPs did not show any detrimental effect on the differentiation potential of the stem cells into adipocytes, osteocytes and chondrocytes, thereby confirming that the inherent properties of stem cells were maintained.

  4. The Effects of Secretion Factors from Umbilical Cord Derived Mesenchymal Stem Cells on Osteogenic Differentiation of Mesenchymal Stem Cells

    PubMed Central

    Wang, Kui-Xing; Xu, Liang-Liang; Rui, Yun-Feng; Huang, Shuo; Lin, Si-En; Xiong, Jiang-Hui; Li, Ying-Hui; Lee, Wayne Yuk-Wai; Li, Gang

    2015-01-01

    Factors synthesized by mesenchymal stem cells (MSCs) contain various growth factors, cytokines, exosomes and microRNAs, which may affect the differentiation abilities of MSCs. In the present study, we investigated the effects of secretion factors of human umbilical cord derived mesenchymal stem cells (hUCMSCs) on osteogenesis of human bone marrow derived MSCs (hBMSCs). The results showed that 20 μg/ml hUCMSCs secretion factors could initiate osteogenic differentiation of hBMSCs without osteogenic induction medium (OIM), and the amount of calcium deposit (stained by Alizarin Red) was significantly increased after the hUCMSCs secretion factors treatment. Real time quantitative reverse transcription-polymerase chain reaction (real time qRT-PCR) demonstrated that the expression of osteogenesis-related genes including ALP, BMP2, OCN, Osterix, Col1α and Runx2 were significantly up-regulated following hUCMSCs secretion factors treatment. In addition, we found that 10 μg hUCMSCs secretion factors together with 2×105 hBMSCs in the HA/TCP scaffolds promoted ectopic bone formation in nude mice. Local application of 10 μg hUCMSCs secretion factors with 50 μl 2% hyaluronic acid hydrogel and 1×105 rat bone marrow derived MSCs (rBMSCs) also significantly enhanced the bone repair of rat calvarial bone critical defect model at both 4 weeks and 8 weeks. Moreover, the group that received the hUCMSCs secretion factors treatment had more cartilage and bone regeneration in the defect areas than those in the control group. Taken together, these findings suggested that hUCMSCs secretion factors can initiate osteogenesis of bone marrow MSCs and promote bone repair. Our study indicates that hUCMSCs secretion factors may be potential sources for promoting bone regeneration. PMID:25799169

  5. Umbilical cord-derived mesenchymal stem cells alleviate liver fibrosis in rats

    PubMed Central

    Chai, Ning-Li; Zhang, Xiao-Bin; Chen, Si-Wen; Fan, Ke-Xing; Linghu, En-Qiang

    2016-01-01

    AIM: To evaluate the efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation in the treatment of liver fibrosis. METHODS: Cultured human UC-MSCs were isolated and transfused into rats with liver fibrosis induced by dimethylnitrosamine (DMN). The effects of UC-MSCs transfusion on liver fibrosis were then evaluated by histopathology; serum interleukin (IL)-4 and IL-10 levels were also measured. Furthermore, Kupffer cells (KCs) in fibrotic livers were isolated and cultured to analyze their phenotype. Moreover, UC-MSCs were co-cultured with KCs in vitro to assess the effects of UC-MSCs on KCs’ phenotype, and IL-4 and IL-10 levels were measured in cell culture supernatants. Finally, UC-MSCs and KCs were cultured in the presence of IL-4 antibodies to block the effects of this cytokine, followed by phenotypical analysis of KCs. RESULTS: UC-MSCs transfused into rats were recruited by the injured liver and alleviated liver fibrosis, increasing serum IL-4 and IL-10 levels. Interestingly, UC-MSCs promoted mobilization of KCs not only in fibrotic livers, but also in vitro. Co-culture of UC-MSCs with KCs resulted in increased production of IL-4 and IL-10. The addition of IL-4 antibodies into the co-culture system resulted in decreased KC mobilization. CONCLUSION: UC-MSCs could increase IL-4 and promote mobilization of KCs both in vitro and in vivo, subsequently alleviating the liver fibrosis induced by DMN. PMID:27468195

  6. Umbilical Cord Derived Mesenchymal Stem Cells Useful in Insulin Production - Another Opportunity in Cell Therapy

    PubMed Central

    Sarang, Shabari; Viswanathan, Chandra

    2016-01-01

    Background and Objectives Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder resulting out of T cell mediated destruction of pancreatic beta cells. Immunomodulatory properties of mesenchymal stem cells may help to regenerate beta cells and/or prevent further destruction of remnant, unaffected beta cells in diabetes. We have assessed the ability of umbilical cord derived MSCs (UCMSCs) to differentiate into functional islet cells in vitro. Methods and Results We have isolated UCMSCs and allowed sequential exposure of various inducing agents and growth factors. We characterized these cells for confirmation of the presence of islet cell markers and their functionality. The spindle shaped undifferentiated UCMSCs, change their morphology to become triangular in shape. These cells then come together to form the islet like structures which then grow in size and mature over time. These cells express pancreatic and duodenal homeobox −1 (PDX-1), neurogenin 3 (Ngn-3), glucose transporter 2 (Glut 2) and other pancreatic cell markers like glucagon, somatostatin and pancreatic polypeptide and lose expression of MSC markers like CD73 and CD105. They were functionally active as demonstrated by release of physiological insulin and C-peptide in response to elevated glucose concentrations. Conclusions Pancreatic islet like cells with desired functionality can thus be obtained in reasonable numbers from undifferentiated UCMSCs invitro. This could help in establishing a “very definitive source” of islet like cells for cell therapy. UCMSCs could thus be a game changer in treatment of diabetes. PMID:27426087

  7. Beneficial effect of human umbilical cord-derived mesenchymal stem cells on an endotoxin-induced rat model of preeclampsia

    PubMed Central

    FU, LIHUA; LIU, YONGJUN; ZHANG, DAN; XIE, JIANG; GUAN, HONGBO; SHANG, TAO

    2015-01-01

    Mesenchymal stem cells (MSCs), which exhibit the property of immune-modulation, have been shown to treat various diseases, including pulmonary hypertension. There is a functional similarity between the pulmonary circulation and the placenta, but it remains to be elucidated whether MSCs can be applied to treat endotoxin-induced hypertension during pregnancy; therefore, the aim of the present study was to investigate the therapeutic effect of a human umbilical cord-derived MSC infusion on endotoxin-induced hypertension during pregnancy. Rats were randomly divided into three groups (n=7 per group): Control, endotoxin-treated and endotoxin + MSCs. The model of preeclampsia (PE) was established via the intravenous injection of endotoxin. In the endotoxin + MSCs group, MSCs at 2×106 cells/rat were injected via the vena caudalis. The blood pressure, urine protein and number of white blood cells were measured. In addition, the protein expression levels of the pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α (TNF-α) and the anti-inflammatory cytokine IL-10 were examined by ELISA. The blood pressure, levels of urine protein and number of white blood cells in the endotoxin-treated group were significantly higher than those in the control group (P<0.05); however, this increase was significantly attenuated in the endotoxin + MSCs group (P<0.05). In addition, the application of MSCs significantly reduced the levels of pro-inflammatory TNF-α and IL-1β and increased the levels of anti-inflammatory IL-10 in the endotoxin-treated rats. In conclusion, umbilical cord-derived MSCs have a protective effect in an endotoxin-induced model of PE, and this effect is likely elicited through the suppression of inflammatory factors. Umbilical cord-derived MSC-based therapy may provide a potential therapeutic method for endotoxin-induced hypertension during pregnancy. PMID:26640561

  8. Intranasal Delivery of Umbilical Cord-Derived Mesenchymal Stem Cells Preserves Myelination in Perinatal Brain Damage.

    PubMed

    Oppliger, Byron; Joerger-Messerli, Marianne; Mueller, Martin; Reinhart, Ursula; Schneider, Philipp; Surbek, Daniel V; Schoeberlein, Andreina

    2016-08-15

    Preterm white matter injury (WMI) is an important cause for long-term disability. Stem cell transplantation has been proposed as a novel therapeutic approach. However, intracerebral transplantation is not feasible for clinical purpose in newborns. Intranasal delivery of cells to the brain might be a promising, noninvasive therapeutic approach to restore the damaged brain. Therefore, our goal is to study the remyelinating potential of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) after intranasal delivery. Wistar rat pups, previously brain-damaged by a combined hypoxic-ischemic and inflammatory insult, received hWJ-MSC (150,000 cells in 3 μL) that were intranasally delivered twice to each nostril (600,000 cells total). WMI was assessed by immunohistochemistry and western blot for myelination, astrogliosis, and microgliosis. The expression of preoligodendrocyte markers, and neurotrophic factors, was analyzed by real-time polymerase chain reaction. Animals treated with intranasally delivered hWJ-MSC showed increased myelination and decreased gliosis compared to untreated animals. hWJ-MSC may, therefore, modulate the activation of microglia and astrocytes, resulting in a change of the brain microenvironment, which facilitates the maturation of oligodendrocyte lineage cells. This is the first study to show that intranasal delivery of hWJ-MSC in rats prevented hypomyelination and microgliosis in a model of WMI in the premature rat brain. Further studies should address the dose and frequency of administration. PMID:27392671

  9. Clinical Observation of Employment of Umbilical Cord Derived Mesenchymal Stem Cell for Juvenile Idiopathic Arthritis Therapy

    PubMed Central

    Wang, Liming; Zhang, Yu; Li, Hongtao; Hong, Jingxin; Chen, Xiaobo; Li, Ming; Bai, Wen; Wang, Jiangang; Liu, Yongjun; Wu, Mingyuan

    2016-01-01

    Juvenile idiopathic arthritis (JIA), known as Juvenile rheumatoid arthritis, is the most common type of arthritis in children aged under 17. It may cause sequelae due to lack of effective treatment. The goal of this study is to explore the therapeutic effect of umbilical cord mesenchymal stem cells (UC-MSCs) for JIA. Ten JIA patients were treated with UC-MSCs and received second infusion three months later. Some key values such as 28-joint disease activity score (DAS28), TNF-α, IL-6, and regulatory T cells (Tregs) were evaluated. Data were collected at 3 months and 6 months after first treatment. DAS28 score of 10 patients was between 2.6 and 3.2 at three months after infusion. WBC, ESR, and CRP were significantly decreased while Tregs were remarkably increased and IL-6 and TNF-α were declined. Similar changes of above values were found after 6 months. At the same time, the amount of NSAIDS and steroid usage in patients was reduced. However, no significant changes were found comparing the data from 3 and 6 months. These results suggest that UC-MSCs can reduce inflammatory cytokines, improve immune network effects, adjust immune tolerance, and effectively alleviate the symptoms and they might provide a safe and novel approach for JIA treatment. PMID:26770214

  10. Extracellular matrix from human umbilical cord-derived mesenchymal stem cells as a scaffold for peripheral nerve regeneration

    PubMed Central

    Xiao, Bo; Rao, Feng; Guo, Zhi-yuan; Sun, Xun; Wang, Yi-guo; Liu, Shu-yun; Wang, Ai-yuan; Guo, Quan-yi; Meng, Hao-ye; Zhao, Qing; Peng, Jiang; Wang, Yu; Lu, Shi-bi

    2016-01-01

    The extracellular matrix, which includes collagens, laminin, or fibronectin, plays an important role in peripheral nerve regeneration. Recently, a Schwann cell-derived extracellular matrix with classical biomaterial was used to mimic the neural niche. However, extensive clinical use of Schwann cells remains limited because of the limited origin, loss of an autologous nerve, and extended in vitro culture times. In the present study, human umbilical cord-derived mesenchymal stem cells (hUCMSCs), which are easily accessible and more proliferative than Schwann cells, were used to prepare an extracellular matrix. We identified the morphology and function of hUCMSCs and investigated their effect on peripheral nerve regeneration. Compared with a non-coated dish tissue culture, the hUCMSC-derived extracellular matrix enhanced Schwann cell proliferation, upregulated gene and protein expression levels of brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and vascular endothelial growth factor in Schwann cells, and enhanced neurite outgrowth from dorsal root ganglion neurons. These findings suggest that the hUCMSC-derived extracellular matrix promotes peripheral nerve repair and can be used as a basis for the rational design of engineered neural niches.

  11. Umbilical cord-derived mesenchymal stem cell transplantation combined with hyperbaric oxygen treatment for repair of traumatic brain injury.

    PubMed

    Zhou, Hai-Xiao; Liu, Zhi-Gang; Liu, Xiao-Jiao; Chen, Qian-Xue

    2016-01-01

    Transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) for repair of traumatic brain injury has been used in the clinic. Hyperbaric oxygen (HBO) treatment has long been widely used as an adjunctive therapy for treating traumatic brain injury. UC-MSC transplantation combined with HBO treatment is expected to yield better therapeutic effects on traumatic brain injury. In this study, we established rat models of severe traumatic brain injury by pressurized fluid (2.5-3.0 atm impact force). The injured rats were then administered UC-MSC transplantation via the tail vein in combination with HBO treatment. Compared with monotherapy, aquaporin 4 expression decreased in the injured rat brain, but growth-associated protein-43 expression, calaxon-like structures, and CM-Dil-positive cell number increased. Following combination therapy, however, rat cognitive and neurological function significantly improved. UC-MSC transplantation combined with HBO therapyfor repair of traumatic brain injury shows better therapeutic effects than monotherapy and significantly promotes recovery of neurological functions. PMID:26981097

  12. Umbilical cord-derived mesenchymal stem cell transplantation combined with hyperbaric oxygen treatment for repair of traumatic brain injury

    PubMed Central

    Zhou, Hai-xiao; Liu, Zhi-gang; Liu, Xiao-jiao; Chen, Qian-xue

    2016-01-01

    Transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) for repair of traumatic brain injury has been used in the clinic. Hyperbaric oxygen (HBO) treatment has long been widely used as an adjunctive therapy for treating traumatic brain injury. UC-MSC transplantation combined with HBO treatment is expected to yield better therapeutic effects on traumatic brain injury. In this study, we established rat models of severe traumatic brain injury by pressurized fluid (2.5–3.0 atm impact force). The injured rats were then administered UC-MSC transplantation via the tail vein in combination with HBO treatment. Compared with monotherapy, aquaporin 4 expression decreased in the injured rat brain, but growth-associated protein-43 expression, calaxon-like structures, and CM-Dil-positive cell number increased. Following combination therapy, however, rat cognitive and neurological function significantly improved. UC-MSC transplantation combined with HBO therapyfor repair of traumatic brain injury shows better therapeutic effects than monotherapy and significantly promotes recovery of neurological functions. PMID:26981097

  13. Transdifferentiation of Umbilical Cord-Derived Mesenchymal Stem Cells Into Epidermal-Like Cells by the Mimicking Skin Microenvironment.

    PubMed

    Chen, Deyun; Hao, Haojie; Tong, Chuan; Liu, Jiejie; Dong, Liang; Ti, Dongdong; Hou, Qian; Liu, Huiling; Han, Weidong; Fu, Xiaobing

    2015-06-01

    Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are multipotent, primitive, and have been widely used for skin tissue engineering. Their transdifferentiation is determined by the local microenvironment. In this study, we investigated the potential epidermal differentiation of UC-MSCs and the formation of epidermis substitutes in a 3-dimensional (3D) microenvironment, which was fabricated by UC-MSCs embedded into collagen-chitosan scaffolds (CCSs) combined with an air-liquid interface (ALI) culture system. Using fluorescence microscope, we observed that UC-MSCs were spindle-shaped and evenly distributed in the scaffold. Methyl thiazolyl blue tetrazolium bromide assay and Live/Dead assay indicated that the CCSs have good biocompatibility with UC-MSCs. Immunohistochemistry and western blotting assay showed that UC-MSCs on the surface of the CCSs were positive for the epidermal markers cytokeratin 19 and involucrin at 14 days. In addition, hematoxylin-eosin staining indicated that multilayered epidermis substitutes were established. The constructed epidermis substitutes were applied to treat full-thickness wounds in rats and proved to promote wound healing. In conclusion, manipulating the 3D microenvironment is a novel method for inducing the epidermal differentiation of MSCs to engineer epidermal substitutes, which provides an alternative strategy for skin tissue engineering. PMID:25700709

  14. Improved explant method to isolate umbilical cord-derived mesenchymal stem cells and their immunosuppressive properties.

    PubMed

    Mori, Yuka; Ohshimo, Jun; Shimazu, Takahisa; He, Haiping; Takahashi, Atsuko; Yamamoto, Yuki; Tsunoda, Hajime; Tojo, Arinobu; Nagamura-Inoue, Tokiko

    2015-04-01

    The umbilical cord (UC) has become one of the major sources of mesenchymal stem cells (MSCs). The common explant method of isolating UC-derived MSCs (UC-MSCs) involves mincing the UCs into small fragments, which are then attached to a culture dish bottom from which the MSCs migrate. However, the fragments frequently float up from the bottom of the dish, thereby reducing the cell recovery rate. To overcome this problem, we demonstrate an improved explant method for UC-MSC isolation, which involves the use of a stainless steel mesh (Cellamigo(®); Tsubakimoto Chain Co.), to protect the tissue from floating after the minced fragments are aligned at regular intervals in culture dishes. The culture medium was refreshed every 3 days and the adherent cells and tissue fragments were harvested using trypsin. The number of UC-MSCs isolated from 1 g of UC using the explant method with Cellamigo was 2.9 ± 1.4 × 10(6)/g, which was significantly higher than that obtained without Cellamigo (0.66 ± 0.53 × 10(6)/g) (n = 6, p < 0.01) when cells reached 80-90% confluence. In addition, the processing and incubation time required to reach 80-90% confluence was reduced in the improved explant method compared with the conventional method. The UC-MSCs isolated using the improved method were positive for CD105, CD73, CD90, and HLA class I expression and negative for CD45 and HLA class II expression. The isolated UC-MSCs efficiently inhibited the responder T cells induced by allogeneic dendritic cells in a mixed lymphocyte reaction. Conclusively, we demonstrated that the use of Cellamigo improves the explant method for isolating UC-MSCs. PMID:25220032

  15. 5-Azacytidine Induces Cardiac Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells by Activating Extracellular Regulated Kinase

    PubMed Central

    Qian, Qian; Qian, Hui; Zhang, Xu; Zhu, Wei; Yan, Yongmin; Ye, Shengqin; Peng, Xiujuan; Li, Wei; Xu, Zhe; Sun, Lingyun

    2012-01-01

    5-Azacytidine (5-Aza) induces differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes. However, the underlying mechanisms are not well understood. Our previous work showed that 5-Aza induces human bone marrow-derived MSCs to differentiate into cardiomyocytes. Here, we demonstrated that 5-Aza induced cardiac differentiation of human umbilical cord-derived MSCs (hucMSCs) and explored the potential signaling pathway. Our results showed that hucMSCs had cardiomyocyte phenotypes after 5-Aza treatment. In addition, myogenic cells differentiated from hucMSCs were positive for mRNA and protein of desmin, β-myosin heavy chain, cardiac troponin T, A-type natriuretic peptide, and Nkx2.5. Human diploid lung fibroblasts treated with 5-Aza expressed no cardiac-specific genes. 5-Aza did not induce hucMSCs to differentiate into osteoblasts. Further study revealed that 5-Aza treatment activated extracellular signal related kinases (ERK) in hucMSCs, but protein kinase C showed no response to 5-Aza administration. U0126, a specific inhibitor of ERK, could inhibit 5-Aza-induced expression of cardiac-specific genes and proteins in hucMSCs. Increased phosphorylation of signal transducers and activators of transcription 3, and up-regulation of myocyte enhancer-binding factor-2c and myogenic differentiation antigen in 5-Aza-treated hucMSCs were also suppressed by U0126. Taken together, these results suggested that sustained activation of ERK by 5-Aza contributed to the induction of the differentiation of hucMSCs into cardiomyocytes in vitro. PMID:21476855

  16. Tetramethylpyrazine induces differentiation of human umbilical cord-derived mesenchymal stem cells into neuron-like cells in vitro

    PubMed Central

    NAN, CHENGRUI; GUO, LI; ZHAO, ZONGMAO; MA, SHUCHENG; LIU, JIXIANG; YAN, DONGDONG; SONG, GUOQIANG; LIU, HANJIE

    2016-01-01

    The present study evaluated the ability and optimal concentration of tetramethylpyrazine (TMP) to induce human umbilical cord-derived mesenchymal stem cells (hUMSCs) to differentiate into neuron-like cells in vitro. Human umbilical cords from full-term caesarean section patients were used to obtain hUMSCs by collagenase digestion after removal of the umbilical artery and vein. The surface antigen expression profile of cultured hUMSCs was monitored by flow cytometry. After amplification, cells of the 5th passage were divided into experimental groups A–C treated with TMP at 4.67, 2.34 and 1.17 mg/ml, respectively, in low glucose-Dulbecco's Modified Eagle's Medium (L-DMEM) (induction medium), while group D (control) was exposed to L-DMEM culture medium only. Differentiation of hUMSCs into neuron-like cells and morphological changes were observed every 0.5 h with an inverted phase contrast microscope for 6 h. After the 6-h induction period, proportions of cells expressing neuronal markers neuron-specific enolase (NSE), neurofilament protein (NF-H) and glial fibrillary acidic protein (GFAP) were detected by immunohistochemistry. The optimal concentration of TMP was selected on the basis of neuron-like cell positive rate. Western blotting and RT-polymerase chain reaction were applied to detect the expression of NSE, NF-H, and GFAP of the group of optimal concentration in each point-in-time. Results showed that most primary cells were adherent 12 h after seeding and first appeared as diamond or polygon shapes. Thereafter, they gradually grew into long spindle-shaped cells and finally in a radiating or swirling pattern. The cells maintained a strong proliferative capacity after continuous passage. Flow cytometry analysis of cultured hUMSCs at the 3rd, 5th and 10th passages expressed CD73, CD90 and CD105, but not CD11b, CD19, CD34, CD45 or human leukocyte antigen-DR. After 6 h of TMP treatment, typical neuron-like cells with many protrusions connected into a net

  17. Human umbilical cord derived mesenchymal stem cells promote interleukin-17 production from human peripheral blood mononuclear cells of healthy donors and systemic lupus erythematosus patients.

    PubMed

    Ren, S; Hu, J; Chen, Y; Yuan, T; Hu, H; Li, S

    2016-03-01

    Inflammation instigated by interleukin (IL)-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. The expansion of IL-17-producing cells from healthy donors is reportedly promoted by mesenchymal stem cells derived from fetal bone marrow. In the present study, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were examined for their effects on lymphocytes from healthy donors and from patients with systemic lupus erythematosus (SLE). Significantly higher levels of IL-17 were produced when CD4(+) T cells from healthy donors were co-cultured with hUC-MSCs than those that were cultured alone. Blocking experiments identified that this effect might be mediated partially through prostaglandin E2 (PGE2 ) and IL-1β, without IL-23 involvement. We then co-cultured hUC-MSCs with human CD4(+) T cells from systemic lupus erythematosus patients. Ex-vivo inductions of IL-17 by hUC-MSCs in stimulated lymphocytes were significantly higher in SLE patients than in healthy donors. This effect was not observed for IL-23. Taken together, our results represent that hUC-MSCs can promote the IL-17 production from CD4(+) T cells in both healthy donor and SLE patients. PGE2 and IL-1β might also be partially involved in the promotive effect of hUC-MSCs. PMID:26507122

  18. Conditioned Media from Human Adipose Tissue-Derived Mesenchymal Stem Cells and Umbilical Cord-Derived Mesenchymal Stem Cells Efficiently Induced the Apoptosis and Differentiation in Human Glioma Cell Lines In Vitro

    PubMed Central

    Lei, Deqiang; Ouyang, Weixiang; Ren, Jinghua; Li, Huiyu; Hu, Jingqiong; Huang, Shiang

    2014-01-01

    Human mesenchymal stem cells (MSCs) have an intrinsic property for homing towards tumor sites and can be used as tumor-tropic vectors for tumor therapy. But very limited studies investigated the antitumor properties of MSCs themselves. In this study we investigated the antiglioma properties of two easily accessible MSCs, namely, human adipose tissue-derived mesenchymal stem cells (ASCs) and umbilical cord-derived mesenchymal stem cells (UC-MSCs). We found (1) MSC conditioned media can significantly inhibit the growth of human U251 glioma cell line; (2) MSC conditioned media can significantly induce apoptosis in human U251 cell line; (3) real-time PCR experiments showed significant upregulation of apoptotic genes of both caspase-3 and caspase-9 and significant downregulation of antiapoptotic genes such as survivin and XIAP after MSC conditioned media induction in U 251 cells; (4) furthermore, MSCs conditioned media culture induced rapid and complete differentiation in U251 cells. These results indicate MSCs can efficiently induce both apoptosis and differentiation in U251 human glioma cell line. Whereas UC-MSCs are more efficient for apoptosis induction than ASCs, their capability of differentiation induction is not distinguishable from each other. Our findings suggest MSCs themselves have favorable antitumor characteristics and should be further explored in future glioma therapy. PMID:24971310

  19. Role of Keratinocyte Growth Factor in the Differentiation of Sweat Gland-Like Cells From Human Umbilical Cord-Derived Mesenchymal Stem Cells

    PubMed Central

    Xu, Yongan; Hong, Yucai; Xu, Mengyan; Ma, Kui; Fu, Xiaobing

    2016-01-01

    Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have higher proliferation potency and lower immune resistance than human bone marrow MSCs and can differentiate into various functional cells. Many regulatory factors, including keratinocyte growth factor (KGF), are involved in the development of skin and cutaneous appendages. Although KGF is important in wound healing, the role of KGF in hUC-MSC differentiation remains unknown. In our previous work, we found the mixing medium (nine parts of basic sweat-gland [SG] medium plus one part of conditioned heat-shock SG medium) could induce hUC-MSC differentiation to sweat gland-like cells (SGCs). In this study, we further improved the inducing medium and determined the effects of KGF in hUC-MSC differentiation. We found KGF expression in the SGCs and that recombinant human KGF could induce hUC-MSC differentiation into SGCs, suggesting KGF plays a pivotal role in promoting hUC-MSC differentiation to SGCs. Furthermore, the SGCs differentiated from hUC-MSCs were applied to severely burned skin of the paw of an in vivo severe combined immunodeficiency mouse burn model. Burned paws treated with SGCs could regenerate functional sparse SGs 21 days after treatment; the untreated control paws could not. Collectively, these results demonstrated that KGF is a critical growth factor for SGC differentiation from hUC-MSCs and the differentiated SGCs from hUC-MSCs may have a potential therapeutic application for regeneration of destroyed SGs and injured skin. Significance There is growing evidence demonstrating a potential therapeutic application of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in injured skin. In the current study, conditioned media and chemically defined media with recombinant human keratinocyte growth factor (KGF) could induce hUC-MSC differentiation into sweat gland-like cells (SGCs). Moreover, the differentiated SGCs from hUC-MSCs could regenerate functional sparse sweat glands in a

  20. Umbilical cord-derived mesenchymal stem cells inhibit growth and promote apoptosis of HepG2 cells.

    PubMed

    Tang, Ying-Mei; Bao, Wei-Min; Yang, Jin-Hui; Ma, Lin-Kun; Yang, Jing; Xu, Ying; Yang, Li-Hong; Sha, Feng; Xu, Zhi-Yuan; Wu, Hua-Mei; Zhou, Wei; Li, Yan; Li, Yu-Hua

    2016-09-01

    Hepatocellular carcinoma is the fifth most common type of cancer worldwide and remains difficult to treat. The aim of this study was to investigate the effects of mesenchymal stem cells (MSCs) derived from the umbilical cord (UC‑MSCs) on HepG2 hepatocellular carcinoma cells. UC‑MSCs were co‑cultured with HepG2 cells and biomarkers of UC‑MSCs were analyzed by flow cytometry. mRNA and protein expression of genes were determined by reverse transcription‑polymerase chain reaction and flow cytometry, respectively. Passage three and seven UC‑MSCs expressed CD29, CD44, CD90 and CD105, whereas CD34 and CD45 were absent on these cells. Co‑culture with UC‑MSCs inhibited proliferation and promoted apoptosis of HepG2 cells in a time‑dependent manner. The initial seeding density of UC‑MSCs also influenced the proliferation and apoptosis of HepG2 cells, with an increased number of UC‑MSCs causing enhanced proliferation inhibition and cell apoptosis. Co‑culture with UC‑MSCs downregulated mRNA and protein expression of α‑fetoprotein (AFP), Bcl‑2 and Survivin in HepG2 cells. Thus, UC‑MSCs may inhibit growth and promote apoptosis of HepG2 cells through downregulation of AFP, Bcl‑2 and Survivin. US-MSCs may be used as a novel therapy for treating hepatocellular carcinoma in the future. PMID:27485485

  1. Enhanced renoprotective effect of IGF-1 modified human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury

    PubMed Central

    Liu, Pengfei; Feng, Yetong; Dong, Delu; Liu, Xiaobo; Chen, Yaoyu; Wang, Yi; Zhou, Yulai

    2016-01-01

    The therapeutic action of umbilical cord-derived mesenchymal stem cells (UC-MSCs) against acute kidney injury (AKI) has been demonstrated by several groups. However, how to further enhance the renoprotective effect of UC-MSCs and improve the therapy effect, are still unclear. In this study, we mainly investigated whether insulin-like growth factor-1 (IGF-1)-modified UC-MSCs hold an enhanced protective effect on gentamicin-induced AKI in vivo. Our results indicated that the IGF-1 overexpression could enhance the therapeutic action of human UC-MSCs, and the AKI rats treated with IGF-1-overexpressed UC-MSCs (UC-MSCs-IGF-1) showed better recovery of biochemical variables in serum or urine associated with renal function, histological injury and renal apoptosis, compared with AKI rats treated with normal UC-MSCs. RNA microarray analysis indicated that some key genes in the signal pathways associated with anti-oxidation, anti-inflammatory, and cell migratory capacity were up-regulated in UC-MSCs-IGF-1, and the results were further confirmed with qPCR. Furthermore, a series of detection in vitro and in vivo indicated that the UC-MSCs-IGF-1 hold better anti-oxidation, anti-inflammatory, and cell migratory capacity for IGF-1 overexpression. Thus, our study indicated that enhancement of UC-MSCs bioactivities with IGF-1 overexpression could increase the UC-MSCs therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI. PMID:26830766

  2. Monitoring the biology stability of human umbilical cord-derived mesenchymal stem cells during long-term culture in serum-free medium.

    PubMed

    Chen, Gecai; Yue, Aihuan; Ruan, Zhongbao; Yin, Yigang; Wang, Ruzhu; Ren, Yin; Zhu, Li

    2014-12-01

    Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have an immunosuppressive effect. The biological stability of MSCs in serum-free medium during long-term culture in vitro has not been elucidated clearly. The morphology, immunophenotype and multi-lineage potential were analyzed at passages 3, 5, 10, 15, 20, and 25 (P3, P5, P10, P15, P20, and P25, respectively). The cell cycle distribution, apoptosis, and karyotype of human umbilical cord-derived (hUC)-MSCs were analyzed at P3, P5, P10, P15, P20, and P25. From P3 to P25, the three defining biological properties of hUC-MSCs [adherence to plastic, specific surface antigen expression, multipotent differentiation potential] met the standards proposed by the International Society for Cellular Therapy for definition of MSCs. The cell cycle distribution analysis at the P25 showed that the percentage of cells at G0/G1 was increased, compared with the cells at P3 (P < 0.05). Cells at P25 displayed an increase in the apoptosis rate (to 183 %), compared to those at P3 (P < 0.01). Within subculture generations 3-20 (P3-P20), the differences between the cell apoptotic rates were not statistically significant (P > 0.05). There were no detectable chromosome eliminations, displacements, or chromosomal imbalances, as assessed by the karyotyping guidelines of the International System for Human Cytogenetic Nomenclature (ISCN, 2009). Long-term culture affects the biological stability of MSCs in serum-free MesenCult-XF medium. MSCs can be expanded up to the 25th passage without chromosomal changes by G-band. The best biological activity period and stability appeared between the third to 20th generations. PMID:24407613

  3. [Rapid differentiation of human umbilical cord-derived mesenchymal stem cells into insulin-secreting cells under the sole induction of biological products].

    PubMed

    Wang, Yue-Chun; Zhang, Yuan; Duan, A-Lin; Lin, Wei-Xia; Zheng, Qiao-Dan; Xu, Wen-Lu

    2010-02-25

    In order to explore the feasibility of inducing the human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) to differentiate into insulin-secreting cells with biological products alone, hUC-MSCs were separated and purified from the whole umbilical cord by the sequent digestion of collagenase II and trypsin followed by two-step centrifugation. hUC-MSCs were induced with IMDM culture medium containing epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and Ginkgo biloba extract (GBE). Before and after the induction, the morphological changes were observed under inverse microscope; the islet-related genes were detected by RT-PCR; islet-like clusters (ILCs) were identified by dithizone (DTZ) staining; PDX-1 and immunoreactive insulin (IRI) were examined by immunofluorescence method; the quantity and quality of IRI secretion were assayed by chemiluminescence immunoassay and Western blot respectively. The results showed that the purified hUC-MSCs presented long spindle-like shape and parallel or spiral arrangement which are typical morphological features of MSCs. After the induction, hUC-MSCs changed gradually into round or oval shape and gathered together to form ILCs; there were more than one hundred clusters on the growth surface of a flask of T25; ILCs were stained into positive mauve by DTZ and positive for PDX-1 and IRI; Western blot displayed that most of the IRI was proinsulin (PI). Therefore, hUC-MSCs can rapidly differentiate into insulin-secreting cells under the sole induction of EGF, bFGF, GBE and IMDM, but ILCs are not mature enough to produce sufficient true insulin. PMID:20179892

  4. An increase in CD3+CD4+CD25+ regulatory T cells after administration of umbilical cord-derived mesenchymal stem cells during sepsis.

    PubMed

    Chao, Yu-Hua; Wu, Han-Ping; Wu, Kang-Hsi; Tsai, Yi-Giien; Peng, Ching-Tien; Lin, Kuan-Chia; Chao, Wan-Ru; Lee, Maw-Sheng; Fu, Yun-Ching

    2014-01-01

    Sepsis remains an important cause of death worldwide, and vigorous immune responses during sepsis could be beneficial for bacterial clearance but at the price of collateral damage to self tissues. Mesenchymal stem cells (MSCs) have been found to modulate the immune system and attenuate sepsis. In the present study, MSCs derived from bone marrow and umbilical cord were used and compared. With a cecal ligation and puncture (CLP) model, the mechanisms of MSC-mediated immunoregulation during sepsis were studied by determining the changes of circulating inflammation-associated cytokine profiles and peripheral blood mononuclear cells 18 hours after CLP-induced sepsis. In vitro, bone marrow-derived MSCs (BMMSCs) and umbilical cord-derived MSCs (UCMSCs) showed a similar morphology and surface marker expression. UCMSCs had stronger potential for osteogenesis but lower for adipogenesis than BMMSCs. Compared with rats receiving PBS only after CLP, the percentage of circulating CD3+CD4+CD25+ regulatory T (Treg) cells and the ratio of Treg cells/T cells were elevated significantly in rats receiving MSCs. Further experiment regarding Treg cell function demonstrated that the immunosuppressive capacity of Treg cells from rats with CLP-induced sepsis was decreased, but could be restored by administration of MSCs. Compared with rats receiving PBS only after CLP, serum levels of interleukin-6 and tumor necrosis factor-α were significantly lower in rats receiving MSCs after CLP. There were no differences between BMMSCs and UCMSCs. In summary, this work provides the first in vivo evidence that administering BMMSCs or UCMSCs to rats with CLP-induced sepsis could increase circulating CD3+CD4+CD25+ Treg cells and Treg cells/T cells ratio, enhance Treg cell suppressive function, and decrease serum levels of interleukin-6 and tumor necrosis factor-α, suggesting the immunomodulatory association of Treg cells and MSCs during sepsis. PMID:25337817

  5. Tetramethylpyrazine induces differentiation of human umbilical cord-derived mesenchymal stem cells into neuron-like cells in vitro.

    PubMed

    Nan, Chengrui; Guo, Li; Zhao, Zongmao; Ma, Shucheng; Liu, Jixiang; Yan, Dongdong; Song, Guoqiang; Liu, Hanjie

    2016-06-01

    The present study evaluated the ability and optimal concentration of tetramethylpyrazine (TMP) to induce human umbilical cord-derived mesenchymal stem cells (hUMSCs) to differentiate into neuron‑like cells in vitro. Human umbilical cords from full-term caesarean section patients were used to obtain hUMSCs by collagenase digestion after removal of the umbilical artery and vein. The surface antigen expression profile of cultured hUMSCs was monitored by flow cytometry. After amplification, cells of the 5th passage were divided into experimental groups A‑C treated with TMP at 4.67, 2.34 and 1.17 mg/ml, respectively, in low glucose‑Dulbecco's Modified Eagle's Medium (L‑DMEM) (induction medium), while group D (control) was exposed to L‑DMEM culture medium only. Differentiation of hUMSCs into neuron‑like cells and morphological changes were observed every 0.5 h with an inverted phase contrast microscope for 6 h. After the 6‑h induction period, proportions of cells expressing neuronal markers neuron‑specific enolase (NSE), neurofilament protein (NF‑H) and glial fibrillary acidic protein (GFAP) were detected by immunohistochemistry. The optimal concentration of TMP was selected on the basis of neuron‑like cell positive rate. Western blotting and RT‑polymerase chain reaction were applied to detect the expression of NSE, NF‑H, and GFAP of the group of optimal concentration in each point‑in‑time. Results showed that most primary cells were adherent 12 h after seeding and first appeared as diamond or polygon shapes. Thereafter, they gradually grew into long spindle‑shaped cells and finally in a radiating or swirling pattern. The cells maintained a strong proliferative capacity after continuous passage. Flow cytometry analysis of cultured hUMSCs at the 3rd, 5th and 10th passages expressed CD73, CD90 and CD105, but not CD11b, CD19, CD34, CD45 or human leukocyte antigen‑DR. After 6 h of TMP treatment, typical neuron‑like cells with

  6. Comparison of biological properties of umbilical cord-derived mesenchymal stem cells from early and late passages: immunomodulatory ability is enhanced in aged cells.

    PubMed

    Zhuang, Yong; Li, Dong; Fu, Jinqiu; Shi, Qing; Lu, Yuanyuan; Ju, Xiuli

    2015-01-01

    Mesenchymal stem cells (MSCs) are a potential source of adult stem cells for cell-based therapeutics due to their substantial multilineage differentiation capacity and secretory functions. No information is presently available regarding the maintenance of immunosuppressive properties of this cell type with repeated passages. It was therefore the aim of the present study to analyze the biological properties, particularly the immunoregulatory effect, of MSCs from late passages. The differences between young and old MSCs in morphology, cell surface antigen phenotype, proliferation, gene expression and immunomodulatory ability were investigated. The results of the current study demonstrated that with the passage of cells, senescent MSCs displayed a characteristically enlarged and flattened morphology, different gene expression profiles and stronger immunosuppressive activities. Increased interleukin-6 production may be a possible underlying mechanism for this enhanced immunomodulatory ability of MSCs. These findings suggest that aged MSCs may provide a treatment option for patients with graft versus host disease and other diseases associated with dysregulation of the immune system. PMID:25339265

  7. Transplantation of umbilical cord-derived mesenchymal stem cells into the striata of R6/2 mice: behavioral and neuropathological analysis

    PubMed Central

    2013-01-01

    Introduction Huntington’s disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat on the short arm of chromosome 4 resulting in cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. Neuropathologically, HD is characterized by a specific loss of medium spiny neurons in the caudate and the putamen, as well as subsequent neuronal loss in the cerebral cortex. The transgenic R6/2 mouse model of HD carries the N-terminal fragment of the human HD gene (145 to 155 repeats) and rapidly develops some of the behavioral characteristics that are analogous to the human form of the disease. Mesenchymal stem cells (MSCs) have shown the ability to slow the onset of behavioral and neuropathological deficits following intrastriatal transplantation in rodent models of HD. Use of MSCs derived from umbilical cord (UC) offers an attractive strategy for transplantation as these cells are isolated from a noncontroversial and inexhaustible source and can be harvested at a low cost. Because UC MSCs represent an intermediate link between adult and embryonic tissue, they may hold more pluripotent properties than adult stem cells derived from other sources. Methods Mesenchymal stem cells, isolated from the UC of day 15 gestation pups, were transplanted intrastriatally into 5-week-old R6/2 mice at either a low-passage (3 to 8) or high-passage (40 to 50). Mice were tested behaviorally for 6 weeks using the rotarod task, the Morris water maze, and the limb-clasping response. Following behavioral testing, tissue sections were analyzed for UC MSC survival, the immune response to the transplanted cells, and neuropathological changes. Results Following transplantation of UC MSCs, R6/2 mice did not display a reduction in motor deficits but there appeared to be transient sparing in a spatial memory task when compared to untreated R6/2 mice. However, R6/2 mice receiving either low- or high-passage UC MSCs

  8. Stirred tank bioreactor culture combined with serum-/xenogeneic-free culture medium enables an efficient expansion of umbilical cord-derived mesenchymal stem/stromal cells.

    PubMed

    Mizukami, Amanda; Fernandes-Platzgummer, Ana; Carmelo, Joana G; Swiech, Kamilla; Covas, Dimas T; Cabral, Joaquim M S; da Silva, Cláudia L

    2016-08-01

    Mesenchymal stem/stromal cells (MSC) are being widely explored as promising candidates for cell-based therapies. Among the different human MSC origins exploited, umbilical cord represents an attractive and readily available source of MSC that involves a non-invasive collection procedure. In order to achieve relevant cell numbers of human MSC for clinical applications, it is crucial to develop scalable culture systems that allow bioprocess control and monitoring, combined with the use of serum/xenogeneic (xeno)-free culture media. In the present study, we firstly established a spinner flask culture system combining gelatin-based Cultispher(®) S microcarriers and xeno-free culture medium for the expansion of umbilical cord matrix (UCM)-derived MSC. This system enabled the production of 2.4 (±1.1) x10(5) cells/mL (n = 4) after 5 days of culture, corresponding to a 5.3 (±1.6)-fold increase in cell number. The established protocol was then implemented in a stirred-tank bioreactor (800 mL working volume) (n = 3) yielding 115 million cells after 4 days. Upon expansion under stirred conditions, cells retained their differentiation ability and immunomodulatory potential. The development of a scalable microcarrier-based stirred culture system, using xeno-free culture medium that suits the intrinsic features of UCM-derived MSC represents an important step towards a GMP compliant large-scale production platform for these promising cell therapy candidates. PMID:27168373

  9. Overexpression of COX-2 but not indoleamine 2,3-dioxygenase-1 enhances the immunosuppressive ability of human umbilical cord-derived mesenchymal stem cells.

    PubMed

    Li, Dong; Han, Yan; Zhuang, Yong; Fu, Jinqiu; Liu, Huan; Shi, Qing; Ju, Xiuli

    2015-05-01

    Owing to their immunosuppressive properties mesenchymal stem cells (MSCs) are widely applicable in the treatment of autoimmune disease. The aim of this study was to investigate whether the indoleamine 2,3-dioxygenase-1 (IDO-1) and cyclooxygenase-2 (COX-2) genes enhanced the immunosuppressive functional ability of MSCs following stable transfection. To strengthen the immunomodulatory ability of MSCs, IDO-1 and COX-2 were overexpressed in umbilical cord progenitor cell-derived MSCs using recombinant plasmids and electroporation. RT-qPCR analysis and western blotting confirmed the expression of IDO-1 and COX-2 in transfected MSCs. Further functional assays in co-culture experiments, including lymphocyte proliferation and cyto-toxicity assays showed that COX-2-transfected MSCs possessed more potent immunomodulatory cells than the untreated MSCs, or MSCs transfected with IDO-1. Additionally, synthesis of interferon-γ and tumor necrosis factor-α (TNF-α) was significantly inhibited in lymphocytes co-cultured with COX-2-transfected MSCs, which was consistent with changes in immune-related genes in MSCs. An enhanced expression of IDO-1, COX-2, heme-oxygenase-1, inducible nitric-oxide synthase, TNF-α-stimulated gene/protein-6, transforming growth factor-β (TGF-β), human leukocyte antigen molecule 5 (HLA-G5) and interleukin-10 (IL-10) was identified following COX-2 transfection. We showed that the overexpression of COX-2 enhanced the immunosuppressive function of MSCs. COX-2-modified MSCs more potently inhibited the activation and proliferation of peripheral blood mononuclear cells. PMID:25777747

  10. Reactive oxygen species induce MMP12-dependent degradation of collagen 5 and fibronectin to promote the motility of human umbilical cord-derived mesenchymal stem cells

    PubMed Central

    Yun, Seung Pil; Lee, Sei-Jung; Oh, Sang Yub; Jung, Young Hyun; Ryu, Jung Min; Suh, Han Na; Kim, Mi Ok; Oh, Keon Bong; Han, Ho Jae

    2014-01-01

    BACKGROUND AND PURPOSE Reactive oxygen species (ROS) are potent regulators of stem cell behaviour; however, their physiological significance as regards MMP-mediated regulation of the motility of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) has not been characterized. In the present study, we investigated the role of hydrogen peroxide (H2O2) and associated signalling pathways in promoting UCB-MSCs motility. EXPERIMENTAL APPROACH The regulatory effects of H2O2 on the activation of PKC, MAPKs, NF-κB and β-catenin were determined. The expressions of MMP and extracellular matrix proteins were examined. Pharmacological inhibitors and gene-specific siRNA were used to identify the signalling pathways of H2O2 that affect UCB-MSCs motility. An experimental skin wound-healing model was used to confirm the functional role of UCB-MSCs treated with H2O2 in ICR mice. KEY RESULTS H2O2 increased the motility of UCB-MSCs by activating PKCα via a calcium influx mechanism. H2O2 activated ERK and p38 MAPK, which are responsible for the distinct activation of transcription factors NF-κB and β-catenin. UCB-MSCs expressed eight MMP genes, but only MMP12 expression was uniquely regulated by NF-κB and β-catenin activation. H2O2 increased the MMP12-dependent degradation of collagen 5 (COL-5) and fibronectin (FN) associated with UCB-MSCs motility. Finally, topical transplantation of UCB-MSCs treated with H2O2 enhanced skin wound healing in mice. CONCLUSIONS AND IMPLICATIONS H2O2 stimulated UCB-MSCs motility by increasing MMP12-dependent degradation of COL-5 and FN through the activation of NF-κB and glycogen synthase kinase-3β/β-catenin, which is critical for providing a suitable microenvironment for MSCs transplantation and re-epithelialization of skin wounds in mice. PMID:24627968

  11. Nicotinamide Promotes Adipogenesis in Umbilical Cord-Derived Mesenchymal Stem Cells and Is Associated with Neonatal Adiposity: The Healthy Start BabyBUMP Project

    PubMed Central

    Shapiro, Allison L. B.; Boyle, Kristen E.; Dabelea, Dana; Patinkin, Zachary W.; De la Houssaye, Becky; Ringham, Brandy M.; Glueck, Deborah H.; Barbour, Linda A.; Norris, Jill M.; Friedman, Jacob E.

    2016-01-01

    The cellular mechanisms whereby excess maternal nutrition during pregnancy increases adiposity of the offspring are not well understood. However, nicotinamide (NAM), a fundamental micronutrient that is important in energy metabolism, has been shown to regulate adipogenesis through inhibition of SIRT1. Here we tested three novel hypotheses: 1) NAM increases the adipogenic response of human umbilical cord tissue-derived mesenchymal stem cells (MSCs) through a SIRT1 and PPARγ pathway; 2) lipid potentiates the NAM-enhanced adipogenic response; and 3) the adipogenic response to NAM is associated with increased percent fat mass (%FM) among neonates. MSCs were derived from the umbilical cord of 46 neonates born to non-obese mothers enrolled in the Healthy Start study. Neonatal %FM was measured using air displacement plethysmography (Pea Pod) shortly after birth. Adipogenic differentiation was induced for 21 days in the 46 MSC sets under four conditions, +NAM (3mM)/–lipid (200 μM oleate/palmitate mix), +NAM/+lipid, –NAM/+lipid, and vehicle-control (–NAM/–lipid). Cells incubated in the presence of NAM had significantly higher PPARγ protein (+24%, p <0.01), FABP4 protein (+57%, p <0.01), and intracellular lipid content (+51%, p <0.01). Lipid did not significantly increase either PPARγ protein (p = 0.98) or FABP4 protein content (p = 0.82). There was no evidence of an interaction between NAM and lipid on adipogenic response of PPARγ or FABP4 protein (p = 0.99 and p = 0.09). In a subset of 9 MSC, SIRT1 activity was measured in the +NAM/-lipid and vehicle control conditions. SIRT1 enzymatic activity was significantly lower (-70%, p <0.05) in the +NAM/-lipid condition than in vehicle-control. In a linear model with neonatal %FM as the outcome, the percent increase in PPARγ protein in the +NAM/-lipid condition compared to vehicle-control was a significant predictor (β = 0.04, 95% CI 0.01–0.06, p <0.001). These are the first data to support that chronic NAM

  12. Promoting the recovery of injured liver with poly (3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) scaffolds loaded with umbilical cord-derived mesenchymal stem cells.

    PubMed

    Li, Pengshan; Zhang, Jin; Liu, Jing; Ma, Huan; Liu, Jie; Lie, Puchang; Wang, Yuechun; Liu, Gexiu; Zeng, Huilan; Li, Zhizhong; Wei, Xing

    2015-02-01

    Cell-based therapies are major focus of current research for treatment of liver diseases. In this study, mesenchymal stem cells were isolated from human umbilical cord Wharton's jelly (WJ-MSCs). Results confirmed that WJ-MSCs isolated in this study could express the typical MSC-specific markers and be induced to differentiate into adipocytes, osteoblasts, and chondrocytes. They could also be induced to differentiate into hepatocyte-like cells. Poly (3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) (PHBVHHx) is a new member of polyhydroxyalkanoate family and biodegradable polyester produced by bacteria. PHBVHHx scaffolds showed much higher cell attachment and viability than the other polymers tested. PHBVHHx scaffolds loaded with WJ-MSCs were transplanted into liver-injured mice. Liver morphology improved after 30 days of transplantation and looked similar to normal liver. Concentrations of serum alanine aminotransferase and total bilirubin were significantly lower, and albumin was significantly higher on days 14 and 30 in the WJ-MSCs+scaffold group than in the carbon tetrachloride (CCl4) group. Hematoxylin-eosin staining showed that liver had similar structure of normal liver lobules and similar size and shape of normal hepatic cells, and Masson staining demonstrated that liver had less blue staining for collagen after 30 days of transplantation. Real-time reverse transcription-polymerase chain reaction (RT-PCR) showed that the expression of the bile duct epithelial cell gene CK-19 in mouse liver is significantly lower on days 14 and 30 in the WJ-MSCs+scaffold group than in the CCl4 group. Real-time RT-PCR, immunocytochemistry, and periodic acid-Schiff staining showed that WJ-MSCs in scaffolds differentiated into hepatocyte-like cells on days 14 and 30 in the WJ-MSCs+scaffold group. Real-time RT-PCR also demonstrated that WJ-MSCs in scaffolds expressed endothelial cell genes Flk-1, vWF, and VE-cadherin on days 14 and 30 in the WJ-MSCs+scaffold group

  13. Nicotinamide Promotes Adipogenesis in Umbilical Cord-Derived Mesenchymal Stem Cells and Is Associated with Neonatal Adiposity: The Healthy Start BabyBUMP Project.

    PubMed

    Shapiro, Allison L B; Boyle, Kristen E; Dabelea, Dana; Patinkin, Zachary W; De la Houssaye, Becky; Ringham, Brandy M; Glueck, Deborah H; Barbour, Linda A; Norris, Jill M; Friedman, Jacob E

    2016-01-01

    The cellular mechanisms whereby excess maternal nutrition during pregnancy increases adiposity of the offspring are not well understood. However, nicotinamide (NAM), a fundamental micronutrient that is important in energy metabolism, has been shown to regulate adipogenesis through inhibition of SIRT1. Here we tested three novel hypotheses: 1) NAM increases the adipogenic response of human umbilical cord tissue-derived mesenchymal stem cells (MSCs) through a SIRT1 and PPARγ pathway; 2) lipid potentiates the NAM-enhanced adipogenic response; and 3) the adipogenic response to NAM is associated with increased percent fat mass (%FM) among neonates. MSCs were derived from the umbilical cord of 46 neonates born to non-obese mothers enrolled in the Healthy Start study. Neonatal %FM was measured using air displacement plethysmography (Pea Pod) shortly after birth. Adipogenic differentiation was induced for 21 days in the 46 MSC sets under four conditions, +NAM (3mM)/-lipid (200 μM oleate/palmitate mix), +NAM/+lipid, -NAM/+lipid, and vehicle-control (-NAM/-lipid). Cells incubated in the presence of NAM had significantly higher PPARγ protein (+24%, p <0.01), FABP4 protein (+57%, p <0.01), and intracellular lipid content (+51%, p <0.01). Lipid did not significantly increase either PPARγ protein (p = 0.98) or FABP4 protein content (p = 0.82). There was no evidence of an interaction between NAM and lipid on adipogenic response of PPARγ or FABP4 protein (p = 0.99 and p = 0.09). In a subset of 9 MSC, SIRT1 activity was measured in the +NAM/-lipid and vehicle control conditions. SIRT1 enzymatic activity was significantly lower (-70%, p <0.05) in the +NAM/-lipid condition than in vehicle-control. In a linear model with neonatal %FM as the outcome, the percent increase in PPARγ protein in the +NAM/-lipid condition compared to vehicle-control was a significant predictor (β = 0.04, 95% CI 0.01-0.06, p <0.001). These are the first data to support that chronic NAM exposure

  14. Enhanced expression of hepatocyte-specific microRNAs in valproic acid mediated hepatic trans-differentiation of human umbilical cord derived mesenchymal stem cells.

    PubMed

    Raut, Akshata; Khanna, Aparna

    2016-05-01

    MicroRNAs (miRNAs) play an important role in the control of cell fate determination during differentiation. In this study, we analyzed the expression pattern of microRNAs (miRNAs) during hepatic trans-differentiation. The protocol employed the use of histone deacetylase inhibitor (HDACI), valproic acid (VPA) to induce hepatic trans-differentiation of human umbilical cord Wharton's jelly derived mesenchymal stem cells (hUC-MSCs). The differentiated hepatocyte like cells (HLCs) from hUC-MSCs shared typical characteristics with mature hepatocytes, including morphology, expression of hepatocyte -specific genes at the molecular and cellular level. Moreover, the functionality of HLCs was confirmed through various liver function tests such as periodic acid-Schiff (PAS) stain for glycogen accumulation, enzyme-linked immunosorbent assay (ELISA) for synthesis of albumin and release of urea. The aim of the present work was to examine the effect of VPA treatment on miRNA expression during hepatic trans-differentiation. The analysis at miRNA level showed that there was a significant increase in expression of miRNAs involved in hepatic differentiation, due to VPA pre-treatment during differentiation. The study, thus demonstrated that improved expression of hepatocyte-specific miRNAs, miR-23b cluster (miR-27b-3p, miR-24-1-5p and miR-23b-3p), miR-30a-5p, miR-26a-5p, miR-148a-3p, miR-192-5p, miR-122-5p due to VPA pre-treatment contributed to a more efficient hepatic trans-differentiation from hUC-MSCs. The putative targets of these upregulated miRNAs were predicted using Bioinformatics analysis. Finally, miR-122-5p, highly upregulated miRNA during hepatic differentiation, was selected for target verification studies. Thus, this study also provides the basis for the function of miR-122-5p during hepatic differentiation of hUC-MSCs. PMID:27001466

  15. Human umbilical cord-derived mesenchymal stem cells suppress proliferation of PHA-activated lymphocytes in vitro by inducing CD4(+)CD25(high)CD45RA(+) regulatory T cell production and modulating cytokine secretion.

    PubMed

    Yang, Hongna; Sun, Jinhua; Li, Yan; Duan, Wei-Ming; Bi, Jianzhong; Qu, Tingyu

    2016-04-01

    Bone marrow-derived mesenchymal stem cells (MSCs) are promising candidate cells for therapeutic application in autoimmune diseases due to their immunomodulatory properties. Unused human umbilical cords (UC) offer an abundant and noninvasive source of MSCs without ethical issues and are emerging as a valuable alternative to bone marrow tissue for producing MSCs. We thus investigated the immunomodulation effect of umbilical cord-derived MSCs (UC-MSCs) on human peripheral blood mononuclear cells (PBMCs), T cells in particular, in a co-culture system. We found that UC-MSCs efficiently suppressed the proliferation of phytohaemagglutinin (PHA)-stimulated PBMCs (p<0.01). Kinetic analysis revealed that UC-MSCs primarily inhibited the division of generation 3 (G3) and 4 (G4) of PBMCs. In addition, UC-MSCs augmented the expression of CD127(+) and CD45RA(+) but reduced the expression of CD25(+) in PBMCs stimulated by PHA (p<0.05). Furthermore, UC-MSCs inhibited PHA-resulted increase in the frequency of CD4(+)CD25(+)CD127(low/-) Tregs significantly (p<0.01) but augmented PHA-resulted increase in the frequency of CD4(+)CD25(high)CD45RA(+) Tregs to about three times in PBMCs. The levels of anti-inflammatory cytokines, PEG2, TGF-β, and IL-10 were greatly up-regulated, accompanied by a significant down-regulation of pro-inflammatory IFN-γ in the co-culture (p<0.01). Our results showed that UC-MSCs are able to suppress mitogen-induced PBMC activation and proliferation in vitro by altering T lymphocyte phenotypes, increasing the frequency of CD4(+)CD25(high)CD45RA(+) Tregs, and modulating the associated cytokine production. Further studies are warranted to investigate the therapeutic potential of UC-MSCs in immunologically-diseased conditions. PMID:26774852

  16. Low levels of TGF-β1 enhance human umbilical cord-derived mesenchymal stem cell fibronectin production and extend survival time in a rat model of lipopolysaccharide-induced acute lung injury.

    PubMed

    Li, Dong; Liu, Qingshen; Qi, Lei; Dai, Xiaoyu; Liu, Huan; Wang, Yunshan

    2016-08-01

    Mesenchymal stem cells (MSCs) are an attractive cellular source for cell‑based therapy, tissue engineering and regenerative medicine. However, the use of MSCs is limited by their low incorporation rate in the graft environment. The majority of cells are lost from the graft within 1 month, due to reduced microenvironment or local inflammation at the graft site. The extracellular matrix (ECM) may assist the survival and expansion of MSCs. The present study aimed to identify an effective approach to increase ECM expression levels by MSCs in order to enhance the therapeutic effect and survival rate of MSCs at the injury site. The concentration‑dependent effect of transforming growth factor (TGF)‑β1 on human umbilical cord (hUC)‑MSC proliferation and expression of ECM genes was investigated. MSCs were successfully isolated, cultured and expanded from hUC. A low concentration of TGF‑β1 (0.1 ng/ml) exhibited the optimal effect on hUC‑MSC proliferation and markedly stimulated the expression of ECM genes, particularly fibronectin (FN). Furthermore, treatment with TGF‑β1 caused no alteration in the immunophenotype and differentiation capacity of MSCs. In vivo experiments in rats demonstrated that intravenous injection of control UC-MSCs or TGF-β1-pre-treated UC-MSCs reduced the severity of lipopolysaccharide-induced lung injury, assessed using histology, measurements of the wet‑dry lung weight ratio, and neutrophil count and protein concentration in bronchoalveolar lavage fluid. However, the short‑term (48 h) therapeutic effects of untreated and TGF‑β1‑pre‑treated UC‑MSCs were similar. The survival of MSCs in damaged lungs, determined by Sry gene expression levels, were significantly increased in MSCs pre‑treated with TGF‑β1. In conclusion, pre‑treatment of MSCs with a low concentration of TGF‑β1 enhanced the expression of ECM components, particularly FN, thus, improving the survival and potential therapeutic benefits of MSCs

  17. Connexin 50 modulates Sox2 expression in spinal-cord-derived ependymal stem/progenitor cells.

    PubMed

    Rodriguez-Jimenez, Francisco Javier; Alastrue, Ana; Stojkovic, Miodrag; Erceg, Slaven; Moreno-Manzano, Victoria

    2016-08-01

    Ion channels included in the family of Connexins (Cx) have been reported to influence the secondary expansion of traumatic spinal cord injury (SCI) and neuropathic pain following SCI. However, Cxs also contribute to spinal cord neurogenesis during the remyelinating process and functional recovery after SCI. Certain Cxs have been recently related to the control of cell proliferation and the differentiation of neuronal progenitors. Adult spinal-cord-derived ependymal stem progenitor cells (epSPC) show high expression levels of Cx50 in non-pathological conditions and lower expression when they actively proliferate after injury (epSPCi). We explore the role of Cx50 in the ependymal population in the modulation of Sox2, a crucial factor of neural progenitor self-renewal and a promising target for promoting neuronal-cell-fate induction for neuronal tissue repair. Short-interfering-RNA ablation or over-expression of Cx50 regulates the expression of Sox2 in both epSPC and epSPCi. Interestingly, Cx50 and Sox2 co-localize at the nucleus indicating a potential role for this ion channel beyond cell-to-cell communication in the spinal cord. In vivo and in vitro experiments with Clotrimazole, a specific pharmacological modulator of Cx50, show the convergent higher expression of Cx50 and Sox2 in the isolated epSPC/epSPCi and in spinal cord tissue. Therefore, the pharmacological modulation of Cx50 might constitute an interesting mechanism for Sox2 induction to modulate the endogenous regenerative potential of neuronal tissue with a potential application in regenerative therapies. PMID:27221278

  18. Evaluation of a new standardized enzymatic isolation protocol for human umbilical cord-derived stem cells.

    PubMed

    Buyl, Karolien; Vanhaecke, Tamara; Desmae, Terry; Lagneaux, Laurence; Rogiers, Vera; Najar, Mehdi; De Kock, Joery

    2015-09-01

    The umbilical cord (UC) represents an important source of mesenchymal stem cells (MSC). These human UC-derived MSC (UC-MSC) have already been isolated using a protocol based on the migratory and plastic adhesive properties of MSC (UC-MSC-Mig). The UC-MSC-Mig isolation method, however, is difficult to standardize. Therefore, we developed an enzymatic isolation protocol (UC-MSC-Enz) to overcome the above mentioned disadvantages. First, we investigated the UC-MSC-Enz for their MSC properties. We found that UC-MSC-Enz express the MSC markers CD73, CD90 and CD105 and are able to differentiate into osteoblasts, adipocytes and chondroblasts fulfilling the MSC criteria of the International Society for Cellular Therapy. Previously we found that UC-MSC-Mig are unique among MSCs due to their significant expression of several hepatic (progenitor) markers. Therefore, we also investigated the expression of hepatic transcription factors and other hepatic markers in UC-MSC-Enz at both the mRNA and protein level. We found that the expression of hepatic transcription factors (GATA4, GATA6, SOX9 and SOX17) and hepatic markers (AFP, DPP4, CX43, DKK1, DSG2, KRT18 and KRT19) in UC-MSC-Enz was not significantly different from those of UC-MSC-Mig. Consequently, this optimized enzyme-based method represents a fast, robust and standardized way to isolate UC-MSC for a broad range of applications. PMID:25541070

  19. Mesenchymal stem cells.

    PubMed

    Ding, Dah-Ching; Shyu, Woei-Cherng; Lin, Shinn-Zong

    2011-01-01

    Stem cells have two features: the ability to differentiate along different lineages and the ability of self-renewal. Two major types of stem cells have been described, namely, embryonic stem cells and adult stem cells. Embryonic stem cells (ESC) are obtained from the inner cell mass of the blastocyst and are associated with tumorigenesis, and the use of human ESCs involves ethical and legal considerations. The use of adult mesenchymal stem cells is less problematic with regard to these issues. Mesenchymal stem cells (MSCs) are stromal cells that have the ability to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as umbilical cord, endometrial polyps, menses blood, bone marrow, adipose tissue, etc. This is because the ease of harvest and quantity obtained make these sources most practical for experimental and possible clinical applications. Recently, MSCs have been found in new sources, such as menstrual blood and endometrium. There are likely more sources of MSCs waiting to be discovered, and MSCs may be a good candidate for future experimental or clinical applications. One of the major challenges is to elucidate the mechanisms of differentiation, mobilization, and homing of MSCs, which are highly complex. The multipotent properties of MSCs make them an attractive choice for possible development of clinical applications. Future studies should explore the role of MSCs in differentiation, transplantation, and immune response in various diseases. PMID:21396235

  20. [Mesenchymal stem cells. A review.].

    PubMed

    Sigurjónsson, O E; Guðmundsson, K O; Guðmundsson, S

    2001-01-01

    The bone marrow contains various types of stem cells. Among them are hematopoietic stem cells, which are the precursors of all blood cells, and mesenchymal stem cells. Mesenchymal stem cells have recently received a lot of attention in biological research because of their capability to self renewal, to expand and transdifferentiate into many different cell types; bone cells, adipocytes, chondrocytes, tendocytes, neural cells and stromal cells of the bone marrow. Mesenchymal stem cells can be cultured in vitro although their differentiation potential is not yet fully understood. Several experiments have been conducted in animal models where mesenchymal stem cells have been transplanted in order to enhance hematopoiesis or to facilitate the repair of mesenchymal tissue. Similar experiments are being conducted in humans. Mesenchymal stem cells are believed to be able to enhance hematopoietic stem cells transplantation by rebuilding the bone marrow microenvironment which is damaged after radiation- and/or chemotherapy. Mesenchymal stem cells are promising as vehicles for gene transfer and therapy. It may prove possible to tranduce them with a gene coding for a defective protein i.e. collagen I in osteogenesis imperfecta. The cells could then be expanded ex vivo and transplanted to the patients where they home to the bone marrow, differentiate and produce the intact protein. Future medicine will probably involve mesenchymal stem cells in various treatment settings. PMID:17018999

  1. Dental mesenchymal stem cells.

    PubMed

    Sharpe, Paul T

    2016-07-01

    Mammalian teeth harbour mesenchymal stem cells (MSCs), which contribute to tooth growth and repair. These dental MSCs possess many in vitro features of bone marrow-derived MSCs, including clonogenicity, expression of certain markers, and following stimulation, differentiation into cells that have the characteristics of osteoblasts, chondrocytes and adipocytes. Teeth and their support tissues provide not only an easily accessible source of MSCs but also a tractable model system to study their function and properties in vivo In addition, the accessibility of teeth together with their clinical relevance provides a valuable opportunity to test stem cell-based treatments for dental disorders. This Review outlines some recent discoveries in dental MSC function and behaviour and discusses how these and other advances are paving the way for the development of new biologically based dental therapies. PMID:27381225

  2. Mesenchymal Stem Cells as Therapeutics

    PubMed Central

    Parekkadan, Biju; Milwid, Jack M.

    2013-01-01

    Mesenchymal stem cells (MSCs) are multipotent cells that are being clinically explored as a new therapeutic for treating a variety of immune-mediated diseases. First heralded as a regenerative therapy for skeletal tissue repair, MSCs have recently been shown to modulate endogenous tissue and immune cells. Preclinical studies of the mechanism of action suggest that the therapeutic effects afforded by MSC transplantation are short-lived and related to dynamic, paracrine interactions between MSCs and host cells. Therefore, representations of MSCs as drug-loaded particles may allow for pharmacokinetic models to predict the therapeutic activity of MSC transplants as a function of drug delivery mode. By integrating principles of MSC biology, therapy, and engineering, the field is armed to usher in the next generation of stem cell therapeutics. PMID:20415588

  3. Mesenchymal Stem Cells in Cardiology.

    PubMed

    White, Ian A; Sanina, Cristina; Balkan, Wayne; Hare, Joshua M

    2016-01-01

    Cardiovascular disease (CVD) accounts for more deaths globally than any other single disease. There are on average 1.5 million episodes of myocardial infarction (heart attack) each year in the United States alone with roughly one-third resulting in death. There is therefore a major need for developing new and effective strategies to promote cardiac repair. Intramyocardial transplantation of mesenchymal stem cells (MSCs) has emerged as a leading contender in the pursuit of clinical intervention and therapy. MSCs are potent mediators of cardiac repair and are therefore an attractive tool in the development of preclinical and clinical trials. MSCs are capable of secreting a large array of soluble factors, which have had demonstrated effects on pathogenic cardiac remolding, fibrosis, immune activation, and cardiac stem cell proliferation within the damaged heart. MSCs are also capable of differentiation into cardiomyocytes, endothelial cells, and vascular smooth muscle cells, although the relative contribution of trilineage differentiation and paracrine effectors on cardiac repair remains the subject of active investigation. PMID:27236666

  4. Mesenchymal stem cells in regenerative rehabilitation.

    PubMed

    Nurkovic, Jasmin; Dolicanin, Zana; Mustafic, Fahrudin; Mujanovic, Rifat; Memic, Mensur; Grbovic, Vesna; Skevin, Aleksandra Jurisic; Nurkovic, Selmina

    2016-06-01

    [Purpose] Regenerative medicine and rehabilitation contribute in many ways to a specific plan of care based on a patient's medical status. The intrinsic self-renewing, multipotent, regenerative, and immunosuppressive properties of mesenchymal stem cells offer great promise in the treatment of numerous autoimmune, degenerative, and graft-versus-host diseases, as well as tissue injuries. As such, mesenchymal stem cells represent a therapeutic fortune in regenerative medicine. The aim of this review is to discuss possibilities, limitations, and future clinical applications of mesenchymal stem cells. [Subjects and Methods] The authors have identified and discussed clinically and scientifically relevant articles from PubMed that have met the inclusion criteria. [Results] Direct treatment of muscle injuries, stroke, damaged peripheral nerves, and cartilage with mesenchymal stem cells has been demonstrated to be effective, with synergies seen between cellular and physical therapies. Over the past few years, several researchers, including us, have shown that there are certain limitations in the use of mesenchymal stem cells. Aging and spontaneous malignant transformation of mesenchymal stem cells significantly affect the functionality of these cells. [Conclusion] Definitive conclusions cannot be made by these studies because limited numbers of patients were included. Studies clarifying these results are expected in the near future. PMID:27390452

  5. Mesenchymal stem cells in regenerative rehabilitation

    PubMed Central

    Nurkovic, Jasmin; Dolicanin, Zana; Mustafic, Fahrudin; Mujanovic, Rifat; Memic, Mensur; Grbovic, Vesna; Skevin, Aleksandra Jurisic; Nurkovic, Selmina

    2016-01-01

    [Purpose] Regenerative medicine and rehabilitation contribute in many ways to a specific plan of care based on a patient’s medical status. The intrinsic self-renewing, multipotent, regenerative, and immunosuppressive properties of mesenchymal stem cells offer great promise in the treatment of numerous autoimmune, degenerative, and graft-versus-host diseases, as well as tissue injuries. As such, mesenchymal stem cells represent a therapeutic fortune in regenerative medicine. The aim of this review is to discuss possibilities, limitations, and future clinical applications of mesenchymal stem cells. [Subjects and Methods] The authors have identified and discussed clinically and scientifically relevant articles from PubMed that have met the inclusion criteria. [Results] Direct treatment of muscle injuries, stroke, damaged peripheral nerves, and cartilage with mesenchymal stem cells has been demonstrated to be effective, with synergies seen between cellular and physical therapies. Over the past few years, several researchers, including us, have shown that there are certain limitations in the use of mesenchymal stem cells. Aging and spontaneous malignant transformation of mesenchymal stem cells significantly affect the functionality of these cells. [Conclusion] Definitive conclusions cannot be made by these studies because limited numbers of patients were included. Studies clarifying these results are expected in the near future. PMID:27390452

  6. Differentiation of isolated human umbilical cord mesenchymal stem cells into neural stem cells

    PubMed Central

    Chen, Song; Zhang, Wei; Wang, Ji-Ming; Duan, Hong-Tao; Kong, Jia-Hui; Wang, Yue-Xin; Dong, Meng; Bi, Xue; Song, Jian

    2016-01-01

    AIM To investigate whether umbilical cord human mesenchymal stem cell (UC-MSC) was able to differentiate into neural stem cell and neuron in vitro. METHODS The umbilical cords were obtained from pregnant women with their written consent and the approval of the Clinic Ethnics Committee. UC-MSC were isolated by adherent culture in the medium contains 20% fetal bovine serum (FBS), then they were maintained in the medium contain 10% FBS and induced to neural cells in neural differentiation medium. We investigated whether UC-MSC was able to differentiate into neural stem cell and neuron in vitro by using flow cytometry, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence (IF) analyzes. RESULTS A substantial number of UC-MSC was harvested using the tissue explants adherent method at about 2wk. Flow cytometric study revealed that these cells expressed common markers of MSCs, such as CD105 (SH2), CD73 (SH3) and CD90. After induction of differentiation of neural stem cells, the cells began to form clusters; RT-PCR and IF showed that the neuron specific enolase (NSE) and neurogenic differentiation 1-positive cells reached 87.3%±14.7% and 72.6%±11.8%, respectively. Cells showed neuronal cell differentiation after induced, including neuron-like protrusions, plump cell body, obviously and stronger refraction. RT-PCR and IF analysis showed that microtubule-associated protein 2 (MAP2) and nuclear factor-M-positive cells reached 43.1%±10.3% and 69.4%±19.5%, respectively. CONCLUSION Human umbilical cord derived MSCs can be cultured and proliferated in vitro and differentiate into neural stem cells, which may be a valuable source for cell therapy of neurodegenerative eye diseases. PMID:26949608

  7. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction.

    PubMed

    Miyahara, Yoshinori; Nagaya, Noritoshi; Kataoka, Masaharu; Yanagawa, Bobby; Tanaka, Koichi; Hao, Hiroyuki; Ishino, Kozo; Ishida, Hideyuki; Shimizu, Tatsuya; Kangawa, Kenji; Sano, Shunji; Okano, Teruo; Kitamura, Soichiro; Mori, Hidezo

    2006-04-01

    Mesenchymal stem cells are multipotent cells that can differentiate into cardiomyocytes and vascular endothelial cells. Here we show, using cell sheet technology, that monolayered mesenchymal stem cells have multipotent and self-propagating properties after transplantation into infarcted rat hearts. We cultured adipose tissue-derived mesenchymal stem cells characterized by flow cytometry using temperature-responsive culture dishes. Four weeks after coronary ligation, we transplanted the monolayered mesenchymal stem cells onto the scarred myocardium. After transplantation, the engrafted sheet gradually grew to form a thick stratum that included newly formed vessels, undifferentiated cells and few cardiomyocytes. The mesenchymal stem cell sheet also acted through paracrine pathways to trigger angiogenesis. Unlike a fibroblast cell sheet, the monolayered mesenchymal stem cells reversed wall thinning in the scar area and improved cardiac function in rats with myocardial infarction. Thus, transplantation of monolayered mesenchymal stem cells may be a new therapeutic strategy for cardiac tissue regeneration. PMID:16582917

  8. Mesenchymal Stem Cells Migration Homing and Tracking

    PubMed Central

    Verfaillie, Catherine M.

    2013-01-01

    In this review, we discuss the migration and homing ability of mesenchymal stem cells (MSCs) and MSC-like cells and factors influencing this. We also discuss studies related to the mechanism of migration and homing and the approaches undertaken to enhance it. Finally, we describe the different methods available and frequently used to track and identify the injected cells in vivo. PMID:24194766

  9. [Glioma treatment strategies using mesenchymal stem cells].

    PubMed

    Namba, Hiroki

    2010-10-01

    Because of the growth characteristics of malignant gliomas that are highly invasive and deeply infiltrate the surrounding brain area; the surgical resection of these gliomas with preservation of neural functions is almost always noncurative. The residual tumor cells are usually resistant to standard adjuvant radiochemotherapy, and therefore, the tumors inevitably recur after a certain period and finally cause the death of the patients. Neural and mesenchymal stem cells have been extensively studied for the development of new strategies for treating malignant gliomas because of these cells possess the intrinsic property of homing toward tumor cells. By using neural and mesenchymal stem cells as vehicles for drug carriers, it is possible to deliver anticancer drugs to the tumor cells that infiltrate functioning normal brain tissue and are difficult to remove. Several cytokines and suicide genes have been tested, and promising results have been reported in animal brain tumor models. However, further studies involving safety issues such as secondary cancer formation are required before human trials of stem cell therapies. In the present paper, the author has reviewed the recent concepts involved in the treatment of malignant gliomas with stem cells, especially mesenchymal stem cells that are much easier to obtain from the patients themselves. PMID:20940507

  10. Mesenchymal stem cell-based therapy.

    PubMed

    Mundra, Vaibhav; Gerling, Ivan C; Mahato, Ram I

    2013-01-01

    Mesenchymal stem cells (MSCs) are multipotent adult stem cells which have self-renewal capacity and differentiation potential into several mesenchymal lineages including bones, cartilages, adipose tissues and tendons. MSCs may repair tissue injuries and prevent immune cell activation and proliferation. Immunomodulation and secretion of growth factors by MSCs have led to realizing the true potential of MSC-based cell therapy. The use of MSCs as immunomodulators has been explored in cell/organ transplant, tissue repair, autoimmune diseases, and prevention of graft vs host disease (GVHD). This review focuses on the clinical applications of MSC-based cell therapy, with particular emphasis on islet transplantation for treating type I diabetes. PMID:23215004

  11. Mesenchymal Stem Cell-Based Therapy

    PubMed Central

    Mundra, Vaibhav; Gerling, Ivan C.; Mahato, Ram I.

    2012-01-01

    Mesenchymal stem cells (MSCs) are multipotent adult stem cells which have self-renewal capacity and differentiation potential into several mesenchymal lineages including bones, cartilages, adipose tissues and tendons. MSCs may repair tissue injuries and prevent immune cell activation and proliferation. Immunomodulation and secretion of growth factors by MSCs have led to realizing the true potential of MSC-based cell therapy. The use of MSCs as immunomdulators has been explored in cell/organ transplant, tissue repair, autoimmune diseases and prevention of graft vs. host disease (GVHD). This review focuses on the clinical applications of MSC-based cell therapy, with particular emphasis on islet transplantation for treating type I diabetes. PMID:23215004

  12. Mesenchymal stem cells induce dermal fibroblast responses to injury

    SciTech Connect

    Smith, Andria N.; Willis, Elise; Chan, Vincent T.; Muffley, Lara A.; Isik, F. Frank; Gibran, Nicole S.; Hocking, Anne M.

    2010-01-01

    Although bone marrow-derived mesenchymal stem cells have been shown to promote repair when applied to cutaneous wounds, the mechanism for this response remains to be determined. The aim of this study was to determine the effects of paracrine signaling from mesenchymal stem cells on dermal fibroblast responses to injury including proliferation, migration and expression of genes important in wound repair. Dermal fibroblasts were co-cultured with bone marrow-derived mesenchymal stem cells grown in inserts, which allowed for paracrine interactions without direct cell contact. In this co-culture model, bone marrow-derived mesenchymal stem cells regulate dermal fibroblast proliferation, migration and gene expression. When co-cultured with mesenchymal stem cells, dermal fibroblasts show increased proliferation and accelerated migration in a scratch assay. A chemotaxis assay also demonstrated that dermal fibroblasts migrate towards bone marrow-derived mesenchymal stem cells. A PCR array was used to analyze the effect of mesenchymal stem cells on dermal fibroblast gene expression. In response to mesenchymal stem cells, dermal fibroblasts up-regulate integrin alpha 7 expression and down-regulate expression of ICAM1, VCAM1 and MMP11. These observations suggest that mesenchymal stem cells may provide an important early signal for dermal fibroblast responses to cutaneous injury.

  13. Umbilical cord mesenchymal stem cells: the new gold standard for mesenchymal stem cell-based therapies?

    PubMed

    El Omar, Reine; Beroud, Jacqueline; Stoltz, Jean-Francois; Menu, Patrick; Velot, Emilie; Decot, Veronique

    2014-10-01

    Due to their self-renewal capacity, multilineage differentiation potential, paracrine effects, and immunosuppressive properties, mesenchymal stromal cells (MSCs) are an attractive and promising tool for regenerative medicine. MSCs can be isolated from various tissues but despite their common immunophenotypic characteristics and functional properties, source-dependent differences in MSCs properties have recently emerged and lead to different clinical applications. Considered for a long time as a medical waste, umbilical cord appears these days as a promising source of MSCs. Several reports have shown that umbilical cord-derived MSCs are more primitive, proliferative, and immunosuppressive than their adult counterparts. In this review, we aim at synthesizing the differences between umbilical cord MSCs and MSCs from other sources (bone marrow, adipose tissue, periodontal ligament, dental pulp,…) with regard to their proliferation capacity, proteic and transcriptomic profiles, and their secretome involved in their regenerative, homing, and immunomodulatory capacities. Although umbilical cord MSCs are until now not particularly used as an MSC source in clinical practice, accumulating evidence shows that they may have a therapeutic advantage to treat several diseases, especially autoimmune and neurodegenerative diseases. PMID:24552279

  14. Cartilage Engineering from Mesenchymal Stem Cells

    NASA Astrophysics Data System (ADS)

    Goepfert, C.; Slobodianski, A.; Schilling, A. F.; Adamietz, P.; Pörtner, R.

    Mesenchymal progenitor cells known as multipotent mesenchymal stromal cells or mesenchymal stem cells (MSC) have been isolated from various tissues. Since they are able to differentiate along the mesenchymal lineages of cartilage and bone, they are regarded as promising sources for the treatment of skeletal defects. Tissue regeneration in the adult organism and in vitro engineering of tissues is hypothesized to follow the principles of embryogenesis. The embryonic development of the skeleton has been studied extensively with respect to the regulatory mechanisms governing morphogenesis, differentiation, and tissue formation. Various concepts have been designed for engineering tissues in vitro based on these developmental principles, most of them involving regulatory molecules such as growth factors or cytokines known to be the key regulators in developmental processes. Growth factors most commonly used for in vitro cultivation of cartilage tissue belong to the fibroblast growth factor (FGF) family, the transforming growth factor-beta (TGF-β) super-family, and the insulin-like growth factor (IGF) family. In this chapter, in vivo actions of members of these growth factors described in the literature are compared with in vitro concepts of cartilage engineering making use of these growth factors.

  15. Spheroid Culture of Mesenchymal Stem Cells

    PubMed Central

    Cesarz, Zoe; Tamama, Kenichi

    2016-01-01

    Compared with traditional 2D adherent cell culture, 3D spheroidal cell aggregates, or spheroids, are regarded as more physiological, and this technique has been exploited in the field of oncology, stem cell biology, and tissue engineering. Mesenchymal stem cells (MSCs) cultured in spheroids have enhanced anti-inflammatory, angiogenic, and tissue reparative/regenerative effects with improved cell survival after transplantation. Cytoskeletal reorganization and drastic changes in cell morphology in MSC spheroids indicate a major difference in mechanophysical properties compared with 2D culture. Enhanced multidifferentiation potential, upregulated expression of pluripotency marker genes, and delayed replicative senescence indicate enhanced stemness in MSC spheroids. Furthermore, spheroid formation causes drastic changes in the gene expression profile of MSC in microarray analyses. In spite of these significant changes, underlying molecular mechanisms and signaling pathways triggering and sustaining these changes are largely unknown. PMID:26649054

  16. Mesenchymal stem cells in osteoarticular diseases.

    PubMed

    Jorgensen, Christian; Noël, Danièle

    2011-11-01

    Multipotent mesenchymal stromal cells or mesenchymal stem cells (MSCs) are mainly isolated from bone marrow or fat tissue. Owing to their potential for multilineage differentiation towards bone, cartilage and fat tissue, they were initially evaluated in innovative strategies for tissue engineering. More recently, they have gained interest for their immunomodulatory properties and have been tested in various clinical trials that aim to modulate the host immune response in graft-versus-host disease or autoimmune diseases. MSC-mediated immunomodulation occurs through the secretion of soluble mediators. The clinical applications of MSCs for rheumatic diseases focus on their potential to promote tissue repair/regeneration and prevent inflammation. This article will focus on the mechanisms by which MSCs might exhibit a therapeutic potential in rheumatology. Special attention is given to their potential for innovative future strategies. PMID:21999261

  17. Mesenchymal stem cells and cardiac repair

    PubMed Central

    Nesselmann, Catharina; Ma, Nan; Bieback, Karen; Wagner, Wolfgang; Ho, Anthony; Konttinen, Yrjö T; Zhang, Hao; Hinescu, Mihail E; Steinhoff, Gustav

    2008-01-01

    Accumulating clinical and experimental evidence indicates that mesenchymal stem cells (MSCs) are promising cell types in the treatment of cardiac dysfunction. They may trigger production of reparative growth factors, replace damaged cells and create an environment that favours endogenous cardiac repair. However, identifying mechanisms which regulate the role of MSCs in cardiac repair is still at work. To achieve the maximal clinical benefits, ex vivo manipulation can further enhance MSC therapeutic potential. This review focuses on the mechanism of MSCs in cardiac repair, with emphasis on ex vivo manipulation. PMID:18684237

  18. Adult Mesenchymal Stem Cells and Radiation Injury.

    PubMed

    Kiang, Juliann G

    2016-08-01

    Recent understanding of the cellular and molecular signaling activations in adult mesenchymal stem cells (MSCs) has provided new insights into their potential clinical applications, particularly for tissue repair and regeneration. This review focuses on these advances, specifically in the context of self-renewal for tissue repair and recovery after radiation injury. Thus far, MSCs have been characterized extensively and shown to be useful in mitigation and therapy for acute radiation syndrome and cognitive dysfunction. Use of MSCs for treating radiation injury alone or in combination with additional trauma is foreseeable. PMID:27356065

  19. Umbilical cord mesenchymal stem cell transplantation ameliorates burn-induced acute kidney injury in rats.

    PubMed

    Lu, Gang; Huang, Sha; Chen, Yongbin; Ma, Kui

    2013-09-01

    Excessive systemic inflammation following burns could lead to acute kidney injury (AKI). Mesenchymal stromal cells (MSCs) suppress immune cell responses and have beneficial effects in various inflammatory-related immune disorders. However, autologous MSCs are not vital enough for the treatment because of the severely burned patients' deleterious condition. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) could be a suitable substitute cell candidate but no data are available on the therapeutic effectiveness of UC-MSCs transplantation for burn injury and its consequences. In this study, UC-MSCs or ulinastatin was administered intravenously in the rats with burn trauma, and the therapeutic effects of UC-MSCs on the survival of severe burn-induced AKI rats and functional protection of kidney were analyzed. Results showed that UC-MSCs promoted the survival and prevented commitment to apoptosis of resident kidney cells and reduced organ microscopic damage in kidneys after thermal trauma. Thus, our study demonstrates that intravenously delivered UC-MSCs protected the host from death caused by kidney injury subsequent to severe burn, identifying UC-MSCs transplantation may be an attractive candidate for cell-based treatments for burns and induced organ damage. PMID:24043673

  20. Proteomic Definitions of Mesenchymal Stem Cells

    PubMed Central

    Maurer, Martin H.

    2011-01-01

    Mesenchymal stem cells (MSCs) are pluripotent cells isolated from the bone marrow and various other organs. They are able to proliferate and self-renew, as well as to give rise to progeny of at least the osteogenic, chondrogenic, and adipogenic lineages. Despite this functional definition, MSCs can also be defined by their expression of a distinct set of cell surface markers. In the current paper, studies investigating the proteome of human MSCs are reviewed with the aim to identify common protein markers of MSCs. The proteomic analysis of MSCs revealed a distinct set of proteins representing the basic molecular inventory, including proteins for (i) cell surface markers, (ii) the responsiveness to growth factors, (iii) the reuse of developmental signaling cascades in adult stem cells, (iv) the interaction with molecules of the extracellular matrix, (v) the expression of genes regulating transcription and translation, (vi) the control of the cell number, and (vii) the protection against cellular stress. PMID:21437194

  1. Viability of mesenchymal stem cells during electrospinning

    PubMed Central

    Zanatta, G.; Steffens, D.; Braghirolli, D.I.; Fernandes, R.A.; Netto, C.A.; Pranke, P.

    2011-01-01

    Tissue engineering is a technique by which a live tissue can be re-constructed and one of its main goals is to associate cells with biomaterials. Electrospinning is a technique that facilitates the production of nanofibers and is commonly used to develop fibrous scaffolds to be used in tissue engineering. In the present study, a different approach for cell incorporation into fibrous scaffolds was tested. Mesenchymal stem cells were extracted from the wall of the umbilical cord and mononuclear cells from umbilical cord blood. Cells were re-suspended in a 10% polyvinyl alcohol solution and subjected to electrospinning for 30 min under a voltage of 21 kV. Cell viability was assessed before and after the procedure by exclusion of dead cells using trypan blue staining. Fiber diameter was observed by scanning electron microscopy and the presence of cells within the scaffolds was analyzed by confocal laser scanning microscopy. After electrospinning, the viability of mesenchymal stem cells was reduced from 88 to 19.6% and the viability of mononuclear cells from 99 to 8.38%. The loss of viability was possibly due to the high viscosity of the polymer solution, which reduced the access to nutrients associated with electric and mechanical stress during electrospinning. These results suggest that the incorporation of cells during fiber formation by electrospinning is a viable process that needs more investigation in order to find ways to protect cells from damage. PMID:22183245

  2. Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis.

    PubMed

    Jung, Younghun; Kim, Jin Koo; Shiozawa, Yusuke; Wang, Jingcheng; Mishra, Anjali; Joseph, Jeena; Berry, Janice E; McGee, Samantha; Lee, Eunsohl; Sun, Hongli; Wang, Jianhua; Jin, Taocong; Zhang, Honglai; Dai, Jinlu; Krebsbach, Paul H; Keller, Evan T; Pienta, Kenneth J; Taichman, Russell S

    2013-01-01

    Tumours recruit mesenchymal stem cells to facilitate healing, which induces their conversion into cancer-associated fibroblasts that facilitate metastasis. However, this process is poorly understood on the molecular level. Here we show that CXCL16, a ligand for CXCR6, facilitates mesenchymal stem cell or very small embryonic-like cells recruitment into prostate tumours. CXCR6 signalling stimulates the conversion of mesenchymal stem cells into cancer-associated fibroblasts, which secrete stromal-derived factor-1, also known as CXCL12. CXCL12 expressed by cancer-associated fibroblasts then binds to CXCR4 on tumour cells and induces an epithelial-to-mesenchymal transition, which ultimately promotes metastasis to secondary tumour sites. Our results provide the molecular basis for mesenchymal stem cell recruitment into tumours and how this process leads to tumour metastasis. PMID:23653207

  3. Mesenchymal stem cells for cardiac cell therapy.

    PubMed

    Choi, Yeong-Hoon; Kurtz, Andreas; Stamm, Christof

    2011-01-01

    Despite refinements of medical and surgical therapies, heart failure remains a fatal disease. Myocardial infarction is the most common cause of heart failure, and only palliative measures are available to relieve symptoms and prolong the patient's life span. Because mammalian cardiomyocytes irreversibly exit the cell cycle at about the time of birth, the heart has traditionally been considered to lack any regenerative capacity. This paradigm, however, is currently shifting, and the cellular composition of the myocardium is being targeted by various regeneration strategies. Adult progenitor and stem cell treatment of diseased human myocardium has been carried out for more than 10 years (Menasche et al., 2001; Stamm et al., 2003), and it has become clear that, in humans, the regenerative capacity of hematopoietic stem cells and endothelial progenitor cells, despite potent proangiogenic effects, is limited (Stamm et al., 2009). More recently, mesenchymal stem cells (MSCs) and related cell types are being evaluated in preclinical models of heart disease as well as in clinical trials (see Published Clinical Trials, below). MSCs have the capacity to self-renew and to differentiate into lineages that normally originate from the embryonic mesenchyme (connective tissues, blood vessels, blood-related organs) (Caplan, 1991; Prockop, 1997; Pittenger et al., 1999). The current definition of MSCs includes plastic adherence in cell culture, specific surface antigen expression (CD105(+)/CD90(+)/CD73(+), CD34(-)/CD45(-)/CD11b(-) or CD14(-)/CD19(-) or CD79α(-)/HLA-DR1(-)), and multilineage in vitro differentiation potential (osteogenic, chondrogenic, and adipogenic) (Dominici et al., 2006 ). If those criteria are not met completely, the term "mesenchymal stromal cells" should be used for marrow-derived adherent cells, or other terms for MSC-like cells of different origin. For the purpose of this review, MSCs and related cells are discussed in general, and cell type

  4. Concise review: mesenchymal stem cells for diabetes.

    PubMed

    Domínguez-Bendala, Juan; Lanzoni, Giacomo; Inverardi, Luca; Ricordi, Camillo

    2012-01-01

    Mesenchymal stem cells (MSCs) have already made their mark in the young field of regenerative medicine. Easily derived from many adult tissues, their therapeutic worth has already been validated for a number of conditions. Unlike embryonic stem cells, neither their procurement nor their use is deemed controversial. Here we review the potential use of MSCs for the treatment of type 1 diabetes mellitus, a devastating chronic disease in which the insulin-producing cells of the pancreas (the β-cells) are the target of an autoimmune process. It has been hypothesized that stem cell-derived β-cells may be used to replenish the islet mass in diabetic patients, making islet transplantation (a form of cell therapy that has already proven effective at clinically restoring normoglycemia) available to millions of prospective patients. Here we review the most current advances in the design and application of protocols for the differentiation of transplantable β-cells, with a special emphasis in analyzing MSC potency according to their tissue of origin. Although no single method appears to be ripe enough for clinical trials yet, recent progress in reprogramming (a biotechnological breakthrough that relativizes the thus far insurmountable barriers between embryonal germ layers) bodes well for the rise of MSCs as a potential weapon of choice to develop personalized therapies for type 1 diabetes. PMID:23197641

  5. Epigenetic Mechanisms Regulating Mesenchymal Stem Cell Differentiation

    PubMed Central

    Pérez-Campo, Flor M.; Riancho, José A.

    2015-01-01

    Human Mesenchymal Stem Cells (hMSCs) have emerged in the last few years as one of the most promising therapeutic cell sources and, in particular, as an important tool for regenerative medicine of skeletal tissues. Although they present a more restricted potency than Embryonic Stem (ES) cells, the use of hMCS in regenerative medicine avoids many of the drawbacks characteristic of ES cells or induced pluripotent stem cells. The challenge in using these cells lies into developing precise protocols for directing cellular differentiation to generate a specific cell lineage. In order to achieve this goal, it is of the upmost importance to be able to control de process of fate decision and lineage commitment. This process requires the coordinate regulation of different molecular layers at transcriptional, posttranscriptional and translational levels. At the transcriptional level, switching on and off different sets of genes is achieved not only through transcriptional regulators, but also through their interplay with epigenetic modifiers. It is now well known that epigenetic changes take place in an orderly way through development and are critical in the determination of lineage-specific differentiation. More importantly, alteration of these epigenetic changes would, in many cases, lead to disease generation and even tumour formation. Therefore, it is crucial to elucidate how epigenetic factors, through their interplay with transcriptional regulators, control lineage commitment in hMSCs. PMID:27019612

  6. Concise Review: Mesenchymal Stem Cells for Diabetes

    PubMed Central

    Domínguez-Bendala, Juan; Lanzoni, Giacomo

    2012-01-01

    Mesenchymal stem cells (MSCs) have already made their mark in the young field of regenerative medicine. Easily derived from many adult tissues, their therapeutic worth has already been validated for a number of conditions. Unlike embryonic stem cells, neither their procurement nor their use is deemed controversial. Here we review the potential use of MSCs for the treatment of type 1 diabetes mellitus, a devastating chronic disease in which the insulin-producing cells of the pancreas (the β-cells) are the target of an autoimmune process. It has been hypothesized that stem cell-derived β-cells may be used to replenish the islet mass in diabetic patients, making islet transplantation (a form of cell therapy that has already proven effective at clinically restoring normoglycemia) available to millions of prospective patients. Here we review the most current advances in the design and application of protocols for the differentiation of transplantable β-cells, with a special emphasis in analyzing MSC potency according to their tissue of origin. Although no single method appears to be ripe enough for clinical trials yet, recent progress in reprogramming (a biotechnological breakthrough that relativizes the thus far insurmountable barriers between embryonal germ layers) bodes well for the rise of MSCs as a potential weapon of choice to develop personalized therapies for type 1 diabetes. PMID:23197641

  7. Proteomic Analysis of Mesenchymal Stem Cells.

    PubMed

    Faça, Vitor Marcel; Orellana, Maristela Delgado; Greene, Lewis Joel; Covas, Dimas Tadeu

    2016-01-01

    Mesenchymal stem or stromal cells (MSCs) are of great interest in biomedical sciences and disease treatment because of their multipotency and wide range of applications for tissue repair and suppression of the immune system. Proteomic analysis of these unique cells has contributed to the identification of important pathways utilized by MSCs to differentiate into distinct tissues as well as important proteins responsible for their special function in vivo and in vitro. However, comparison of proteomic studies in MSCs still suffers from the heterogeneity of MSC preparations. In addition, as proteomics technology advances, several studies can be revisited in order to increase the depth of analysis and, therefore, elucidate more refined mechanisms involved in MSC functionalities. Here, we present detailed protocols to obtain MSCs, as well as protocols to perform in-depth profiling and quantification of alterations in MSC proteomes. PMID:27236693

  8. Mechanical regulation of mesenchymal stem cell differentiation.

    PubMed

    Steward, Andrew J; Kelly, Daniel J

    2015-12-01

    Biophysical cues play a key role in directing the lineage commitment of mesenchymal stem cells or multipotent stromal cells (MSCs), but the mechanotransductive mechanisms at play are still not fully understood. This review article first describes the roles of both substrate mechanics (e.g. stiffness and topography) and extrinsic mechanical cues (e.g. fluid flow, compression, hydrostatic pressure, tension) on the differentiation of MSCs. A specific focus is placed on the role of such factors in regulating the osteogenic, chondrogenic, myogenic and adipogenic differentiation of MSCs. Next, the article focuses on the cellular components, specifically integrins, ion channels, focal adhesions and the cytoskeleton, hypothesized to be involved in MSC mechanotransduction. This review aims to illustrate the strides that have been made in elucidating how MSCs sense and respond to their mechanical environment, and also to identify areas where further research is needed. PMID:25382217

  9. Mesenchymal Stem Cells: Angels or Demons?

    PubMed Central

    Wong, Rebecca S. Y.

    2011-01-01

    Mesenchymal stem cells (MSCs) have been used in cell-based therapy in various disease conditions such as graft-versus-host and heart diseases, osteogenesis imperfecta, and spinal cord injuries, and the results have been encouraging. However, as MSC therapy gains popularity among practitioners and researchers, there have been reports on the adverse effects of MSCs especially in the context of tumour modulation and malignant transformation. These cells have been found to enhance tumour growth and metastasis in some studies and have been related to anticancer-drug resistance in other instances. In addition, various studies have also reported spontaneous malignant transformation of MSCs. The mechanism of the modulatory behaviour and the tumorigenic potential of MSCs, warrant urgent exploration, and the use of MSCs in patients with cancer awaits further evaluation. However, if MSCs truly play a role in tumour modulation, they can also be potential targets of cancer treatment. PMID:21822372

  10. Labeling and Imaging Mesenchymal Stem Cells with Quantum Dots

    EPA Science Inventory

    Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into bone, cartilage, adipose and muscle cells. Adult derived MSCs are being actively investigated because of their potential to be utilized for therapeutic cell-based transplantation. Methods...

  11. Mesenchymal stem cell therapy for heart disease.

    PubMed

    Gnecchi, Massimiliano; Danieli, Patrizia; Cervio, Elisabetta

    2012-08-19

    Mesenchymal stem cells (MSC) are adult stem cells with capacity for self-renewal and multi-lineage differentiation. Initially described in the bone marrow, MSC are also present in other organs and tissues. From a therapeutic perspective, because of their easy preparation and immunologic privilege, MSC are emerging as an extremely promising therapeutic agent for tissue regeneration and repair. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSC to engraft and differentiate into cardiomyocytes and vascular cells. Most importantly, engrafted MSC secrete a wide array of soluble factors that mediate beneficial paracrine effects and may greatly contribute to cardiac repair. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. In this review we will focus on the current understanding of MSC biology and MSC mechanism of action in cardiac repair. PMID:22521741

  12. Glutamate Increases In Vitro Survival and Proliferation and Attenuates Oxidative Stress-Induced Cell Death in Adult Spinal Cord-Derived Neural Stem/Progenitor Cells via Non-NMDA Ionotropic Glutamate Receptors.

    PubMed

    Hachem, Laureen D; Mothe, Andrea J; Tator, Charles H

    2016-08-15

    Traumatic spinal cord injury (SCI) leads to a cascade of secondary chemical insults, including oxidative stress and glutamate excitotoxicity, which damage host neurons and glia. Transplantation of exogenous neural stem/progenitor cells (NSPCs) has shown promise in enhancing regeneration after SCI, although survival of transplanted cells remains poor. Understanding the response of NSPCs to the chemical mediators of secondary injury is essential in finding therapies to enhance survival. We examined the in vitro effects of glutamate and glutamate receptor agonists on adult rat spinal cord-derived NSPCs. NSPCs isolated from the periventricular region of the adult rat spinal cord were exposed to various concentrations of glutamate for 96 h. We found that glutamate treatment (500 μM) for 96 h significantly increased live cell numbers, reduced cell death, and increased proliferation, but did not significantly alter cell phenotype. Concurrent glutamate treatment (500 μM) in the setting of H2O2 exposure (500 μM) for 10 h increased NSPC survival compared to H2O2 exposure alone. The effects of glutamate on NSPCs were blocked by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist GYKI-52466, but not by the N-methyl-D-aspartic acid receptor antagonist MK-801 or DL-AP5, or the mGluR3 antagonist LY-341495. Furthermore, treatment of NSPCs with AMPA, kainic acid, or the kainate receptor-specific agonist (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid mimicked the responses seen with glutamate both alone and in the setting of oxidative stress. These findings offer important insights into potential mechanisms to enhance NSPC survival and implicate a potential role for glutamate in promoting NSPC survival and proliferation after traumatic SCI. PMID:27316370

  13. Biocompatibility and Favorable Response of Mesenchymal Stem Cells on Fibronectin-Gold Nanocomposites

    PubMed Central

    Hung, Huey-Shan; Tang, Cheng-Ming; Lin, Chien-Hsun; Lin, Shinn-Zong; Chu, Mei-Yun; Sun, Wei-Shen; Kao, Wei-Chien; Hsien-Hsu, Hsieh

    2013-01-01

    A simple surface modification method, comprising of a thin coating with gold nanoparticles (AuNPs) and fibronectin (FN), was developed to improve the biocompatibility required for cardiovascular devices. The nanocomposites from FN and AuNPs (FN-Au) were characterized by the atomic force microscopy (AFM), UV-Vis spectrophotometry (UV-Vis), and Fourier transform infrared spectroscopy (FTIR). The biocompatibility of the nanocomposites was evaluated by the response of monocytes and platelets to the material surface in vitro. FN-Au coated surfaces demonstrated low monocyte activation and platelet activation. The behavior of human umbilical cord-derived mesenchymal stem cells (MSCs) on FN-Au was further investigated. MSCs on FN-Au nanocomposites particularly that containing 43.5 ppm of AuNPs (FN-Au 43.5 ppm) showed cell proliferation, low ROS generation, as well as increases in the protein expression levels of matrix metalloproteinase-9 (MMP-9) and endothelial nitric oxide synthase (eNOS), which may account for the enhanced MSC migration on the nanocomposites. These results suggest that the FN-Au nanocomposite thin film coating may serve as a potential and simple solution for the surface modification of blood-contacting devices such as vascular grafts. PMID:23826082

  14. Mesenchymal stem cells: From stem cells to sarcomas.

    PubMed

    Lye, Kwan Liang; Nordin, Norshariza; Vidyadaran, Sharmili; Thilakavathy, Karuppiah

    2016-06-01

    Mesenchymal stem cells (MSCs) have garnered vast interests in clinical settings, especially in regenerative medicine due to their unique properties-they are reliably isolated and expanded from various tissue sources; they are able to differentiate into mesodermal tissues such as bones, cartilages, adipose tissues, and muscles; and they have unique immunosuppressive properties. However, there are some concerns pertaining to the role of MSCs in the human body. On one hand, they are crucial component in the regeneration and repair of the human body. On the contrary, they are shown to transform into sarcomas. Although the exact mechanisms are still unknown, many new leads have pointed to the belief that MSCs do play a role in sarcomagenesis. This review focuses on the current updates and findings of the role of MSCs in their transformation process into sarcomas. PMID:26992453

  15. Mesenchymal stem cell therapy and lung diseases.

    PubMed

    Akram, Khondoker M; Samad, Sohel; Spiteri, Monica; Forsyth, Nicholas R

    2013-01-01

    Mesenchymal stem cells (MSCs), a distinct population of adult stem cells, have amassed significant interest from both medical and scientific communities. An inherent multipotent differentiation potential offers a cell therapy option for various diseases, including those of the musculoskeletal, neuronal, cardiovascular and pulmonary systems. MSCs also secrete an array of paracrine factors implicated in the mitigation of pathological conditions through anti-inflammatory, anti-apoptotic and immunomodulatory mechanisms. The safety and efficacy of MSCs in human application have been confirmed through small- and large-scale clinical trials. However, achieving the optimal clinical benefit from MSC-mediated regenerative therapy approaches is entirely dependent upon adequate understanding of their healing/regeneration mechanisms and selection of appropriate clinical conditions. MSC-mediated acute alveolar injury repair. A cartoon depiction of an injured alveolus with associated inflammation and AEC apoptosis. Proposed routes of MSC delivery into injured alveoli could be by either intratracheal or intravenous routes, for instance. Following delivery a proposed mechanism of MSC action is to inhibit/reduce alveolar inflammation by abrogation of IL-1_-depenedent Tlymphocyte proliferation and suppression of TNF-_ secretion via macrophage activation following on from stimulation by MSC-secreted IL-1 receptor antagonist (IL-1RN). The inflammatory environment also stimulates MSC to secrete prostaglandin-E2 (PGE2) which can stimulate activated macrophages to secrete the anti-inflammatory cytokine IL-10. Inhibition of AEC apoptosis following injury can also be promoted via MSC stimulated up-regulation of the anti-apoptotic Bcl-2 gene. MSC-secreted KGF can stimulate AECII proliferation and migration propagating alveolar epithelial restitution. Alveolar structural engraftment of MSC is a rare event. PMID:22772131

  16. Mesenchymal stem cells: from experiment to clinic

    PubMed Central

    2011-01-01

    There is currently much interest in adult mesenchymal stem cells (MSCs) and their ability to differentiate into other cell types, and to partake in the anatomy and physiology of remote organs. It is now clear these cells may be purified from several organs in the body besides bone marrow. MSCs take part in wound healing by contributing to myofibroblast and possibly fibroblast populations, and may be involved in epithelial tissue regeneration in certain organs, although this remains more controversial. In this review, we examine the ability of MSCs to modulate liver, kidney, heart and intestinal repair, and we update their opposing qualities of being less immunogenic and therefore tolerated in a transplant situation, yet being able to contribute to xenograft models of human tumour formation in other contexts. However, such observations have not been replicated in the clinic. Recent studies showing the clinical safety of MSC in several pathologies are discussed. The possible opposing powers of MSC need careful understanding and control if their clinical potential is to be realised with long-term safety for patients. PMID:21902837

  17. Mesenchymal stem cells in cartilage regeneration.

    PubMed

    Savkovic, Vuk; Li, Hanluo; Seon, Jong-Keun; Hacker, Michael; Franz, Sandra; Simon, Jan-Christoph

    2014-01-01

    Articular cartilage provides life-long weight-bearing and mechanical lubrication with extraordinary biomechanical performance and simple structure. However, articular cartilage is apparently vulnerable to multifactorial damage and insufficient to self-repair, isolated in articular capsule without nerves or blood vessels. Osteoarthritis (OA) is known as a degenerative articular cartilage deficiency progressively affecting large proportion of the world population, and restoration of hyaline cartilage is clinical challenge to repair articular cartilage lesion and recreate normal functionality over long period. Mesenchymal stem cells (MSC) are highly proliferative and multipotent somatic cells that are able to differentiate mesoderm-derived cells including chondrocytes and osteoblasts. Continuous endeavors in basic research and preclinical trial have achieved promising outcomes in cartilage regeneration using MSCs. This review focuses on rationale and technologies of MSC-based hyaline cartilage repair involving tissue engineering, 3D biomaterials and growth factors. By comparing conventional treatment and current research progress, we describe insights of advantage and challenge in translation and application of MSC-based chondrogenesis for OA treatment. PMID:25005451

  18. Mesenchymal Stem Cells Reduce Murine Atherosclerosis Development

    PubMed Central

    Frodermann, Vanessa; van Duijn, Janine; van Pel, Melissa; van Santbrink, Peter J.; Bot, Ilze; Kuiper, Johan; de Jager, Saskia C. A.

    2015-01-01

    Mesenchymal stem cells (MSCs) have regenerative properties, but recently they were also found to have immunomodulatory capacities. We therefore investigated whether MSCs could reduce atherosclerosis, which is determined by dyslipidaemia and chronic inflammation. We adoptively transferred MSCs into low-density lipoprotein-receptor knockout mice and put these on a Western-type diet to induce atherosclerosis. Initially after treatment, we found higher levels of circulating regulatory T cells. In the long-term, overall numbers of effector T cells were reduced by MSC treatment. Moreover, MSC-treated mice displayed a significant 33% reduction in circulating monocytes and a 77% reduction of serum CCL2 levels. Most strikingly, we found a previously unappreciated effect on lipid metabolism. Serum cholesterol was reduced by 33%, due to reduced very low-density lipoprotein levels, likely a result of reduced de novo hepatic lipogenesis as determined by a reduced expression of Stearoyl-CoA desaturase-1 and lipoprotein lipase. MSCs significantly affected lesion development, which was reduced by 33% in the aortic root. These lesions contained 56% less macrophages and showed a 61% reduction in T cell numbers. We show here for the first time that MSC treatment affects not only inflammatory responses but also significantly reduces dyslipidaemia in mice. This makes MSCs a potent candidate for atherosclerosis therapies. PMID:26490642

  19. Mesenchymal Stem Cell Transplantation in Multiple Sclerosis

    PubMed Central

    Cohen, Jeffrey A.

    2013-01-01

    Mesenchymal stem cells (MSCs) are a pluripotent non-hematopoietic precursor cells that can be isolated from bone marrow and numerous other tissues, culture-expanded to purity, and induced to differentiate in vitro and in vivo into mesodermal derivatives. MSCs exhibit many phenotypic and functional similarities to pericytes. The immunomodulatory, tissue protective, and repair-promoting properties of MSCs demonstrated both in vitro and in animal models make them an attractive potential therapy for MS and other conditions characterized by inflammation and/or tissue injury. Other potential advantages of MSCs as a therapeutic include the relative ease of culture expansion, relative immunoprivilege allowing allogeneic transplantation, and their ability to traffic from blood to areas of tissue allowing intravascular administration. The overall published experience with MSC transplantation in MS is modest, but several small case series and preliminary studies yielded promising results. Several groups, including us, recently initiated formal studies of autologous, culture-expanded, bone-marrow-derived MSC transplantation in MS. Although there are several potential safety concerns, to date, the procedure has been well tolerated. Future studies that more definitively assess efficacy also will need to address several technical issues. PMID:23294498

  20. Clinical applications of mesenchymal stem cells

    PubMed Central

    2012-01-01

    Mesenchymal stem cells (MSC) have generated a great amount of enthusiasm over the past decade as a novel therapeutic paradigm for a variety of diseases. Currently, MSC based clinical trials have been conducted for at least 12 kinds of pathological conditions, with many completed trials demonstrating the safety and efficacy. This review provides an overview of the recent clinical findings related to MSC therapeutic effects. Roles of MSCs in clinical trials conducted to treat graft-versus-host-disease (GVHD) and cardiovascular diseases are highlighted. Clinical application of MSC are mainly attributed to their important four biological properties- the ability to home to sites of inflammation following tissue injury when injected intravenously; to differentiate into various cell types; to secrete multiple bioactive molecules capable of stimulating recovery of injured cells and inhibiting inflammation and to perform immunomodulatory functions. Here, we will discuss these four properties. Moreover, the issues surrounding clinical grade MSCs and principles for MSC therapeutic approaches are also addressed on the transition of MSCs therapy from bench side to bedside. PMID:22546280

  1. Mesenchymal stem cells and inflammatory lung diseases.

    PubMed

    Iyer, S S; Co, C; Rojas, M

    2009-03-01

    Mesenchymal stem cells (MSCs) are emerging as a therapeutic modality in various inflammatory disease states. A number of ongoing randomized Phase I/II clinical trials are evaluating the effects of allogeneic MSC infusion in patients with multiple sclerosis, graft-versus-host disease, Crohn's disease, and severe chronic myocardial ischemia. MSCs are also being considered as a potential therapy in patients with inflammatory lung diseases. Several studies, including our own, have demonstrated compelling benefits from the administration of MSCs in animal models of lung injury. These studies are leading to growing interest in the therapeutic use of MSCs in inflammatory lung diseases. In this Review, we describe how the immunoregulatory effects of MSCs can confer substantial protection in the setting of lung diseases such as acute lung injury, chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. We also address potential pitfalls related to the therapeutic use of MSCs in fibrotic lung diseases such as idiopathic pulmonary fibrosis. In addition, we identify emerging areas for MSC- based therapies in modulating oxidative stress and in attenuating inflammation in alcohol-related acute lung injury. PMID:19352305

  2. Mesenchymal Stem Cells in Kidney Repair.

    PubMed

    Morigi, Marina; Rota, Cinzia; Remuzzi, Giuseppe

    2016-01-01

    Every year 13.3 million people suffer acute kidney injury (AKI), which is associated with a high risk of death or development of long-term chronic kidney disease (CKD) in a substantial percentage of patients besides other organ dysfunctions. To date, the mortality rate per year for AKI exceeds 50 % at least in patients requiring early renal replacement therapy and is higher than the mortality for breast and prostate cancer, heart failure and diabetes combined.Until now, no effective treatments able to accelerate renal recovery and improve survival post AKI have been developed. In search of innovative and effective strategies to foster the limited regeneration capacity of the kidney, several studies have evaluated the ability of mesenchymal stem cells (MSCs) of different origin as an attractive therapeutic tool. The results obtained in several models of AKI and CKD document that MSCs have therapeutic potential in repair of renal injury, preserving renal function and structure thus prolonging animal survival through differentiation-independent pathways. In this chapter, we have summarized the mechanisms underlying the regenerative processes triggered by MSC treatment, essentially due to their paracrine activity. The capacity of MSC to migrate to the site of injury and to secrete a pool of growth factors and cytokines with anti-inflammatory, mitogenic, and immunomodulatory effects is described. New modalities of cell-to-cell communication via the release of microvesicles and exosomes by MSCs to injured renal cells will also be discussed. The translation of basic experimental data on MSC biology into effective care is still limited to preliminary phase I clinical trials and further studies are needed to definitively assess the efficacy of MSC-based therapy in humans. PMID:27236667

  3. Anisotropic mechanosensing by mesenchymal stem cells

    PubMed Central

    Kurpinski, Kyle; Chu, Julia; Hashi, Craig; Li, Song

    2006-01-01

    Mesenchymal stem cells (MSCs) are a potential source for the construction of tissue-engineered vascular grafts. However, how vascular mechanical forces regulate the genetic reprogramming in MSCs is not well understood. Mechanical strain in the vascular wall is anisotropic and mainly in the circumferential direction. We have shown that cyclic uniaxial strain on elastic substrates causes the cells to align perpendicularly to the strain axis, which is different from that in the vascular wall. To simulate the vascular cell alignment and investigate the anisotropic mechanical sensing by MSCs, we used soft lithography to create elastomeric membranes with parallel microgrooves. This topographic pattern kept MSCs aligned parallel to the strain axis, and the cells were subjected to 5% cyclic uniaxial strain (1 Hz) for 2–4 days. DNA microarray analysis revealed global gene expression changes, including an increase in the smooth muscle marker calponin 1, decreases in cartilage matrix markers, and alterations in cell signaling (e.g., down-regulation of the Jagged1 signaling pathway). In addition, uniaxial strain increased MSC proliferation. However, when micropatterning was used to align cells perpendicularly to the axis of mechanical strain, the changes of some genes were diminished, and MSC proliferation was not affected. This study suggests that mechanical strain plays an important role in MSC differentiation and proliferation, and that the effects of mechanotransduction depend on the orientation of cells with respect to the strain axis. The differential cellular responses to the anisotropic mechanical environment have important implications in cardiovascular development, tissue remodeling, and tissue engineering. PMID:17060641

  4. [Mesenchymal stem cells: from biology to clinical applications].

    PubMed

    Franchini, Massimo

    2003-11-01

    Mesenchymal stem cells (MSC) are multipotent cells present in a variety of tissues during human development and in adults mainly in bone marrow. Mesenchymal stem cells may be isolated and expanded in vitro and they are capable to differentiate into a variety of tissues, including bone, cartilage, muscle and adipose tissue. In this review we briefly analyze the main biological features of MSC with particular attention to their interaction with hemopoietic system and to their differentiative properties. Finally, we focus on the main MSC applications both in the fields of genetic and tissue engineering. PMID:14679915

  5. The adult human brain harbors multipotent perivascular mesenchymal stem cells.

    PubMed

    Paul, Gesine; Özen, Ilknur; Christophersen, Nicolaj S; Reinbothe, Thomas; Bengzon, Johan; Visse, Edward; Jansson, Katarina; Dannaeus, Karin; Henriques-Oliveira, Catarina; Roybon, Laurent; Anisimov, Sergey V; Renström, Erik; Svensson, Mikael; Haegerstrand, Anders; Brundin, Patrik

    2012-01-01

    Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue-specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co-express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain. PMID:22523602

  6. Hypoxia and Stem Cell-Based Engineering of Mesenchymal Tissues

    PubMed Central

    Ma, Teng; Grayson, Warren L.; Fröhlich, Mirjam; Vunjak-Novakovic, Gordana

    2009-01-01

    Stem cells have the ability for prolonged self-renewal and differentiation into mature cells of various lineages, which makes them important cell sources for tissue engineering applications. Their remarkable ability to replenish and differentiate in vivo is regulated by both intrinsic and extrinsic cellular mechanisms. The anatomical location where the stem cells reside, known as the “stem cell niche or microenvironment,” provides signals conducive to the maintenance of definitive stem cell properties. Physiological condition including oxygen tension is an important component of the stem cell microenvironment and has been shown to play a role in regulating both embryonic and adult stem cells. This review focuses on oxygen as a signaling molecule and the way it regulates the stem cells' development into mesenchymal tissues in vitro. The physiological relevance of low oxygen tension as an environmental parameter that uniquely benefits stem cells' expansion and maintenance is described along with recent findings on the regulatory effects of oxygen on embryonic stem cells and adult mesenchymal stem cells. The relevance to tissue engineering is discussed in the context of the need to specifically regulate the oxygen content in the cellular microenvironment in order to optimize in vitro tissue development. PMID:19198002

  7. Research Advancements in Porcine Derived Mesenchymal Stem Cells.

    PubMed

    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

  8. Mesenchymal stem cells/multipotent mesenchymal stromal cells (MSCs): potential role in healing cutaneous chronic wounds.

    PubMed

    Zou, Ji-Ping; Huang, Sha; Peng, Yan; Liu, Hong-Wei; Cheng, Biao; Fu, Xiao-Bing; Xiang, Xiao-Fei

    2012-12-01

    Chronic wounds remain a major challenge in modern medicine and represent a significant health care burden. Several treatments have been suggested, but without a full understanding of the exact mechanism by which chronic wound occurs. Numerous studies have shown that mesenchymal stem cells/multipotent mesenchymal stromal cells (MSCs) may have therapeutic potential in healing cutaneous chronic wounds through various mechanisms. So far, a series of hypotheses have been proposed, but a holistic image of them is lacking. This review provides a systematic analysis of recent research in animal models and preclinical or clinic trails to evaluate the potential role of MSCs in chronic cutaneous wound healing. Most important, we highlight how mesenchymal stem cells could potentially revolutionize our approach to treating cutaneous chronic wounds. Special attention should be focused on ongoing research regarding the challenges in using and prospects of MSCs in clinical settings. PMID:23222159

  9. Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice.

    PubMed

    Fujita, Kosuke; Kuge, Katsunori; Ozawa, Noriyasu; Sahara, Shunya; Zaiki, Kaori; Nakaoji, Koichi; Hamada, Kazuhiko; Takenaka, Yukiko; Tanahashi, Takao; Tamai, Katsuto; Kaneda, Yasufumi; Maeda, Akito

    2015-01-01

    Substances that enhance the migration of mesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair. We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration of mesenchymal stem cells and improved wound healing in a mouse model. We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells into the blood circulation was enhanced in cinnamtannin B-1-treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be relevant to its effects on

  10. Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice

    PubMed Central

    Fujita, Kosuke; Kuge, Katsunori; Ozawa, Noriyasu; Sahara, Shunya; Zaiki, Kaori; Nakaoji, Koichi; Hamada, Kazuhiko; Takenaka, Yukiko; Tanahashi, Takao; Tamai, Katsuto; Kaneda, Yasufumi; Maeda, Akito

    2015-01-01

    Substances that enhance the migration of mesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair. We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration of mesenchymal stem cells and improved wound healing in a mouse model. We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells into the blood circulation was enhanced in cinnamtannin B-1-treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be relevant to its effects on

  11. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation

    PubMed Central

    Kolf, Catherine M; Cho, Elizabeth; Tuan, Rocky S

    2007-01-01

    Recent advances in understanding the cellular and molecular signaling pathways and global transcriptional regulators of adult mesenchymal stem cells have provided new insights into their biology and potential clinical applications, particularly for tissue repair and regeneration. This review focuses on these advances, specifically in the context of self-renewal and regulation of lineage-specific differentiation of mesenchymal stem cells. In addition we review recent research on the concept of stem cell niche, and its relevance to adult mesenchymal stem cells. PMID:17316462

  12. Challenge of Mesenchymal Stem Cells Against Diabetic Foot Ulcer.

    PubMed

    Şener, Leyla Türker; Albeniz, Işıl

    2015-01-01

    Mesenchymal stem cells (MSCs) play an important role in embryonic development and tissue regeneration in adult life owing to their high competency and self-renewal features. MSCs represent an important stem cell population with multipotent capabilities that may have high utility for translational clinical applications. MSCs can differentiate into a variety of cell types, especially fascia originated cells, and provide soluble factors for regeneration of tissues and organs. In in vitro environments, stem cells are capable of reproducing while preserving their properties; therefore, assuming stem cells could be reproduced in sufficient quantity, they would be appropriate for genetic operations. Stem cells can be used in tissue engineering, preventing rejection of bone marrow/ stem cell grafts by supporting hematopoiesis and recovery of autoimmune diseases, and cell therapy through their immunosuppressive properties. Mesenchymal stem cells have the potential capability to renew deformed organs and assist in tissue repair. In the field of wound healing, use of BM-MSCs is effective through modulating inflammation, extracellular matrix production, migration of keratinocytes, and angiogenesis for cell therapies. A significant complication of diabetes is diabetic foot ulcers, which affect quality of life and threaten life. In this article, we review recent studies with favorable results related to MSCs, which have become an important area of study in terms of tissue regeneration and regenerative medicine with diabetic foot ulcers. PMID:25986622

  13. Expression and significance of DLL4--Notch signaling pathway in the differentiation of human umbilical cord derived mesenchymal stem cells into cardiomyocytes induced by 5-azacytidine.

    PubMed

    Zhu, Li; Ruan, Zhongbao; Yin, Yigang; Chen, Gecai

    2015-01-01

    hUCMSCs were isolated and purified from the umbilical cords of normal or cesarean term deliveries under sterile conditions. Flow cytometry analysis revealed that CD13, CD29, CD44, CD90, and CD105 were highly expressed on the surface of passage-3 hUCMSCs, but negative for CD31, CD34, CD45, and HLA-DR. Immunocytochemistry showed that 5-azacytidine (5-aza) could induce the cTnI expression of hUCMSCs. RT-PCR showed that a stable higher level expression of DLL4 and Notch1 gene in 5-aza-induced group was observed compared to that in the control group. There was a higher expression level in the induced group. Compared with control group, the expression levels of Notch1 were, respectively, increased 6.60, 7.36, 7.595, and 7.805 times at 1, 3, 5, and 7 days after intervention of 5-aza. Statistically higher Ct value of Notch1 mRNA in induced group was observed in comparison with that of the control group (0.51 ± 0.21 vs 7.85 ± 0.35, t = 35.98, P < 0.01). The expression level of DLL4 increased stably compared with the control group. Compared with control group, the expression levels of DLL4 were, respectively, increased 11.53, 10.1, 10.17, and 11.46 times at 1, 3, 5, and 7 days after intervention of 5-aza. There was a significant difference of DLL4 Ct value between the 5-aza-induced group and the control group (1.60 ± 0.49 vs 12.42 ± 0.73, t = 11.71, P < 0.01). In conclusion, hUCMSCs can be differentiated into myocardial cells in vitro. The DLL4-Notch signaling pathway may be involved in the differentiation of hUCMSCs into cardiomyocytes induced by 5-aza. PMID:25343938

  14. Autophagy prevents irradiation injury and maintains stemness through decreasing ROS generation in mesenchymal stem cells

    PubMed Central

    Hou, J; Han, Z-p; Jing, Y-y; Yang, X; Zhang, S-s; Sun, K; Hao, C; Meng, Y; Yu, F-h; Liu, X-q; Shi, Y-f; Wu, M-c; Zhang, L; Wei, L-x

    2013-01-01

    Stem cells were characterized by their stemness: self-renewal and pluripotency. Mesenchymal stem cells (MSCs) are a unique type of adult stem cells that have been proven to be involved in tissue repair, immunoloregulation and tumorigenesis. Irradiation is a well-known factor that leads to functional obstacle in stem cells. However, the mechanism of stemness maintenance in human MSCs exposed to irradiation remains unknown. We demonstrated that irradiation could induce reactive oxygen species (ROS) accumulation that resulted in DNA damage and stemness injury in MSCs. Autophagy induced by starvation or rapamycin can reduce ROS accumulation-associated DNA damage and maintain stemness in MSCs. Further, inhibition of autophagy leads to augment of ROS accumulation and DNA damage, which results in the loss of stemness in MSCs. Our results indicate that autophagy may have an important role in protecting stemness of MSCs from irradiation injury. PMID:24113178

  15. Mesenchymal stem cells: isolation, in vitro expansion and characterization.

    PubMed

    Beyer Nardi, N; da Silva Meirelles, L

    2006-01-01

    Mesenchymal stem cells (MSC), one type of adult stem cell, are easy to isolate, culture, and manipulate in ex vivo culture. These cells have great plasticity and the potential for therapeutic applications, but their properties are poorly understood. MSCs can be found in bone marrow and in many other tissues, and these cells are generally identified through a combination of poorly defined physical, phenotypic, and functional properties; consequently, multiple names have been given to these cell populations. Murine MSCs have been directly applied to a wide range of murine models of diseases, where they can act as therapeutic agents per se, or as vehicles for the delivery of therapeutic genes. In addition to their systemic engraftment capabilities, MSCs show great potential for the replacement of damaged tissues such as bone, cartilage, tendon, and ligament. Their pharmacological importance is related to four points: MSCs secrete biologically important molecules, express specific receptors, can be genetically manipulated, and are susceptible to molecules that modify their natural behavior. Due to their low frequency and the lack of knowledge on cell surface markers and their location of origin, most information concerning MSCs is derived from in vitro studies. The search for the identity of the mesenchymal stem cell has depended mainly on three culture systems: the CFU-F assay, the analysis of bone marrow stroma, and the cultivation of mesenchymal stem cell lines. Other cell populations, more or less related to the MSC, have also been described. Isolation and culture conditions used to expand these cells rely on the ability of MSCs, although variable, to adhere to plastic surfaces. Whether these conditions selectively favor the expansion of different bone marrow precursors or cause similar cell populations to acquire different phenotypes is not clear. The cell populations could also represent different points of a hierarchy or a continuum of differentiation. These

  16. Improvement of mesenchymal stem cell differentiation into the endoderm lineage by four step sequential method in biocompatible biomaterial

    PubMed Central

    Azandeh, Saeed; Mohammad Gharravi, Anneh; Orazizadeh, Mahmoud; Khodadi, Ali; Hashemi Tabar, Mahmoud

    2016-01-01

    Introduction: The goal of the study described here, was to investigate the potential of umbilical cord derived mesenchymal stem cell (UC-MSCs) into hepatocyte like cells in a sequential 2D and 3D differentiation protocols as alternative therapy. Methods: Mesenchymal stem cells (MSCs) were isolated from the umbilical cord (UC) and CD markers were analyzed by flow cytometry. For hepatic differentiation of UC-MSCs, cells were induced with a sequential 4-step protocol in 3D and 2D culture system. Urea concentration and albumin secretion into the culture medium was quantified by ELISA. Gene expression levels of AFP, ALB, and CK18 were determined by RT-PCR. Data were statistically analyzed by the SPSS software. The difference between the mean was considered significant when p < 0.05. Results: Growth factor dependent morphological changes from elongated fibroblast-like cells to round epithelial cell morphology were observed in 2D culture. Cell proliferation analysis showed round-shaped morphology with clear cytoplasm and nucleus on the alginate scaffold in 3D culture. The mean valuses of albumin production and urea secretion were significantly higher in the 3D Culture system when compared with the 2D culture (p = 0.005 vs p = 0.001), respectively. Treatment of cells with TSA in the final step of differentiation induced an increased expression of CK18 and a decreased expression of αFP in both the 3D and 2D cultures (p = 0.026), but led to a decreased albumin gene expression, and an increased expression in the 2D culture (p = 0.001). Conclusion: Findings of the present study indicated that sequential exposure of UC-MSCs with growth factors in 3D culture improves hepatic differentiation. PMID:27340619

  17. Involvement of Wnt/β-catenin signaling in the mesenchymal stem cells promote metastatic growth and chemoresistance of cholangiocarcinoma

    PubMed Central

    Yuan, Jiahui; Yan, Congcong; Hu, Shaoping; Tong, Yinping; Mao, Yubin; Hu, Tianhui; Zhang, Bing; Song, Gang

    2015-01-01

    Mesenchymal stem cells (MSCs) are multi-potent progenitor cells with ability to differentiate into multiple lineages, including bone, cartilage, fat, and muscles. Recent research indicates that MSCs can be efficiently recruited to tumor sites, modulating tumor growth and metastasis. However, the underlying molecular mechanisms are not fully understood. Here, we first demonstrated that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), when mixed with human cholangiocarcinoma cell lines QBC939 in a xenograft tumor model, significantly increased the cancer cells proliferation and metastatic potency. MSCs and their conditioned media (MSC-CM) could improve the drug resistance of tumor when the compound K (CK) as an anti-cancer drug, a major intestinal bacterial metabolite of panaxoside, was administered to xenograft tumor mice. Furthermore, MSCs greatly increased the colony formation and invasion of cholangiocarcinoma cells QBC939 and Mz-ChA-1. Immunochemistry studies of cholangiocarcinoma tissue chips and transplantation tumor from nude mice showed that the expression of β-catenin was important for cholangiocarcinoma development. We further demonstrated that MSCs and MSCs-CM could promote proliferation and migration of cholangiocarcinoma cells through targeting the Wnt/β-catenin signaling pathway. hUC-MSCs or MSCs-CM stimulated Wnt activity by promoting the nuclear translocation of β-catenin, and up-regulated Wnt target genes MMPs family, cyclin D1 and c-Myc. Together, our studies highlight a critical role for MSCs on cancer metastasis and indicate MSCs promote metastatic growth and chemoresistance of cholangiocarcinoma cells via activation of Wnt/β-catenin signaling. PMID:26474277

  18. Adult mesenchymal stem cells: differentiation potential and therapeutic applications.

    PubMed

    Jackson, L; Jones, D R; Scotting, P; Sottile, V

    2007-01-01

    Adult mesenchymal stem cells (MSCs) are a population of multipotent cells found primarily in the bone marrow. They have long been known to be capable of osteogenic, adipogenic and chondrogenic differentiation and are currently the subject of a number of trials to assess their potential use in the clinic. Recently, the plasticity of these cells has come under close scrutiny as it has been suggested that they may have a differentiation potential beyond the mesenchymal lineage. Myogenic and in particular cardiomyogenic potential has been shown in vitro. MSCs have also been shown to have the ability to form neural cells both in vitro and in vivo, although the molecular mechanisms underlying these apparent transdifferentiation events are yet to be elucidated. We describe here the cellular characteristics and differentiation potential of MSCs, which represent a promising stem cell population for future applications in regenerative medicine. PMID:17495381

  19. Elastin-based biomaterials and mesenchymal stem cells

    PubMed Central

    Ozsvar, Jazmin; Mithieux, Suzanne M.; Wang, Richard; Weiss, Anthony S.

    2015-01-01

    Elastin is the dominant mammalian elastic protein found in soft tissue. Elastin-based biomaterials have the potential to repair elastic tissues by improving local elasticity and providing appropriate cellular interactions and signaling. Studies that combine these biomaterials with mesenchymal stem cells have demonstrated their capacity to also regenerate non-elastic tissue. Mesenchymal stem cell differentiation can be controlled by their immediate environment, and their sensitivity to elasticity makes them an ideal candidate for combining with elastin-based biomaterials. With the growing accessibility of the elastin precursor, tropoelastin, and elastin-derived materials, the amount of research interest in combining these two fields has increased and, subsequently, is leading to the realization of a potentially new strategy for regenerative medicine. PMID:26146549

  20. Functionally Active Gap Junctions between Connexin 43-Positive Mesenchymal Stem Cells and Glioma Cells.

    PubMed

    Gabashvili, A N; Baklaushev, V P; Grinenko, N F; Levinskii, A B; Mel'nikov, P A; Cherepanov, S A; Chekhonin, V P

    2015-05-01

    The formation of functional gap junctions between mesenchymal stem cells and cells of low-grade rat glioma C6 cells was studied in in vitro experiments. Immunocytochemical analysis with antibodies to connexin 43 extracellular loop 2 showed that mesenchymal stem cells as well as C6 glioma cells express the main astroglial gap junction protein connexin 43. Analysis of migration activity showed that mesenchymal stem cells actively migrate towards C6 glioma cells. During co-culturing, mesenchymal stem cells and glioma C6 form functionally active gap junctions mediating the transport of cytoplasmic dye from glioma cells to mesenchymal stem cells in the opposite direction. Fluorometry showed that the intensity of transport of low-molecular substances through heterologous gap junctions between mesenchymal stem cells and glioma cells is similar to that through homologous gap junctions between glioma cells. This phenomenon can be used for the development of new methods of cell therapy of high-grade gliomas. PMID:26033611

  1. The Alliance of Mesenchymal Stem Cells, Bone, and Diabetes

    PubMed Central

    Napoli, Nicola; Paladini, Angela; Briganti, Silvia I.; Pozzilli, Paolo; Epstein, Sol

    2014-01-01

    Bone fragility has emerged as a new complication of diabetes. Several mechanisms in diabetes may influence bone homeostasis by impairing the action between osteoblasts, osteoclasts, and osteocytes and/or changing the structural properties of the bone tissue. Some of these mechanisms can potentially alter the fate of mesenchymal stem cells, the initial precursor of the osteoblast. In this review, we describe the main factors that impair bone health in diabetic patients and their clinical impact. PMID:25140176

  2. Immunotolerant Properties of Mesenchymal Stem Cells: Updated Review

    PubMed Central

    Faiella, Whitney; Atoui, Rony

    2016-01-01

    Stem cell transplantation is a potential therapeutic option to regenerate damaged myocardium and restore function after infarct. Current research is focused on the use of allogeneic mesenchymal stem cells (MSCs) due to their unique immunomodulatory characteristics and ability to be harvested from young and healthy donors. Both animal and human studies support the immunoprivileged state of MSCs and even demonstrate improvements in cardiac function after transplantation. This research continues to be a topic of interest, as advances will ultimately enable the clinical use of these universal cells for therapy after a myocardial infarction. Updated in vitro, in vivo, and clinical trial studies are discussed in detail in the following review. PMID:26839557

  3. Biological properties of mesenchymal Stem Cells from different sources

    PubMed Central

    Giai Via, Alessio; Frizziero, Antonio; Oliva, Francesco

    2012-01-01

    Summary Mesenchymal stem cells (MSCs) are adult, nonhematopoietic, stem cells that were initially isolated from bone marrow. Now they can be isolated from almost every tissue of the body. They have the ability to self-renew and differentiate into multiple cell lineage, including bone, chondrocytes, adipocytes, tenocytes and cardiomyocytes, and it makes them an attractive cell source for a new generation of cell-based regenerative therapies. In this review we try to summarize data on sources and the biological properties of MSCs. PMID:23738292

  4. The Effects of Graphene Nanostructures on Mesenchymal Stem Cells

    PubMed Central

    Lalwani, Gaurav; Kanakia, Shruti; Sitharaman, Balaji

    2014-01-01

    We report the effects of two-dimensional graphene nanostructures; graphene nano-onions (GNOs), graphene oxide nanoribbons (GONRs), and graphene oxide nanoplatelets (GONPs) on viability, and differentiation of human mesenchymal stem cells (MSCs). Cytotoxicity of GNOs, GONRs, and GONPs dispersed in distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)] (DSPE-PEG), on adipose derived mesenchymal stem cells (adMSCs), and bone marrow-derived mesenchymal stem cells (bmMSCs) was assessed by AlamarBlue and Calcein AM viability assays at concentrations ranging from 5–300 μg/ml for 24 or 72 hours. Cytotoxicity of the 2D graphene nanostructures was found to be dose dependent, not time dependent, with concentrations less than 50 μg/ml showing no significant differences compared to untreated controls. Differentiation potential of adMSCs to adipocytes and osteoblasts, --characterized by Oil Red O staining and elution, alkaline phosphatase activity, calcium matrix deposition and Alizarin Red S staining-- did not change significantly when treated with the three graphene nanoparticles at a low (10 μg/ml) and high (50 μg/ml) concentration for 24 hours. Transmission electron microscopy (TEM) and confocal Raman spectroscopy indicated cellular uptake of only GNOs and GONPs. The results lay the foundation for the use of these nanoparticles at potentially safe doses as ex vivo labels for MSC-based imaging and therapy. PMID:24674462

  5. Therapeutic Potential of HGF-Expressing Human Umbilical Cord Mesenchymal Stem Cells in Mice with Acute Liver Failure

    PubMed Central

    Tang, Yunxia; Li, Qiongshu; Meng, Fanwei; Huang, Xingyu; Li, Chan; Zhou, Xin; Zeng, Xiaoping; He, Yixin; Liu, Jia; Hu, Xiang; Hu, Ji-Fan; Li, Tao

    2016-01-01

    Human umbilical cord-derived mesenchymal stem cells (UCMSCs) are particularly attractive cells for cellular and gene therapy in acute liver failure (ALF). However, the efficacy of this cell therapy in animal studies needs to be significantly improved before it can be translated into clinics. In this study, we investigated the therapeutic potential of UCMSCs that overexpress hepatocyte growth factor (HGF) in an acetaminophen-induced acute liver failure mouse model. We found that the HGF-UCMSC cell therapy protected animals from acute liver failure by reducing liver damage and prolonging animal survival. The therapeutic effect of HGF-UCMSCs was associated with the increment in serum glutathione (GSH) and hepatic enzymes that maintain redox homeostasis, including γ-glutamylcysteine synthetase (γ-GCS), superoxide dismutase (SOD), and catalase (CAT). Immunohistochemical staining confirmed that HGF-UCMSCs were mobilized to the injured areas of the liver. Additionally, HGF-UCMSCs modulated apoptosis by upregulating the antiapoptotic Bcl2 and downregulating proapoptotic genes, including Bax and TNFα. Taken together, these data suggest that ectopic expression of HGF in UCMSCs protects animals from acetaminophen-induced acute liver failure through antiapoptosis and antioxidation mechanisms. PMID:27057357

  6. Mesenchymal markers on human adipose stem/progenitor cells

    PubMed Central

    Zimmerlin, Ludovic; Donnenberg, Vera S.; Rubin, J. Peter; Donnenberg, Albert D.

    2014-01-01

    The stromal-vascular fraction (SVF) of adipose tissue is a rich source of multipotent stem cells. We and others have described 3 major populations of stem/progenitor cells in this fraction, all closely associated with small blood vessels: endothelial progenitor cells (EPC, CD45−/CD31+/CD34+), pericytes (CD45−/CD31−/CD146+) and supra-adventitial adipose stromal cells (SA-ASC, CD45−/CD31−/CD146−/CD34+). EPC are luminal, pericytes are adventitial and SA-ASC surround the vessel like a sheath. The multipotency of the pericytes and SA-ASC compartments is strikingly similar to that of CD45−/CD34−/CD73+/CD105+/CD90+ bone marrow-derived mesenchymal stem cells (BM-MSC). Here we determine the extent to which this mesenchymal expression pattern is expressed on the 3 adipose stem/progenitor populations. Eight independent adipose tissue samples were analyzed in a single tube (CD105-FITC/CD73-PE/CD146-PETXR/CD14-PECY5/CD33-PECY5/CD235A-PECY5/CD31-PECY7/CD90-APC/CD34-A700/CD45-APCCY7/DAPI). Adipose EPC were highly proliferative with 14.3±2.8% (mean ± SEM) having >2N DNA. About half (53.1±7.6%) coexpressed CD73 and CD105, and 71.9±7.4% expressed CD90. Pericytes were less proliferative (8.2±3.4% >2N DNA) with a smaller proportion (29.6±6.9% CD73+/CD105+, 60.5±10.2% CD90+) expressing mesenchymal associated markers. However, the CD34+ subset of CD146+ pericytes, were both highly proliferative (15.1±3.6% with >2N DNA) and of uniform mesenchymal phenotype (93.3±3.7% CD73+/CD105+, 97.8±0.7% CD90+), suggesting transit amplifying progenitor cells. SA-ASC were the least proliferative (3.7 ± 0.8%>2N DNA) but were also highly mesenchymal in phenotype (94.4±3.2% CD73+/CD105+, 95.5±1.2% CD90+). These data imply a progenitor/progeny relationship between pericytes and SA-ASC, the most mesenchymal of SVF cells. Despite phenotypic and functional similarities to BM-MSC, SA-ASC are distinguished by CD34 expression. PMID:23184564

  7. Bone marrow mesenchymal stem cell therapy in ischemic stroke: mechanisms of action and treatment optimization strategies

    PubMed Central

    Li, Guihong; Yu, Fengbo; Lei, Ting; Gao, Haijun; Li, Peiwen; Sun, Yuxue; Huang, Haiyan; Mu, Qingchun

    2016-01-01

    Animal and clinical studies have confirmed the therapeutic effect of bone marrow mesenchymal stem cells on cerebral ischemia, but their mechanisms of action remain poorly understood. Here, we summarize the transplantation approaches, directional migration, differentiation, replacement, neural circuit reconstruction, angiogenesis, neurotrophic factor secretion, apoptosis, immunomodulation, multiple mechanisms of action, and optimization strategies for bone marrow mesenchymal stem cells in the treatment of ischemic stroke. We also explore the safety of bone marrow mesenchymal stem cell transplantation and conclude that bone marrow mesenchymal stem cell transplantation is an important direction for future treatment of cerebral ischemia. Determining the optimal timing and dose for the transplantation are important directions for future research. PMID:27482235

  8. Bone marrow mesenchymal stem cell therapy in ischemic stroke: mechanisms of action and treatment optimization strategies.

    PubMed

    Li, Guihong; Yu, Fengbo; Lei, Ting; Gao, Haijun; Li, Peiwen; Sun, Yuxue; Huang, Haiyan; Mu, Qingchun

    2016-06-01

    Animal and clinical studies have confirmed the therapeutic effect of bone marrow mesenchymal stem cells on cerebral ischemia, but their mechanisms of action remain poorly understood. Here, we summarize the transplantation approaches, directional migration, differentiation, replacement, neural circuit reconstruction, angiogenesis, neurotrophic factor secretion, apoptosis, immunomodulation, multiple mechanisms of action, and optimization strategies for bone marrow mesenchymal stem cells in the treatment of ischemic stroke. We also explore the safety of bone marrow mesenchymal stem cell transplantation and conclude that bone marrow mesenchymal stem cell transplantation is an important direction for future treatment of cerebral ischemia. Determining the optimal timing and dose for the transplantation are important directions for future research. PMID:27482235

  9. Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury

    PubMed Central

    Anbari, Fatemeh; Khalili, Mohammad Ali; Bahrami, Ahmad Reza; Khoradmehr, Arezoo; Sadeghian, Fatemeh; Fesahat, Farzaneh; Nabi, Ali

    2014-01-01

    To investigate the supplement of lost nerve cells in rats with traumatic brain injury by intravenous administration of allogenic bone marrow mesenchymal stem cells, this study established a Wistar rat model of traumatic brain injury by weight drop impact acceleration method and administered 3 × 106 rat bone marrow mesenchymal stem cells via the lateral tail vein. At 14 days after cell transplantation, bone marrow mesenchymal stem cells differentiated into neurons and astrocytes in injured rat cerebral cortex and rat neurological function was improved significantly. These findings suggest that intravenously administered bone marrow mesenchymal stem cells can promote nerve cell regeneration in injured cerebral cortex, which supplement the lost nerve cells. PMID:25206912

  10. 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

  11. Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis.

    PubMed

    Xiao, Juan; Yang, Rongbing; Biswas, Sangita; Qin, Xin; Zhang, Min; Deng, Wenbin

    2015-01-01

    Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC) and induced pluripotent stem cell (iPSCs) derived precursor cells can modulate the autoimmune response in the central nervous system (CNS) and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS. PMID:25918935

  12. The Impact of Epigenetics on Mesenchymal Stem Cell Biology.

    PubMed

    Ozkul, Yusuf; Galderisi, Umberto

    2016-11-01

    Changes in epigenetic marks are known to be important regulatory factors in stem cell fate determination and differentiation. In the past years, the investigation of the epigenetic regulation of stem cell biology has largely focused on embryonic stem cells (ESCs). Contrarily, less is known about the epigenetic control of gene expression during differentiation of adult stem cells (AdSCs). Among AdSCs, mesenchymal stem cells (MSCs) are the most investigated stem cell population because of their enormous potential for therapeutic applications in regenerative medicine and tissue engineering. In this review, we analyze the main studies addressing the epigenetic changes in MSC landscape during in vitro cultivation and replicative senescence, as well as follow osteocyte, chondrocyte, and adipocyte differentiation. In these studies, histone acetylation, DNA methylation, and miRNA expression are among the most investigated phenomena. We describe also epigenetic changes that are associated with in vitro MSC trans-differentiation. Although at the at initial stage, the epigenetics of MSCs promise to have profound implications for stem cell basic and applied research. J. Cell. Physiol. 231: 2393-2401, 2016. © 2016 Wiley Periodicals, Inc. PMID:26960183

  13. Isolation of functionally distinct mesenchymal stem cell subsets using antibodies against CD56, CD271, and mesenchymal stem cell antigen-1

    PubMed Central

    Battula, Venkata Lokesh; Treml, Sabrina; Bareiss, Petra M.; Gieseke, Friederike; Roelofs, Helene; de Zwart, Peter; Müller, Ingo; Schewe, Bernhard; Skutella, Thomas; Fibbe, Willem E.; Kanz, Lothar; Bühring, Hans-Jörg

    2009-01-01

    Background Conventionally, mesenchymal stem cells are functionally isolated from primary tissue based on their capacity to adhere to a plastic surface. This isolation procedure is hampered by the unpredictable influence of co-cultured hematopoietic and/or other unrelated cells and/or by the elimination of a late adhering mesenchymal stem cells subset during removal of undesired cells. To circumvent these limitations, several antibodies have been developed to facilitate the prospective isolation of mesenchymal stem cells. Recently, we described a panel of monoclonal antibodies with superior selectivity for mesenchymal stem cells, including the monoclonal antibodies W8B2 against human mesenchymal stem cell antigen-1 (MSCA-1) and 39D5 against a CD56 epitope, which is not expressed on natural killer cells. Design and Methods Bone marrow derived mesenchymal stem cells from healthy donors were analyzed and isolated by flow cytometry using a large panel of antibodies against surface antigens including CD271, MSCA-1, and CD56. The growth of mesenchymal stem cells was monitored by colony formation unit fibroblast (CFU-F) assays. The differentiation of mesenchymal stem cells into defined lineages was induced by culture in appropriate media and verified by immunostaining. Results Multicolor cell sorting and CFU-F assays showed that mesenchymal stem cells were ~90-fold enriched in the MSCA-1+CD56− fraction and ~180-fold in the MSCA-1+CD56+ fraction. Phenotype analysis revealed that the expression of CD10, CD26, CD106, and CD146 was restricted to the MSCA-1+CD56− mesenchymal stem cells subset and CD166 to MSCA-1+CD56± mesenchymal stem cells. Further differentiation of these subsets showed that chondrocytes and pancreatic-like islets were predominantly derived from MSCA-1+CD56± cells whereas adipocytes emerged exclusively from MSCA-1+CD56− cells. The culture of single sorted MSCA-1+CD56+ cells resulted in the appearance of phenotypically heterogeneous clones with

  14. Osteogenic potential of sorted equine mesenchymal stem cell subpopulations

    PubMed Central

    Radtke, Catherine L.; Nino-Fong, Rodolfo; Rodriguez-Lecompte, Juan Carlos; Esparza Gonzalez, Blanca P.; Stryhn, Henrik; McDuffee, Laurie A.

    2015-01-01

    The objectives of this study were to use non-equilibrium gravitational field-flow fractionation (GrFFF), an immunotag-less method of sorting mesenchymal stem cells (MSCs), to sort equine muscle tissue-derived mesenchymal stem cells (MMSCs) and bone marrow-derived mesenchymal stem cells (BMSC) into subpopulations and to carry out assays in order to compare their osteogenic capabilities. Cells from 1 young adult horse were isolated from left semitendinosus muscle tissue and from bone marrow aspirates of the fourth and fifth sternebrae. Aliquots of 800 × 103 MSCs from each tissue source were sorted into 5 fractions using non-equilibrium GrFFF (GrFFF proprietary system). Pooled fractions were cultured and expanded for use in osteogenic assays, including flow cytometry, histochemistry, bone nodule assays, and real-time quantitative polymerase chain reaction (qPCR) for gene expression of osteocalcin (OCN), RUNX2, and osterix. Equine MMSCs and BMSCs were consistently sorted into 5 fractions that remained viable for use in further osteogenic assays. Statistical analysis confirmed strongly significant upregulation of OCN, RUNX2, and osterix for the BMSC fraction 4 with P < 0.00001. Flow cytometry revealed different cell size and granularity for BMSC fraction 4 and MMSC fraction 2 compared to unsorted controls and other fractions. Histochemisty and bone nodule assays revealed positive staining nodules without differences in average nodule area, perimeter, or stain intensity between tissues or fractions. As there are different subpopulations of MSCs with different osteogenic capacities within equine muscle- and bone marrow-derived sources, these differences must be taken into account when using equine stem cell therapy to induce bone healing in veterinary medicine. PMID:25852225

  15. Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy.

    PubMed

    Ding, Dah-Ching; Chang, Yu-Hsun; Shyu, Woei-Cherng; Lin, Shinn-Zong

    2015-01-01

    The human umbilical cord is a promising source of mesenchymal stem cells (HUCMSCs). Unlike bone marrow stem cells, HUCMSCs have a painless collection procedure and faster self-renewal properties. Different derivation protocols may provide different amounts and populations of stem cells. Stem cell populations have also been reported in other compartments of the umbilical cord, such as the cord lining, perivascular tissue, and Wharton's jelly. HUCMSCs are noncontroversial sources compared to embryonic stem cells. They can differentiate into the three germ layers that promote tissue repair and modulate immune responses and anticancer properties. Thus, they are attractive autologous or allogenic agents for the treatment of malignant and nonmalignant solid and soft cancers. HUCMCs also can be the feeder layer for embryonic stem cells or other pluripotent stem cells. Regarding their therapeutic value, storage banking system and protocols should be established immediately. This review critically evaluates their therapeutic value, challenges, and future directions for their clinical applications. PMID:25622293

  16. Mesenchymal stem cells in pathogenesis of myelodysplastic syndromes

    PubMed Central

    Wang, Jingya

    2014-01-01

    Myelodysplastic syndromes (MDS) are clonal malignant stem cell disorders characterized by inefficient hematopoiesis. The role of the marrow microenvironment in the pathogenesis of the disease has been controversial. Emerging evidence indicated that mesenchymal stem cells (MSC) derived from MDS patients were cytogenetically abnormal, and they showed a deficient hematopoietic-supportive capacity and increased production of cytokine such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interferon γ (IFN-γ). From the point of some evidence, the abnormal microenvironment seems to participate in the progression of the disease by contributing to the selective expansion of the malignant clone. In this review, we will discuss the most recent progress related to identification of normal MSC and the importance of the stem cell niche in development and maintenance of MDS.

  17. Recent Advances in Hydroxyapatite Scaffolds Containing Mesenchymal Stem Cells

    PubMed Central

    Michel, John; Penna, Matthew; Kochen, Juan; Cheung, Herman

    2015-01-01

    Modern day tissue engineering and cellular therapies have gravitated toward using stem cells with scaffolds as a dynamic modality to aid in differentiation and tissue regeneration. Mesenchymal stem cells (MSCs) are one of the most studied stem cells used in combination with scaffolds. These cells differentiate along the osteogenic lineage when seeded on hydroxyapatite containing scaffolds and can be used as a therapeutic option to regenerate various tissues. In recent years, the combination of hydroxyapatite and natural or synthetic polymers has been studied extensively. Due to the interest in these scaffolds, this review will cover the wide range of hydroxyapatite containing scaffolds used with MSCs for in vitro and in vivo experiments. Further, in order to maintain a progressive scope of the field this review article will only focus on literature utilizing adult human derived MSCs (hMSCs) published in the last three years. PMID:26106425

  18. Mesenchymal stem cell subpopulations: phenotype, property and therapeutic potential.

    PubMed

    Mo, Miaohua; Wang, Shan; Zhou, Ying; Li, Hong; Wu, Yaojiong

    2016-09-01

    Mesenchymal stem cells (MSC) are capable of differentiating into cells of multiple cell lineages and have potent paracrine effects. Due to their easy preparation and low immunogenicity, MSC have emerged as an extremely promising therapeutic agent in regenerative medicine for diverse diseases. However, MSC are heterogeneous with respect to phenotype and function in current isolation and cultivation regimes, which often lead to incomparable experimental results. In addition, there may be specific stem cell subpopulations with definite differentiation capacity toward certain lineages in addition to stem cells with multi-differentiation potential. Recent studies have identified several subsets of MSC which exhibit distinct features and biological activities, and enhanced therapeutic potentials for certain diseases. In this review, we give an overview of these subsets for their phenotypic, biological and functional properties. PMID:27141940

  19. The role of mesenchymal stem cells and serotonin in the development of experimental pancreatitis.

    PubMed

    Lazebnic, L B; Lychkova, A E; Knyazev, O V

    2013-08-01

    Pancreatitis was modeled before and after preliminary transplantation of stem cells and serotonin. It was demonstrated that transplantation of mesenchymal stem cells and activation of serotoninergic system prevent the development of pancreatitis. PMID:24143388

  20. Recruitment of Mesenchymal Stem Cells Into Prostate Tumors Promotes Metastasis

    PubMed Central

    Jung, Younghun; Kim, Jin Koo; Shiozawa, Yusuke; Wang, Jingcheng; Mishra, Anjali; Joseph, Jeena; Berry, Janice E.; McGee, Samantha; Lee, Eunsohl; Sun, Hongli; Wang, Jianhua; Jin, Taocong; Zhang, Honglai; Dai, Jinlu; Krebsbach, Paul H.; Keller, Evan T.; Pienta, Kenneth J.; Taichman, Russell S.

    2013-01-01

    Tumors recruit mesenchymal stem cells (MSCs) to facilitate healing, which induces their conversion into cancer-associated fibroblasts that facilitate metastasis. However, this process is poorly understood on the molecular level. Here we show that the CXCR6 ligand CXCL16 facilitates MSC or Very Small Embryonic-Like (VSEL) cells recruitment into prostate tumors. CXCR6 signaling stimulates the conversion of MSCs into cancer-associated fibroblasts, which secrete stromal-derived factor-1, also known as CXCL12. CXCL12 expressed by cancer-associated fibroblasts then binds to CXCR4 on tumor cells and induces an epithelial to mesenchymal transition, which ultimately promotes metastasis to secondary tumor sites. Our results provide the molecular basis for MSC recruitment into tumors and how this process leads to tumor metastasis. PMID:23653207

  1. Immunoregulation by Mesenchymal Stem Cells: Biological Aspects and Clinical Applications

    PubMed Central

    Castro-Manrreza, Marta E.; Montesinos, Juan J.

    2015-01-01

    Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiation into mesenchymal lineages and that can be isolated from various tissues and easily cultivated in vitro. Currently, MSCs are of considerable interest because of the biological characteristics that confer high potential applicability in the clinical treatment of many diseases. Specifically, because of their high immunoregulatory capacity, MSCs are used as tools in cellular therapies for clinical protocols involving immune system alterations. In this review, we discuss the current knowledge about the capacity of MSCs for the immunoregulation of immunocompetent cells and emphasize the effects of MSCs on T cells, principal effectors of the immune response, and the immunosuppressive effects mediated by the secretion of soluble factors and membrane molecules. We also describe the mechanisms of MSC immunoregulatory modulation and the participation of MSCs as immune response regulators in several autoimmune diseases, and we emphasize the clinical application in graft versus host disease (GVHD). PMID:25961059

  2. Immunomodulatory effects of human umbilical cord Wharton's jelly-derived mesenchymal stem cells on differentiation, maturation and endocytosis of monocyte-derived dendritic cells.

    PubMed

    Saeidi, Mohsen; Masoud, Ahmad; Shakiba, Yadollah; Hadjati, Jamshid; Mohyeddin Bonab, Mandana; Nicknam, Mohammad Hossein; Latifpour, Mostafa; Nikbin, Behrooz

    2013-03-01

    The Wharton's jelly of the umbilical cord is believed to be a source of mesenchymal stem cells (MSCs) which can be therapeutically applied in degenerative diseases.In this study, we investigated the immunomodulatory effect of umbilical cord derived-mesenchymal stem cells (UC-MSCs) and bone marrow-derived-mesenchymal stem cells (BM-MSCs) on differentiation, maturation, and endocytosis of monocyte-derived dendritic cells in a transwell culture system under laboratory conditions. Monocytes were differentiated into immature dendritic cells (iDCs) in the presence of GM-CSF and IL-4 for 6 days and then differentiated into mature dendritic cells (mDCs) in the presence of TNF-α for 2 days. In every stage of differentiation, immature and mature dendritic cells were separately co-cultured with UC-MSCs and BM-MSCs. The findings showed that UC-MSCs and BM-MSCs inhibited strongly differentiation and maturation of dendritic cells at higher dilution ratios (1:1). The BM-MSCs and UC-MSCs showed more inhibitory effect on CD1a, CD83, CD86 expression, and dendritic cell endocytic activity, respectively. On the other hand, these cells severely up-regulated CD14 marker expression. We concluded that UC-MSCs and BM-MSCs could inhibit differentiation, maturation and endocytosis in monocyte-derived DCs through the secreted factors and free of any cell-cell contacts under laboratory conditions. As DCs are believed to be the main antigen presenting cells for naïve T cells in triggering immune responses, it would be logical that their inhibitory effect on differentiation, maturation and function can decrease or modulate immune and inflammatory responses. PMID:23454777

  3. Expansion of Mesenchymal Stem Cells under Atmospheric Carbon Dioxide

    PubMed Central

    Brodsky, Arthur Nathan; Zhang, Jing; Visconti, Richard P.; Harcum, Sarah W.

    2013-01-01

    Stem cells are needed for an increasing number of scientific applications, including both fundamental research and clinical disease treatment. To meet this rising demand, improved expansion methods to generate high quantities of high quality stem cells must be developed. Unfortunately, the bicarbonate buffering system – which relies upon an elevated CO2 environment – typically used to maintain pH in stem cell cultures introduces several unnecessary limitations in bioreactor systems. In addition to artificially high dissolved CO2 levels negatively affecting cell growth, but more importantly, the need to sparge CO2 into the system complicates the ability to control culture parameters. This control is especially important for stem cells, whose behavior and phenotype is highly sensitive to changes in culture conditions such as dissolved oxygen and pH. As a first step, this study developed a buffer to support expansion of mesenchymal stem cells (MSC) under an atmospheric CO2 environment in static cultures. MSC expanded under atmospheric CO2 with this buffer achieved equivalent growth rates without adaptation compared to those grown in standard conditions and also maintained a stem cell phenotype, self-renewal properties, and the ability to differentiate into multiple lineages after expansion. PMID:23894049

  4. Mesenchymal stem cells as feeder cells for pancreatic islet transplants.

    PubMed

    Sordi, Valeria; Piemonti, Lorenzo

    2010-01-01

    Allogeneic islet transplantation serves as a source of insulin-secreting beta-cells for the maintenance of normal glucose levels and treatment of diabetes. However, limited availability of islets, high rates of islet graft failure, and the need for life-long non-specific immunosuppressive therapy are major obstacles to the widespread application of this therapeutic approach. To overcome these problems, pancreatic islet transplantation was recently suggested as a potential target of the "therapeutic plasticity" of adult stem cells. In fact, new results suggest that stem/precursor cells, and mesenchymal stem cells in particular, co-transplanted with islets can promote tissue engraftment and beta-cell survival via bystander mechanisms, mainly exerted by creating a milieu of cytoprotective and immunomodulatory molecules. This evidence consistently challenges the limited view that stem/precursor cells work exclusively through beta-cell replacement in diabetes therapy. It proposes that stem cells also act as "feeder" cells for islets, and supporter of graft protection, tissue revascularization, and immune acceptance. This article reviews the experience of using stem cell co-transplantation as strategy to improve islet transplantation. It highlights that comprehension of the mechanisms involved will help to identify new molecular targets and promote development of new pharmacological strategies to treat type 1 and type 2 diabetes patients. PMID:21060972

  5. Multilineage potential research of bovine amniotic fluid mesenchymal stem cells.

    PubMed

    Gao, Yuhua; Zhu, Zhiqiang; Zhao, Yuhua; Hua, Jinlian; Ma, Yuehui; Guan, Weijun

    2014-01-01

    The use of amnion and amniotic fluid (AF) are abundant sources of mesenchymal stem cells (MSCs) that can be harvested at low cost and do not pose ethical conflicts. In human and veterinary research, stem cells derived from these tissues are promising candidates for disease treatment, specifically for their plasticity, their reduced immunogenicity, and high anti-inflammatory potential. This work aimed to obtain and characterize bovine amniotic fluid mesenchymal stem cells (AFMSC). The bovine AF from the amniotic cavity of pregnant gilts in the early stages of gestation (3- and 4-m-old bovine embryos) was collected. AFMSCs exhibit a fibroblastic-like morphology only starting from the fourth passage, being heterogeneous during the primary culture. Immunofluorescence results showed that AFMSCs were positive for β-integrin, CD44, CD73 and CD166, but negative for CD34, CD45. Meanwhile, AFMSCs expressed ES cell markers, such as Oct4, and when appropriately induced, are capable of differentiating into ectodermal and mesodermal lineages. This study reinforces the emerging importance of these cells as ideal tools in veterinary medicine; future studies aimed at a deeper evaluation of their immunological properties will allow a better understanding of their role in cellular therapy. PMID:24590129

  6. Mesenchymal stem cell therapy for acute radiation syndrome.

    PubMed

    Fukumoto, Risaku

    2016-01-01

    Acute radiation syndrome affects military personnel and civilians following the uncontrolled dispersal of radiation, such as that caused by detonation of nuclear devices and inappropriate medical treatments. Therefore, there is a growing need for medical interventions that facilitate the improved recovery of victims and patients. One promising approach may be cell therapy, which, when appropriately implemented, may facilitate recovery from whole body injuries. This editorial highlights the current knowledge regarding the use of mesenchymal stem cells for the treatment of acute radiation syndrome, the benefits and limitations of which are under investigation. Establishing successful therapies for acute radiation syndrome may require using such a therapeutic approach in addition to conventional approaches. PMID:27182446

  7. Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis.

    PubMed

    Burke, John; Hunter, Monte; Kolhe, Ravindra; Isales, Carlos; Hamrick, Mark; Fulzele, Sadanand

    2016-12-01

    Osteoarthritis (OA) is a chronic degenerative disease affecting articular cartilage in joints, and it is a leading cause of disability in the United States. Current pharmacological treatment strategies are ineffective to prevent the OA progression; however, cellular therapies have the potential to regenerate the lost cartilage, combat cartilage degeneration, provide pain relief, and improve patient mobility. One of the most promising sources of cellular regenerative medicine is from mesenchymal stem cells (MSCs). MSCs can be isolated from adipose tissue, bone marrow, synovial tissue, and other sources. The aim of this review is to compile recent advancement in cellular based therapy more specifically in relation to MSCs in the treatment of osteoarthritis. PMID:27510262

  8. In vitro Differentiation Potential of Mesenchymal Stem Cells

    PubMed Central

    Gimble, Jeffrey M.; Guilak, Farshid; Nuttall, Mark E.; Sathishkumar, Solomon; Vidal, Martin; Bunnell, Bruce A.

    2008-01-01

    Summary Mesenchymal stem cells (MSCs) represent a class of multipotent progenitor cells that have been isolated from multiple tissue sites. Of these, adipose tissue and bone marrow offer advantages in terms of access, abundance, and the extent of their documentation in the literature. This review focuses on the in vitro differentiation capability of cells derived from adult human tissue. Multiple, independent studies have demonstrated that MSCs can commit to mesodermal (adipocyte, chondrocyte, hematopoietic support, myocyte, osteoblast, tenocyte), ectodermal (epithelial, glial, neural), and endodermal (hepatocyte, islet cell) lineages. The limitations and promises of these studies in the context of tissue engineering are discussed. PMID:21547120

  9. Mesenchymal Stem Cell-Derived Hepatocytes for Functional Liver Replacement

    PubMed Central

    Christ, Bruno; Stock, Peggy

    2012-01-01

    Mesenchymal stem cells represent an alternate cell source to substitute for primary hepatocytes in hepatocyte transplantation because of their multiple differentiation potential and nearly unlimited availability. They may differentiate into hepatocyte-like cells in vitro and maintain specific hepatocyte functions also after transplantation into the regenerating livers of mice or rats both under injury and non-injury conditions. Depending on the underlying liver disease their mode of action is either to replace the diseased liver tissue or to support liver regeneration through their anti-inflammatory and anti-apoptotic as well as their pro-proliferative action. PMID:22737154

  10. Age-associated changes in the ecological niche: implications for mesenchymal stem cell aging

    PubMed Central

    2013-01-01

    Adult stem cells are critical for organ-specific regeneration and self-renewal with advancing age. The prospect of being able to reverse tissue-specific post-injury sequelae by harvesting, culturing and transplanting a patient’s own stem and progenitor cells is exciting. Mesenchymal stem cells have emerged as a reliable stem cell source for this treatment modality and are currently being tested in numerous ongoing clinical trials. Unfortunately, the fervor over mesenchymal stem cells is mitigated by several lines of evidence suggesting that their efficacy is limited by natural aging. This article discusses the mechanisms and manifestations of age-associated deficiencies in mesenchymal stem cell efficacy. A consideration of recent experimental findings suggests that the ecological niche might be responsible for mesenchymal stem cell aging. PMID:23673056

  11. Immunoregulatory effects of bone marrow-derived mesenchymal stem cells in the nasal polyp microenvironment.

    PubMed

    Pezato, Rogério; de Almeida, Danilo Cândido; Bezerra, Thiago Freire; Silva, Fernando de Sá; Perez-Novo, Claudina; Gregório, Luís Carlos; Voegels, Richard Louis; Câmara, Niels Olsen; Bachert, Claus

    2014-01-01

    Nasal polyposis is a severe, chronic inflammatory condition of the paranasal sinuses and is frequently associated with asthma and aspirin sensitivity. Mesenchymal stem cells exhibit a potent immunosuppressive effect in several inflammatory conditions, and their role in nasal polyposis remains little explored. Hence, we investigated whether bone marrow-derived mesenchymal stem cells could modulate cell phenotype in the nasal polyp milieu. After coculture with mesenchymal stem cells, the frequency of these inflammatory cells was found to decrease. Furthermore, mesenchymal stem cells promoted strong inhibition of CD4+ and CD8+ T cell proliferation, increased the frequency of CD4+CD25+Foxp3 T cells, and changed the global cytokine profile from an inflammatory to an anti-inflammatory response. We believe that mesenchymal stem cells may be a very useful adjunct for investigation of the inflammatory process in nasal polyposis, contributing to better understanding of the inflammatory course of this condition. PMID:24707116

  12. 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

  13. Composition of Mineral Produced by Dental Mesenchymal Stem Cells

    PubMed Central

    Volponi, A.A.; Gentleman, E.; Fatscher, R.; Pang, Y.W.Y.; Gentleman, M.M.; Sharpe, P.T.

    2015-01-01

    Mesenchymal stem cells isolated from different dental tissues have been described to have osteogenic/odontogenic-like differentiation capacity, but little attention has been paid to the biochemical composition of the material that each produces. Here, we used Raman spectroscopy to analyze the mineralized materials produced in vitro by different dental cell populations, and we compared them with the biochemical composition of native dental tissues. We show that different dental stem cell populations produce materials that differ in their mineral and matrix composition and that these differ from those of native dental tissues. In vitro, BCMP (bone chip mass population), SCAP (stem cells from apical papilla), and SHED (stem cells from human-exfoliated deciduous teeth) cells produce a more highly mineralized matrix when compared with that produced by PDL (periodontal ligament), DPA (dental pulp adult), and GF (gingival fibroblast) cells. Principal component analyses of Raman spectra further demonstrated that the crystallinity and carbonate substitution environments in the material produced by each cell type varied, with DPA cells, for example, producing a more carbonate-substituted mineral and with SCAP, SHED, and GF cells creating a less crystalline material when compared with other dental stem cells and native tissues. These variations in mineral composition reveal intrinsic differences in the various cell populations, which may in turn affect their specific clinical applications. PMID:26253190

  14. Mesenchymal Stem Cell Therapy in Diabetes Mellitus: Progress and Challenges

    PubMed Central

    El-Badri, Nagwa; Ghoneim, Mohamed A.

    2013-01-01

    Advanced type 2 diabetes mellitus is associated with significant morbidity and mortality due to cardiovascular, nervous, and renal complications. Attempts to cure diabetes mellitus using islet transplantation have been successful in providing a source for insulin secreting cells. However, limited donors, graft rejection, the need for continued immune suppression, and exhaustion of the donor cell pool prompted the search for a more sustained source of insulin secreting cells. Stem cell therapy is a promising alternative for islet transplantation in type 2 diabetic patients who fail to control hyperglycemia even with insulin injection. Autologous stem cell transplantation may provide the best outcome for those patients, since autologous cells are readily available and do not entail prolonged hospital stays or sustained immunotoxic therapy. Among autologous adult stem cells, mesenchymal stem cells (MSCs) therapy has been applied with varying degrees of success in both animal models and in clinical trials. This review will focus on the advantages of MSCs over other types of stem cells and the possible mechanisms by which MSCs transplant restores normoglycemia in type 2 diabetic patients. Sources of MSCs including autologous cells from diabetic patients and the use of various differentiation protocols in relation to best transplant outcome will be discussed. PMID:23762531

  15. Mesenchymal stem cells are sensitive to bleomycin treatment

    PubMed Central

    Nicolay, Nils H.; Rühle, Alexander; Perez, Ramon Lopez; Trinh, Thuy; Sisombath, Sonevisay; Weber, Klaus-Josef; Ho, Anthony D.; Debus, Jürgen; Saffrich, Rainer; Huber, Peter E.

    2016-01-01

    Mesenchymal stem cells (MSCs) have been shown to attenuate pulmonary damage induced by bleomycin-based anticancer treatments, but the influence of bleomycin on the stem cells themselves remains largely unknown. Here, we demonstrate that human bone marrow-derived MSCs are relatively sensitive to bleomycin exposure compared to adult fibroblasts. MSCs revealed increased levels of apoptosis after bleomycin treatment, while cellular morphology, stem cell surface marker expression and the ability for adhesion and migration remained unchanged. Bleomycin treatment also resulted in a reduced adipogenic differentiation potential of these stem cells. MSCs were found to efficiently repair DNA double strand breaks induced by bleomycin, mostly through non-homologous end joining repair. Low mRNA and protein expression levels of the inactivating enzyme bleomycin hydrolase were detected in MSCs that may contribute to the observed bleomycin-sensitive phenotype of these cells. The sensitivity of MSCs against bleomycin needs to be taken into consideration for ongoing and future treatment protocols investigating these stem cells as a potential treatment option for bleomycin-induced pulmonary damage in the clinic. PMID:27215195

  16. Mesenchymal stem cells and immunomodulation: current status and future prospects

    PubMed Central

    Gao, F; Chiu, S M; Motan, D A L; Zhang, Z; Chen, L; Ji, H-L; Tse, H-F; Fu, Q-L; Lian, Q

    2016-01-01

    The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy. PMID:26794657

  17. Transplantation of mesenchymal stem cells improves type 1 diabetes mellitus.

    PubMed

    Li, Lisha; Li, Furong; Gao, Feng; Yang, Yali; Liu, Yuanyuan; Guo, Pingping; Li, Yulin

    2016-05-01

    Bone-marrow-derived stem cells can regenerate pancreatic tissue in a model of type 1 diabetes mellitus. Mesenchymal stem cells (MSCs) form the main part of bone marrow. We show that the intrapancreatic transplantation of MSCs elevates serum insulin and C-peptide, while decreasing blood glucose. MSCs engrafted into the damaged rat pancreas become distributed into the blood vessels, acini, ducts, and islets. Renascent islets, islet-like clusters, and a small number of MSCs expressing insulin protein have been observed in the pancreas of diabetic rats. Intrapancreatic transplantation of MSCs triggers a series of molecular and cellular events, including differentiation towards the pancreas directly and the provision of a niche to start endogenous pancreatic regeneration, which ameliorates hypoinsulinemia and hyperglycemia caused by streptozotocin. These data establish the many roles of MSCs in the restoration of the function of an injured organ. PMID:26650464

  18. Effects of Oxidative Stress on Mesenchymal Stem Cell Biology.

    PubMed

    Denu, Ryan A; Hematti, Peiman

    2016-01-01

    Mesenchymal stromal/stem cells (MSCs) are multipotent stem cells present in most fetal and adult tissues. Ex vivo culture-expanded MSCs are being investigated for tissue repair and immune modulation, but their full clinical potential is far from realization. Here we review the role of oxidative stress in MSC biology, as their longevity and functions are affected by oxidative stress. In general, increased reactive oxygen species (ROS) inhibit MSC proliferation, increase senescence, enhance adipogenic but reduce osteogenic differentiation, and inhibit MSC immunomodulation. Furthermore, aging, senescence, and oxidative stress reduce their ex vivo expansion, which is critical for their clinical applications. Modulation of sirtuin expression and activity may represent a method to reduce oxidative stress in MSCs. These findings have important implications in the clinical utility of MSCs for degenerative and immunological based conditions. Further study of oxidative stress in MSCs is imperative in order to enhance MSC ex vivo expansion and in vivo engraftment, function, and longevity. PMID:27413419

  19. Effects of Oxidative Stress on Mesenchymal Stem Cell Biology

    PubMed Central

    2016-01-01

    Mesenchymal stromal/stem cells (MSCs) are multipotent stem cells present in most fetal and adult tissues. Ex vivo culture-expanded MSCs are being investigated for tissue repair and immune modulation, but their full clinical potential is far from realization. Here we review the role of oxidative stress in MSC biology, as their longevity and functions are affected by oxidative stress. In general, increased reactive oxygen species (ROS) inhibit MSC proliferation, increase senescence, enhance adipogenic but reduce osteogenic differentiation, and inhibit MSC immunomodulation. Furthermore, aging, senescence, and oxidative stress reduce their ex vivo expansion, which is critical for their clinical applications. Modulation of sirtuin expression and activity may represent a method to reduce oxidative stress in MSCs. These findings have important implications in the clinical utility of MSCs for degenerative and immunological based conditions. Further study of oxidative stress in MSCs is imperative in order to enhance MSC ex vivo expansion and in vivo engraftment, function, and longevity. PMID:27413419

  20. Mesenchymal stem cells are resistant to carbon ion radiotherapy

    PubMed Central

    Nicolay, Nils H.; Liang, Yingying; Perez, Ramon Lopez; Bostel, Tilman; Trinh, Thuy; Sisombath, Sonevisay; Weber, Klaus-Josef; Ho, Anthony D.; Debus, Jürgen; Saffrich, Rainer; Huber, Peter E.

    2015-01-01

    Mesenchymal stem cells (MSCs) participate in regeneration of tissues damaged by ionizing radiation. However, radiation can damage MSCs themselves. Here we show that cellular morphology, adhesion and migration abilities were not measurably altered by photon or carbon ion irradiation. The potential for differentiation was unaffected by either form of radiation, and established MSC surface markers were found to be stably expressed irrespective of radiation treatment. MSCs were able to efficiently repair DNA double strand breaks induced by both high-dose photon and carbon ion radiation. We have shown for the first time that MSCs are relatively resistant to therapeutic carbon ion radiotherapy. Additionally, this form of radiation did not markedly alter the defining stem cell properties or the expression of established surface markers in MSCs. PMID:25504442

  1. Interaction between Mesenchymal Stem Cells and B-Cells

    PubMed Central

    Fan, Linxiao; Hu, Chenxia; Chen, Jiajia; Cen, Panpan; Wang, Jie; Li, Lanjuan

    2016-01-01

    Mesenchymal stem cells (MSCs) are multipotent; non-hematopoietic stem cells. Because of their immunoregulatory abilities; MSCs are widely used for different clinical applications. Compared with that of other immune cells; the investigation of how MSCs specifically regulate B-cells has been superficial and insufficient. In addition; the few experimental studies on this regulation are often contradictory. In this review; we summarize the various interactions between different types or states of MSCs and B-cells; address how different types of MSCs and B-cells affect this interaction and examine how other immune cells influence the regulation of B-cells by MSCs. Finally; we hypothesize why there are conflicting results on the interaction between MSCs and B-cells in the literature. PMID:27164080

  2. Mesenchymal stem cell therapy for cutaneous radiation syndrome.

    PubMed

    Akita, Sadanori; Akino, Kozo; Hirano, Akiyoshi; Ohtsuru, Akira; Yamashita, Shunichi

    2010-06-01

    Systemic and local radiation injuries caused by nuclear power reactor accidents, therapeutic irradiation, or nuclear terrorism should be prevented or properly treated in order to improve wound management and save lives. Currently, regenerative surgical modalities should be attempted with temporal artificial dermis impregnated and sprayed with a local angiogenic factor such as basic fibroblast growth factor, and secondary reconstruction can be a candidate for demarcation and saving the donor morbidity. Human mesenchymal stem cells and adipose-derived stem cells, together with angiogenic and mitogenic factor of basic fibroblast growth factor and an artificial dermis, were applied over the excised irradiated skin defect and were tested for differentiation and local stimulation effects in the radiation-exposed wounds. The perforator flap and artificial dermal template with growth factor were successful for reconstruction in patients who were suffering from complex underlying disease. Patients were uneventfully treated with minimal morbidities. In the experiments, the hMSCs are strongly proliferative even after 20 Gy irradiation in vitro. In vivo, 4 Gy rat whole body irradiation demonstrated that sustained marrow stromal (mesenchymal stem) cells survived in the bone marrow. Immediate artificial dermis application impregnated with cells and the cytokine over the 20 Gy irradiated skin and soft tissues demonstrated the significantly improved fat angiogenesis, architected dermal reconstitution, and less inflammatory epidermal recovery. Detailed understanding of underlying diseases and rational reconstructive procedures brings about good outcomes for difficult irradiated wound healing. Adipose-derived stem cells are also implicated in the limited local injuries for short cell harvesting and processing time in the same subject. PMID:20445394

  3. Human mesenchymal stem cells - current trends and future prospective

    PubMed Central

    Ullah, Imran; Subbarao, Raghavendra Baregundi; Rho, Gyu Jin

    2015-01-01

    Stem cells are cells specialized cell, capable of renewing themselves through cell division and can differentiate into multi-lineage cells. These cells are categorized as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells. Mesenchymal stem cells (MSCs) are adult stem cells which can be isolated from human and animal sources. Human MSCs (hMSCs) are the non-haematopoietic, multipotent stem cells with the capacity to differentiate into mesodermal lineage such as osteocytes, adipocytes and chondrocytes as well ectodermal (neurocytes) and endodermal lineages (hepatocytes). MSCs express cell surface markers like cluster of differentiation (CD)29, CD44, CD73, CD90, CD105 and lack the expression of CD14, CD34, CD45 and HLA (human leucocyte antigen)-DR. hMSCs for the first time were reported in the bone marrow and till now they have been isolated from various tissues, including adipose tissue, amniotic fluid, endometrium, dental tissues, umbilical cord and Wharton's jelly which harbours potential MSCs. hMSCs have been cultured long-term in specific media without any severe abnormalities. Furthermore, MSCs have immunomodulatory features, secrete cytokines and immune-receptors which regulate the microenvironment in the host tissue. Multilineage potential, immunomodulation and secretion of anti-inflammatory molecules makes MSCs an effective tool in the treatment of chronic diseases. In the present review, we have highlighted recent research findings in the area of hMSCs sources, expression of cell surface markers, long-term in vitro culturing, in vitro differentiation potential, immunomodulatory features, its homing capacity, banking and cryopreservation, its application in the treatment of chronic diseases and its use in clinical trials. PMID:25797907

  4. Human mesenchymal stem cells - current trends and future prospective.

    PubMed

    Ullah, Imran; Subbarao, Raghavendra Baregundi; Rho, Gyu Jin

    2015-01-01

    Stem cells are cells specialized cell, capable of renewing themselves through cell division and can differentiate into multi-lineage cells. These cells are categorized as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells. Mesenchymal stem cells (MSCs) are adult stem cells which can be isolated from human and animal sources. Human MSCs (hMSCs) are the non-haematopoietic, multipotent stem cells with the capacity to differentiate into mesodermal lineage such as osteocytes, adipocytes and chondrocytes as well ectodermal (neurocytes) and endodermal lineages (hepatocytes). MSCs express cell surface markers like cluster of differentiation (CD)29, CD44, CD73, CD90, CD105 and lack the expression of CD14, CD34, CD45 and HLA (human leucocyte antigen)-DR. hMSCs for the first time were reported in the bone marrow and till now they have been isolated from various tissues, including adipose tissue, amniotic fluid, endometrium, dental tissues, umbilical cord and Wharton's jelly which harbours potential MSCs. hMSCs have been cultured long-term in specific media without any severe abnormalities. Furthermore, MSCs have immunomodulatory features, secrete cytokines and immune-receptors which regulate the microenvironment in the host tissue. Multilineage potential, immunomodulation and secretion of anti-inflammatory molecules makes MSCs an effective tool in the treatment of chronic diseases. In the present review, we have highlighted recent research findings in the area of hMSCs sources, expression of cell surface markers, long-term in vitro culturing, in vitro differentiation potential, immunomodulatory features, its homing capacity, banking and cryopreservation, its application in the treatment of chronic diseases and its use in clinical trials. PMID:25797907

  5. Heterogeneity in proliferative potential of ovine mesenchymal stem cell colonies.

    PubMed

    Rhodes, N P; Srivastava, J K; Smith, R F; Longinotti, C

    2004-04-01

    Bone marrow biopsies were taken from the iliac crest of 28 individual sheep from three different breeds, ranging in age from 4 months to 8 years and mesenchymal stem cells (MSCs) isolated using selection due to plastic adherence. Cells were cultured in medium that had been selected for its effect on observed MSC proliferation, until populations of greater than 50 million had been obtained from each biopsy. The identity of the isolated cell populations as progenitors of the mesenchymal lineage was verified by deriving both osteoblastic and chondrocytic phenotypes when cultured in osteogenic and chondrogenic medium supplements, respectively. The rate of cell proliferation for each marrow biopsy was measured at each passage and the number of initial stem cells in each sample estimated. There was no statistically significant correlation between the age of the sheep and MSC proliferative potential, or age and estimated initial MSC number. There was no apparent significant difference between proliferation rate and sheep breed and colonies established from frozen cells grew at similar rates to pre-frozen cells. Counter intuitively, there appeared to be a negatively correlated trend between proliferation rate and MSC concentration in the samples. It is concluded that no initial descriptive statistics of the marrow biopsies can assist in estimating the proliferative potential, and therefore the timing of future surgeries, of MSCs sampled for the purposes of tissue engineering. PMID:15332606

  6. Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy

    PubMed Central

    Glenn, Justin D; Whartenby, Katharine A

    2014-01-01

    Mesenchymal stem cells (MSCs) are a pleiotropic population of cells that are self-renewing and capable of differentiating into canonical cells of the mesenchyme, including adipocytes, chondrocytes, and osteocytes. They employ multi-faceted approaches to maintain bone marrow niche homeostasis and promote wound healing during injury. Biomedical research has long sought to exploit their pleiotropic properties as a basis for cell therapy for a variety of diseases and to facilitate hematopoietic stem cell establishment and stromal reconstruction in bone marrow transplantation. Early results demonstrated their usage as safe, and there was little host response to these cells. The discovery of their immunosuppressive functions ushered in a new interest in MSCs as a promising therapeutic tool to suppress inflammation and down-regulate pathogenic immune responses in graft-versus-host and autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. MSCs produce a large number of soluble and membrane-bound factors, some of which inhibit immune responses. However, the full range of MSC-mediated immune-modulation remains incompletely understood, as emerging reports also reveal that MSCs can adopt an immunogenic phenotype, stimulate immune cells, and yield seemingly contradictory results in experimental animal models of inflammatory disease. The present review describes the large body of literature that has been accumulated on the fascinating biology of MSCs and their complex effects on immune responses. PMID:25426250

  7. Induction of mesenchymal stem cell chondrogenesis by polyacrylate substrates

    PubMed Central

    Glennon-Alty, Laurence; Williams, Rachel; Dixon, Simon; Murray, Patricia

    2013-01-01

    Mesenchymal stem cells (MSCs) can generate chondrocytes in vitro, but typically need to be cultured as aggregates in the presence of transforming growth factor beta (TGF-β), which makes scale-up difficult. Here we investigated if polyacrylate substrates modelled on the functional group composition and distribution of the Arg-Gly-Asp (RGD) integrin-binding site could induce MSCs to undergo chondrogenesis in the absence of exogenous TGF-β. Within a few days of culture on the biomimetic polyacrylates, both mouse and human MSCs, and a mesenchymal-like mouse-kidney-derived stem cell line, began to form multi-layered aggregates and started to express the chondrocyte-specific markers, Sox9, collagen II and aggrecan. Moreover, collagen II tended to be expressed in the centre of the aggregates, similarly to developing limb buds in vivo. Surface analysis of the substrates indicated that those with the highest surface amine content were most effective at promoting MSC chondrogenesis. These results highlight the importance of surface group functionality and the distribution of those groups in the design of substrates to induce MSC chondrogenesis. PMID:23237986

  8. Induction of mesenchymal stem cell chondrogenesis by polyacrylate substrates.

    PubMed

    Glennon-Alty, Laurence; Williams, Rachel; Dixon, Simon; Murray, Patricia

    2013-04-01

    Mesenchymal stem cells (MSCs) can generate chondrocytes in vitro, but typically need to be cultured as aggregates in the presence of transforming growth factor beta (TGF-β), which makes scale-up difficult. Here we investigated if polyacrylate substrates modelled on the functional group composition and distribution of the Arg-Gly-Asp (RGD) integrin-binding site could induce MSCs to undergo chondrogenesis in the absence of exogenous TGF-β. Within a few days of culture on the biomimetic polyacrylates, both mouse and human MSCs, and a mesenchymal-like mouse-kidney-derived stem cell line, began to form multi-layered aggregates and started to express the chondrocyte-specific markers, Sox9, collagen II and aggrecan. Moreover, collagen II tended to be expressed in the centre of the aggregates, similarly to developing limb buds in vivo. Surface analysis of the substrates indicated that those with the highest surface amine content were most effective at promoting MSC chondrogenesis. These results highlight the importance of surface group functionality and the distribution of those groups in the design of substrates to induce MSC chondrogenesis. PMID:23237986

  9. Cryopreservation of Adipose-Derived Mesenchymal Stem Cells

    PubMed Central

    Miyagi-Shiohira, Chika; Kurima, Kiyoto; Kobayashi, Naoya; Saitoh, Issei; Watanabe, Masami; Noguchi, Yasufumi; Matsushita, Masayuki; Noguchi, Hirofumi

    2015-01-01

    Mesenchymal stem cells (MSCs) have the potential to differentiate into cells of mesodermal origin such as osteoblasts, adipocytes, myocytes, and chondrocytes. They possess an immunosuppressive effect, which makes them a viable cell population for the cell-based therapy of treatment-resistant immune diseases. Adipose-derived mesenchymal stem cells (ASCs) have been demonstrated to have the ability to acquire the properties of subcutaneous adipose tissue particularly easily, and cryopreservation is currently performed as a routine method for preserving ASCs to safely acquire large numbers of cells. However, many studies have reported that cellular activity after freezing and thawing may be affected by the solutions used for cryopreservation. Dimethyl sulfoxide (DMSO) is commonly used as a cryopreservation medium as it diffuses into the cell through the plasma membrane and protects the cells from the damage caused by freezing. As substitutes for DMSO or animal-derived serum, cell banker series, polyvinylpyrrolidone (PVP), sericin and maltose, and methyl cellulose (MC) have been investigated for their clinical applications. It is critical to develop a reliable cell cryopreservation protocol for regenerative medicine using MSCs. PMID:26858903

  10. Cryopreservation of Adipose-Derived Mesenchymal Stem Cells.

    PubMed

    Miyagi-Shiohira, Chika; Kurima, Kiyoto; Kobayashi, Naoya; Saitoh, Issei; Watanabe, Masami; Noguchi, Yasufumi; Matsushita, Masayuki; Noguchi, Hirofumi

    2015-12-17

    Mesenchymal stem cells (MSCs) have the potential to differentiate into cells of mesodermal origin such as osteoblasts, adipocytes, myocytes, and chondrocytes. They possess an immunosuppressive effect, which makes them a viable cell population for the cell-based therapy of treatment-resistant immune diseases. Adipose-derived mesenchymal stem cells (ASCs) have been demonstrated to have the ability to acquire the properties of subcutaneous adipose tissue particularly easily, and cryopreservation is currently performed as a routine method for preserving ASCs to safely acquire large numbers of cells. However, many studies have reported that cellular activity after freezing and thawing may be affected by the solutions used for cryopreservation. Dimethyl sulfoxide (DMSO) is commonly used as a cryopreservation medium as it diffuses into the cell through the plasma membrane and protects the cells from the damage caused by freezing. As substitutes for DMSO or animal-derived serum, cell banker series, polyvinylpyrrolidone (PVP), sericin and maltose, and methyl cellulose (MC) have been investigated for their clinical applications. It is critical to develop a reliable cell cryopreservation protocol for regenerative medicine using MSCs. PMID:26858903

  11. Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?

    PubMed

    Chen, Q; Shou, P; Zheng, C; Jiang, M; Cao, G; Yang, Q; Cao, J; Xie, N; Velletri, T; Zhang, X; Xu, C; Zhang, L; Yang, H; Hou, J; Wang, Y; Shi, Y

    2016-07-01

    Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance. PMID:26868907

  12. Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?

    PubMed Central

    Chen, Q; Shou, P; Zheng, C; Jiang, M; Cao, G; Yang, Q; Cao, J; Xie, N; Velletri, T; Zhang, X; Xu, C; Zhang, L; Yang, H; Hou, J; Wang, Y; Shi, Y

    2016-01-01

    Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance. PMID:26868907

  13. Wnt/β-Catenin Signaling Determines the Vasculogenic Fate of Postnatal Mesenchymal Stem Cells.

    PubMed

    Zhang, Zhaocheng; Nör, Felipe; Oh, Min; Cucco, Carolina; Shi, Songtao; Nör, Jacques E

    2016-06-01

    Vasculogenesis is the process of de novo blood vessel formation observed primarily during embryonic development. Emerging evidence suggest that postnatal mesenchymal stem cells are capable of recapitulating vasculogenesis when these cells are engaged in tissue regeneration. However, the mechanisms underlining the vasculogenic differentiation of mesenchymal stem cells remain unclear. Here, we used stem cells from human permanent teeth (dental pulp stem cells [DPSC]) or deciduous teeth (stem cells from human exfoliated deciduous teeth [SHED]) as models of postnatal primary human mesenchymal stem cells to understand mechanisms regulating their vasculogenic fate. GFP-tagged mesenchymal stem cells seeded in human tooth slice/scaffolds and transplanted into immunodeficient mice differentiate into human blood vessels that anastomize with the mouse vasculature. In vitro, vascular endothelial growth factor (VEGF) induced the vasculogenic differentiation of DPSC and SHED via potent activation of Wnt/β-catenin signaling. Further, activation of Wnt signaling is sufficient to induce the vasculogenic differentiation of postnatal mesenchymal stem cells, while Wnt inhibition blocked this process. Notably, β-catenin-silenced DPSC no longer differentiate into endothelial cells in vitro, and showed impaired vasculogenesis in vivo. Collectively, these data demonstrate that VEGF signaling through the canonical Wnt/β-catenin pathway defines the vasculogenic fate of postnatal mesenchymal stem cells. Stem Cells 2016;34:1576-1587. PMID:26866635

  14. Transplantation of Simian Mesenchymal Stem Cells to Baboons with Experimentally Induced Myocardial Infarction.

    PubMed

    Agrba, V Z; Porkhanov, V A; Karal-Ogly, D D; Leontyuk, A V; Kovalenko, A L; Sholin, I Yu; Gvozdik, T E; Ignatova, I E; Agumava, A A; Chuguev, Yu P; Gvaramiya, I A; Lapin, B A

    2016-02-01

    Culture of mesenchymal stem cells isolated from the bone marrow of primates by their characteristics met the requirements of stem cells. It was shown that transplantation of allogeneic mesenchymal stem cells (2 million cells per 1 kg body weight) immediately after ligation of the left anterior descending coronary artery between the middle and upper thirds led to neovascularization and capillarization of the ischemic myocardium. PMID:26906203

  15. Mesenchymal Stem Cells in Tissue Growth and Repair

    PubMed Central

    Kalinina, N.I.; Sysoeva, V.Yu.; Rubina, K.A.; Parfenova, Ye.V.; Tkachuk, V.A.

    2011-01-01

    It has been established in the recent several decades that stem cells play a crucial role in tissue renewal and regeneration. Mesenchymal stem cells (MSCs) are part of the most important population of adult stem cells. These cells have hereby been identified for the very first time and subsequently isolated from bone marrow stroma. Bone marrow-derived MSCs have been believed to play the role of a source of cells for the renewal and repair of connective tissues, including bone, cartilage and adipose tissues. Cells similar to bone marrow-derived MSCs have now been identified in all postnatal tissues. Data on the distribution and function of MSCsin vivocollected using novel approaches pertaining to the identification of MSCsin situ, to their isolation from tissues, and finally to the determination of their biological properties have enabled successful revision of the role of MSCs in various organs and tissues. This review summarizes our own, as well as others’, data concerning the role of MSCs in the regulation processes of tissue repair and regeneration. In our opinion, MSCs provide the connection between the blood-vascular, immune, endocrine, and nervous systems and tissue-specific stem cells in the body. PMID:22649702

  16. Use of Mesenchymal Stem Cells for Therapy of Cardiac Disease

    PubMed Central

    Karantalis, Vasileios; Hare, Joshua M.

    2015-01-01

    Despite substantial clinical advances over the past 65 years, cardiovascular disease remains the leading cause of death in America. The past 15 years has witnessed major basic and translational interest in the use of stem and/or precursor cells as a therapeutic agent for chronically injured organs. Among the cell types under investigation, adult mesenchymal stem cells (MSCs) are widely studied and in early stage clinical studies show promise for repair and regeneration of cardiac tissues. The ability of MSCs to differentiate into mesoderm and non-mesoderm derived tissues, their immunomodulatory effects, their availability and their key role in maintaining and replenishing endogenous stem cell niches have rendered them one of the most heavily investigated and clinically tested type of stem cell. Accumulating data from preclinical and early phase clinical trials document their safety when delivered as either autologous or allogeneic forms in a range of cardiovascular diseases, but also importantly define parameters of clinical efficacy that justify further investigation in larger clinical trials. Here, we review the biology of MSCs, their interaction with endogenous molecular and cellular pathways, and their modulation of immune responses. Additionally, we discuss factors that enhance their proliferative and regenerative ability and factors that may hinder their effectiveness in the clinical setting. PMID:25858066

  17. RNA-Seq Reveals the Angiogenesis Diversity between the Fetal and Adults Bone Mesenchyme Stem Cell

    PubMed Central

    Zhao, Xin; Han, Yingmin; Liang, Yu; Nie, Chao; Wang, Jian

    2016-01-01

    In this research, we used RNA sequencing (RNA-seq) to analyze 23 single cell samples and 2 bulk cells sample from human adult bone mesenchyme stem cell line and human fetal bone mesenchyme stem cell line. The results from the research demonstrated that there were big differences between two cell lines. Adult bone mesenchyme stem cell lines showed a strong trend on the blood vessel differentiation and cell motion, 48/49 vascular related differential expressed genes showed higher expression in adult bone mesenchyme stem cell lines (Abmsc) than fetal bone mesenchyme stem cell lines (Fbmsc). 96/106 cell motion related genes showed the same tendency. Further analysis showed that genes like ANGPT1, VEGFA, FGF2, PDGFB and PDGFRA showed higher expression in Abmsc. This work showed cell heterogeneity between human adult bone mesenchyme stem cell line and human fetal bone mesenchyme stem cell line. Also the work may give an indication that Abmsc had a better potency than Fbmsc in the future vascular related application. PMID:26901069

  18. RNA-Seq Reveals the Angiogenesis Diversity between the Fetal and Adults Bone Mesenchyme Stem Cell.

    PubMed

    Zhao, Xin; Han, Yingmin; Liang, Yu; Nie, Chao; Wang, Jian

    2016-01-01

    In this research, we used RNA sequencing (RNA-seq) to analyze 23 single cell samples and 2 bulk cells sample from human adult bone mesenchyme stem cell line and human fetal bone mesenchyme stem cell line. The results from the research demonstrated that there were big differences between two cell lines. Adult bone mesenchyme stem cell lines showed a strong trend on the blood vessel differentiation and cell motion, 48/49 vascular related differential expressed genes showed higher expression in adult bone mesenchyme stem cell lines (Abmsc) than fetal bone mesenchyme stem cell lines (Fbmsc). 96/106 cell motion related genes showed the same tendency. Further analysis showed that genes like ANGPT1, VEGFA, FGF2, PDGFB and PDGFRA showed higher expression in Abmsc. This work showed cell heterogeneity between human adult bone mesenchyme stem cell line and human fetal bone mesenchyme stem cell line. Also the work may give an indication that Abmsc had a better potency than Fbmsc in the future vascular related application. PMID:26901069

  19. CD271 as a marker to identify mesenchymal stem cells from diverse sources before culture

    PubMed Central

    Álvarez-Viejo, María; Menéndez-Menéndez, Yolanda; Otero-Hernández, Jesús

    2015-01-01

    Mesenchymal stem cells, due to their characteristics are ideal candidates for cellular therapy. Currently, in culture these cells are defined by their adherence to plastic, specific surface antigen expression and multipotent differentiation potential. However, the in vivo identification of mesenchymal stem cells, before culture, is not so well established. Pre-culture identification markers would ensure higher purity than that obtained with selection based on adherence to plastic. Up until now, CD271 has been described as the most specific marker for the characterization and purification of human bone marrow mesenchymal stem cells. This marker has been shown to be specifically expressed by these cells. Thus, CD271 has been proposed as a versatile marker to selectively isolated and expand multipotent mesenchymal stem cells with both immunosuppressive and lymphohematopoietic engraftment-promoting properties. This review focuses on this marker, specifically on identification of mesenchymal stem cells from different tissues. Literature revision suggests that CD271 should not be defined as a universal marker to identify mesenchymal stem cells before culture from different sources. In the case of bone marrow or adipose tissue, CD271 could be considered a quite suitable marker; however this marker seems to be inadequate for the isolation of mesenchymal stem cells from other tissues such as umbilical cord blood or wharton’s jelly among others. PMID:25815130

  20. CD271 as a marker to identify mesenchymal stem cells from diverse sources before culture.

    PubMed

    Álvarez-Viejo, María; Menéndez-Menéndez, Yolanda; Otero-Hernández, Jesús

    2015-03-26

    Mesenchymal stem cells, due to their characteristics are ideal candidates for cellular therapy. Currently, in culture these cells are defined by their adherence to plastic, specific surface antigen expression and multipotent differentiation potential. However, the in vivo identification of mesenchymal stem cells, before culture, is not so well established. Pre-culture identification markers would ensure higher purity than that obtained with selection based on adherence to plastic. Up until now, CD271 has been described as the most specific marker for the characterization and purification of human bone marrow mesenchymal stem cells. This marker has been shown to be specifically expressed by these cells. Thus, CD271 has been proposed as a versatile marker to selectively isolated and expand multipotent mesenchymal stem cells with both immunosuppressive and lymphohematopoietic engraftment-promoting properties. This review focuses on this marker, specifically on identification of mesenchymal stem cells from different tissues. Literature revision suggests that CD271 should not be defined as a universal marker to identify mesenchymal stem cells before culture from different sources. In the case of bone marrow or adipose tissue, CD271 could be considered a quite suitable marker; however this marker seems to be inadequate for the isolation of mesenchymal stem cells from other tissues such as umbilical cord blood or wharton's jelly among others. PMID:25815130

  1. Depolarization Alters Phenotype, Maintains Plasticity of Predifferentiated Mesenchymal Stem Cells

    PubMed Central

    Sundelacruz, Sarah; Levin, Michael

    2013-01-01

    Although adult stem cell transplantation has been implemented as a therapy for tissue repair, it is limited by the availability of functional adult stem cells. A potential approach to generate stem and progenitor cells may be to modulate the differentiated status of somatic cells. Therefore, there is a need for a better understanding of how the differentiated phenotype of mature cells is regulated. We hypothesize that bioelectric signaling plays an important role in the maintenance of the differentiated state, as it is a functional regulator of the differentiation process in various cells and tissues. In this study, we asked whether the mature phenotype of osteoblasts and adipocytes derived from human mesenchymal stem cells (hMSCs) could be altered by modulation of their membrane potential. hMSC-derived osteoblasts and adipocytes were depolarized by treatment with ouabain, a Na+/K+ ATPase inhibitor, or by treatment with high concentrations of extracellular K+. To characterize the effect of voltage modulation on the differentiated state, the depolarized cells were evaluated for (1) the loss of differentiation markers; (2) the up-regulation of stemness markers and stem properties; and (3) differences in gene expression profiles in response to voltage modulation. hMSC-derived osteoblasts and adipocytes exhibited significant down-regulation of bone and fat tissue markers in response to depolarization, despite the presence of differentiation-inducing soluble factors, suggesting that bioelectric signaling overrides biochemical signaling in the maintenance of cell state. Suppression of the osteoblast or adipocyte phenotype was not accompanied by up-regulation of genes associated with the stem state. Thus, depolarization does not activate the stem cell genetic signature and, therefore, does not induce a full reprogramming event. However, after transdifferentiating the depolarized cells to evaluate for multi-lineage potential, depolarized osteoblasts demonstrated improved

  2. Mesenchymal Stem Cell Fate: Applying Biomaterials for Control of Stem Cell Behavior

    PubMed Central

    Anderson, Hilary J.; Sahoo, Jugal Kishore; Ulijn, Rein V.; Dalby, Matthew J.

    2016-01-01

    The materials pipeline for biomaterials and tissue engineering applications is under continuous development. Specifically, there is great interest in the use of designed materials in the stem cell arena as materials can be used to manipulate the cells providing control of behavior. This is important as the ability to “engineer” complexity and subsequent in vitro growth of tissues and organs is a key objective for tissue engineers. This review will describe the nature of the materials strategies, both static and dynamic, and their influence specifically on mesenchymal stem cell fate. PMID:27242999

  3. Mesenchymal Stem Cell Fate: Applying Biomaterials for Control of Stem Cell Behavior.

    PubMed

    Anderson, Hilary J; Sahoo, Jugal Kishore; Ulijn, Rein V; Dalby, Matthew J

    2016-01-01

    The materials pipeline for biomaterials and tissue engineering applications is under continuous development. Specifically, there is great interest in the use of designed materials in the stem cell arena as materials can be used to manipulate the cells providing control of behavior. This is important as the ability to "engineer" complexity and subsequent in vitro growth of tissues and organs is a key objective for tissue engineers. This review will describe the nature of the materials strategies, both static and dynamic, and their influence specifically on mesenchymal stem cell fate. PMID:27242999

  4. [Bone and Stem Cells. The mechanism of osteogenic differentiation from mesenchymal stem cell].

    PubMed

    Ohata, Yasuhisa; Ozono, Keiichi

    2014-04-01

    Osteoblasts and osteocytes originate from pluripotent mesenchymal stem cells. Mesenchymal stem cells commit to osteogenic lineage and differentiate into mature osteoblasts and osteocytes through osteoprogenitor cells and preosteoblasts in response to multiple stimuli. The osteoblast commitment, differentiation, and functions are governed by several transcription factors. Among these transcription factors, runt-related transcription factor 2 (Runx2) is a crucial factor in osteoblast differentiation and controls bone formation. Differentiation toward these osteogenic lineage is controlled by a multitude of cytokines including WNTs, bone morphogenetic protein (BMP) , transforming growth factor-β (TGF-β) , hedgehog, parathyroid hormone (PTH) /parathyroid hormone related protein (PTHrP) , insulin-like growth factor-1 (IGF-1) , fibroblast growth factor (FGF) , and Notch. Although regulation of Runx2 activity is a point of convergence of many of the signal transduction routes, there is also a high degree of cross-talk between these pathways. Thus, the combined action of the signal transduction pathways induced by some cytokines determines the commitment and differentiation of mesenchymal stem cells toward the osteogenic lineage. PMID:24681495

  5. Induced pluripotent stem cell-derived mesenchymal stem cells: A leap toward personalized therapies.

    PubMed

    Whitt, Jason; Vallabhaneni, Krishna C; Penfornis, Patrice; Pochampally, Radhika

    2016-01-01

    Mesenchymal Stem/stromal cell (MSCs) transplantation procedures have been used since the 1960's to treat leukemia and other diseases, but due to the risks involved only patients with life threatening illnesses were typically subjected to the transplantation procedure until the last decade. Recent advancements in transplantation techniques have made it more feasible to use it for non-life-threatening diseases. However, the potential uses for stem cells are still limited by their rarity, and, in the case of allogeneic transplants, graft-vs.-host complications. An evolving alternative to conventional stem cell therapies is induced pluripotent stem-cell derived mesenchymal stem/stromal cells (iPSC- MSCs), which have a multi-lineage potential comparable to conventionally acquired MSCs with the added benefit of being less immunoreactive. However there are still many hurdles left to be overcome before they can be used regularly for personalized therapies. This review will focus on recent advancements that have been made regarding the role MSCs play in tumor development and the potential uses iPSC-MSCs may have in future cancer treatment. PMID:26423301

  6. Mesenchymal stem cells: potential application in intervertebral disc regeneration

    PubMed Central

    Shen, Bojiang; Williams, Lisa; Diwan, Ashish

    2014-01-01

    Chronic low back pain is one of the leading public health problems in developed countries. Degeneration of the intervertebral disc (IVD) is a major pathological process implicated in low back pain, which is characterized by cellular apoptosis and senescence with reduced synthesis of extracellular matrix (ECM). Currently, there is no clinical therapy targeting the reversal of disc degeneration. Recent advances in cellular and molecular biology have provided an exciting approach to disc regeneration that focuses on the delivery of viable cells to the degenerative disc. Adult mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal capacities and are able to differentiate into diverse specialized cell types, including chondrocyte lineages. The potential of stem cell therapy in disc degeneration is to repopulate the disc with viable cells capable of producing the ECM and restoring damaged tissue. The present literature review summarizes recent advances in basic research and clinical trials of MSCs to provide an outline of the key roles of MSCs therapies in disc repair. The review also discusses the controversies, challenges and therapeutic concepts for the future. PMID:26835326

  7. Paracrine effects of haematopoietic cells on human mesenchymal stem cells

    PubMed Central

    Zhou, Shuanhu

    2015-01-01

    Stem cell function decline during ageing can involve both cell intrinsic and extrinsic mechanisms. Bone and blood formation are intertwined in bone marrow, therefore haematopoietic cells and bone cells could be extrinsic factors for each other. In this study, we assessed the paracrine effects of extrinsic factors from haematopoietic cells on human mesenchymal stem cells (MSCs). Our data showed that haematopoietic cells stimulate proliferation, osteoblast differentiation and inhibit senescence of MSCs; TNF-α, PDGF-β, Wnt1, 4, 6, 7a and 10a, sFRP-3 and sFRP-5 are dominantly expressed in haematopoietic cells; the age-related increase of TNF-α in haematopoietic cells may perform as a negative factor in the interactions of haematopoietic cells on MSCs via TNF-α receptors and then activating NF-κB signaling or Wnt/β-catenin signaling to induce senescence and reduce osteoblast differentiation in MSCs. In conclusion, our data demonstrated that there are paracrine interactions of haematopoietic cells on human MSCs; immunosenescence may be one of the extrinsic mechanisms by which skeletal stem cell function decline during human skeletal ageing. PMID:26030407

  8. Human mesenchymal stem cells: New sojourn of bacterial pathogens.

    PubMed

    Kohli, Sakshi; Singh, Yadvir; Sowpati, Divya Tej; Ehtesham, Nasreen Z; Dobrindt, Ulrich; Hacker, Jörg; Hasnain, Seyed E

    2015-05-01

    Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), is the leading infectious disease which claims one human life every 15-20s globally. The persistence of this deadly disease in human population can be attributed to the ability of the bacterium to stay in latent form. M. tuberculosis possesses a plethora of mechanisms not only to survive latently under harsh conditions inside the host but also modulate the host immune cells in its favour. Various M. tuberculosis gene families have also been described to play a role in this process. Recently, human bone marrow derived mesenchymal stem cells (MSCs) have been reported as a niche for dormant M. tuberculosis. MSCs possess abilities to alter the host immune response. The bacterium finds this self-renewal and immune privileged nature of MSCs very favourable not only to modulate the host immune system, with some help from its own genes, but also to avoid the external drug pressure. We suggest that the MSCs not only provide a resting place for M. tuberculosis but could also, by virtue of their intrinsic ability to disseminate in the body, explain the genesis of extra-pulmonary TB. A similar exploitation of stem cells by other bacterial pathogens is a distinct possibility. It may be likely that other intracellular bacterial pathogens adopt this strategy to 'piggy-back' on to ovarian stem cells to ensure vertical transmission and successful propagation to the next generation. PMID:25648374

  9. Postnatal epithelium and mesenchyme stem/progenitor cells in bioengineered amelogenesis and dentinogenesis.

    PubMed

    Jiang, Nan; Zhou, Jian; Chen, Mo; Schiff, Michael D; Lee, Chang H; Kong, Kimi; Embree, Mildred C; Zhou, Yanheng; Mao, Jeremy J

    2014-02-01

    Rodent incisors provide a classic model for studying epithelial-mesenchymal interactions in development. However, postnatal stem/progenitor cells in rodent incisors have not been exploited for tooth regeneration. Here, we characterized postnatal rat incisor epithelium and mesenchyme stem/progenitor cells and found that they formed enamel- and dentin-like tissues in vivo. Epithelium and mesenchyme cells were harvested separately from the apical region of postnatal 4-5 day rat incisors. Epithelial and mesenchymal phenotypes were confirmed by immunocytochemistry, CFU assay and/or multi-lineage differentiation. CK14+, Sox2+ and Lgr5+ epithelium stem cells from the cervical loop enhanced amelogenin and ameloblastin expression upon BMP4 or FGF3 stimulation, signifying their differentiation towards ameloblast-like cells, whereas mesenchyme stem/progenitor cells upon BMP4, BMP7 and Wnt3a treatment robustly expressed Dspp, a hallmark of odontoblastic differentiation. We then control-released microencapsulated BMP4, BMP7 and Wnt3a in transplants of epithelium and mesenchyme stem/progenitor cells in the renal capsule of athymic mice in vivo. Enamel and dentin-like tissues were generated in two integrated layers with specific expression of amelogenin and ameloblastin in the newly formed, de novo enamel-like tissue, and DSP in dentin-like tissue. These findings suggest that postnatal epithelium and mesenchyme stem/progenitor cells can be primed towards bioengineered tooth regeneration. PMID:24345734

  10. Mesenchymal stem cells suppress CaN/NFAT expression in the pulmonary arteries of rats with pulmonary hypertension

    PubMed Central

    LIU, JUNFENG; HAN, ZHIBO; HAN, ZHONGCHAO; HE, ZHIXU

    2015-01-01

    Inflammation and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is considered the primary pathological feature of pulmonary hypertension (PH). The present study determined that mesenchymal stem cells (MSCs) suppress the expression of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT) in the pulmonary arteries of rats, and this may exert a therapeutic effect on PH. The potential therapeutic effects of MSCs on PH were assessed via the transplantation of human umbilical cord-derived MSCs, which were cultured in serum-free medium, into a monocrotaline (MCT)-induced PH rat model. Subsequently, the expression levels of tumor necrosis factor (TNF)-α in lung tissue and plasma, and of CaN and NFATc2 in pulmonary arteries were assessed. In the rat model of MCT-induced PH, investigated in the present study, TNF-α expression levels were detected in the lung tissue, and the levels of TNF-α in the plasma were increased. Furthermore, in addition to hemodynamic changes and the evident medial hypertrophy of the pulmonary muscular arterioles, CaN and NFATc2 expression levels were significantly upregulated in the pulmonary arteries. In the present study, the transplantation of MSCs, cultured in serum-free medium, decreased the levels of TNF-α in the lung tissue and plasma of rats, and downregulated CaN and NFATc2 expression in the pulmonary arteries. Furthermore, hemodynamic abnormalities and medial hypertrophy of the pulmonary muscular arterioles were notably improved. Therefore, the results of the present study may suggest that the administration of MSCs in PH may suppress the production of TNF-α, and downregulate the expression of CaN and NFATc2 in pulmonary arteries, which may provide an effective treatment for PH by suppressing the pathological proliferation of PASMCs. PMID:26640533

  11. Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction.

    PubMed

    Zhao, Liyan; Liu, Xiaolin; Zhang, Yuelin; Liang, Xiaoting; Ding, Yue; Xu, Yan; Fang, Zhen; Zhang, Fengxiang

    2016-05-15

    Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted into the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-Akt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease. PMID:27025401

  12. Time-Series Expression of Toll-Like Receptor 4 Signaling in Septic Mice Treated with Mesenchymal Stem Cells.

    PubMed

    Wu, Kang-Hsi; Wu, Han-Ping; Chao, Wan-Ru; Lo, Wei-Yu; Tseng, Pei-Chi; Lee, Chih-Jui; Peng, Ching-Tien; Lee, Maw-Sheng; Chao, Yu-Hua

    2016-06-01

    Sepsis remains an important cause of mortality worldwide, and early deaths resulting from overwhelming inflammation in septic patients have been reported. Vigorous immune reactions are beneficial for bacterial clearance in this circumstance but at the price of self-tissue damage. Mesenchymal stem cells (MSCs) have been found to modulate immune function and attenuate sepsis. As the Toll-like receptor 4 pathway plays an important role in response to infections, here we investigated the mechanisms of MSC-mediated immunomodulation by determining the expression of Toll-like receptor 4 signaling in the liver and by circulating cytokines at 0, 1, 2, 3, and 6 h after cecal ligation and puncture (CLP)-induced sepsis in mice. We found that administration of umbilical cord-derived MSCs (UCMSCs) was beneficial for survival. Six hours after CLP, UCMSC administration decreased the expression of MyD88 mRNA and protein in the liver tissues of the mice, and also the ratio of NFκB phosphorylation (P = 0.041 and 0.005, respectively). Serum levels of TNF-α, MCP-1, IFN-γ, and IL-6 were significantly lower and IL-10 significantly higher 6 h after CLP in the mice receiving UCMSCs compared with those receiving PBS only. Our study provides the first in vivo evidence for the association of the MyD88-NFκB pathway and MSC-mediated immunomodulation during sepsis. The immunomodulatory effect of UCMSCs was noted from 3 to 6 h after injection, and the MyD88-NFκB pathway played an important role in response to the immunomodulatory signals from UCMSCs. PMID:26682950

  13. Intestinal stem cells and epithelial-mesenchymal interactions in the crypt and stem cell niche

    PubMed Central

    Shaker, Anisa; Rubin, Deborah C.

    2010-01-01

    The intestinal epithelium contains a rapidly proliferating and perpetually differentiating epithelium. The principal functional unit of the small intestine is the crypt-villus axis. Stem cells located in the crypts of Lieberkühn give rise to proliferating progenitor or transit amplifying cells that differentiate into the four major epithelial cell types. The study of adult gastrointestinal tract stem cells has progressed rapidly with the recent discovery of a number of putative stem cell markers. Substantial evidence suggests that there are two populations of stem cells: long-term quiescent (reserved) and actively cycling (primed) stem cells. These are in adjoining locations and are presumably maintained by the secretion of specific proteins generated in a unique microenvironment or stem cell niche surrounding each population. The relationship between these two populations, and the cellular sources and composition of the surrounding environment remains to be defined, and is an active area of research. In this review we will outline progress in identifying stem cells and defining epithelial-mesenchymal interactions in the crypt. We will summarize early advances using stem cells for therapy of gastrointestinal disorders. PMID:20801415

  14. Osteogenic and adipogenic potential of porcine adipose mesenchymal stem cells.

    PubMed

    Qu, Chang-qing; Zhang, Guo-hua; Zhang, Li-jie; Yang, Gong-she

    2007-02-01

    Human, rat, and mouse studies have demonstrated the existence of a population of adipose mesenchymal stem cells (AMSCs) that can undergo multilineage differentiation in vitro. Understanding the clinical potential of AMSCs may require their use in preclinical large-animal models such as pigs. Thus, the objectives of this study were to establish a protocol for the isolation of porcine AMSCs from adipose tissue and to examine their ex vivo differentiation potential to adipocytes and osteoblast. The porcine AMSCs from passage 4 were selected for differentiation analysis. The adipocytes were identified morphologically by staining with Oil Red O, and the adipogenic marker genes were examined by RT-PCR technique. Osteogenic lineage was documented by deposition of calcium stained with Alzarin Red S, visualization of alkaline phosphatase activity, and expression of marker gene. Our result indicates that porcine AMSCs have been successfully isolated and induced differentiation into adipocytes and osteoblasts. This study suggested that porcine AMSCs are also a valuable model system for the study on the mesenchymal lineages for basic research and tissue engineering. PMID:17570023

  15. IL-17 Inhibits Chondrogenic Differentiation of Human Mesenchymal Stem Cells

    PubMed Central

    Kondo, Masahiro; Yamaoka, Kunihiro; Sonomoto, Koshiro; Fukuyo, Shunsuke; Oshita, Koichi; Okada, Yosuke; Tanaka, Yoshiya

    2013-01-01

    Objective Mesenchymal stem cells (MSCs) can differentiate into cells of mesenchymal lineages, such as osteoblasts and chondrocytes. Here we investigated the effects of IL-17, a key cytokine in chronic inflammation, on chondrogenic differentiation of human MSCs. Methods Human bone marrow MSCs were pellet cultured in chondrogenic induction medium containing TGF-β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression. Results Over-expression of cartilage matrix and chondrogenic marker genes was noted in chondrogenic cultures, but was inhibited by IL-17 in a dose-dependent manner. Expression and phosphorylation of SOX9, the master transcription factor for chondrogenesis, were induced within 2 days and phosphorylated SOX9 was stably maintained until day 21. IL-17 did not alter total SOX9 expression, but significantly suppressed SOX9 phosphorylation in a dose-dependent manner. At day 7, IL-17 also suppressed the activity of cAMP-dependent protein kinase A (PKA), which is known to phosphorylate SOX9. H89, a selective PKA inhibitor, also suppressed SOX9 phosphorylation, expression of chondrogenic markers and cartilage matrix, and also decreased chondrogenesis. Conclusions IL-17 inhibited chondrogenesis of human MSCs through the suppression of PKA activity and SOX9 phosphorylation. These results suggest that chondrogenic differentiation of MSCs can be inhibited by a mechanism triggered by IL-17 under chronic inflammation. PMID:24260226

  16. Therapeutic Potential of Mesenchymal Stem Cells in Regenerative Medicine

    PubMed Central

    Patel, Devang M.; Shah, Jainy; Srivastava, Anand S.

    2013-01-01

    Mesenchymal stem cells (MSCs) are stromal cells that have the ability to self-renew and also exhibit multilineage differentiation into both mesenchymal and nonmesenchymal lineages. The intrinsic properties of these cells make them an attractive candidate for clinical applications. MSCs are of keen interest because they can be isolated from a small aspirate of bone marrow or adipose tissues and can be easily expanded in vitro. Moreover, their ability to modulate immune responses makes them an even more attractive candidate for regenerative medicine as allogeneic transplant of these cells is feasible without a substantial risk of immune rejection. MSCs secrete various immunomodulatory molecules which provide a regenerative microenvironment for a variety of injured tissues or organ to limit the damage and to increase self-regulated tissue regeneration. Autologous/allogeneic MSCs delivered via the bloodstream augment the titers of MSCs that are drawn to sites of tissue injury and can accelerate the tissue repair process. MSCs are currently being tested for their potential use in cell and gene therapy for a number of human debilitating diseases and genetic disorders. This paper summarizes the current clinical and nonclinical data for the use of MSCs in tissue repair and potential therapeutic role in various diseases. PMID:23577036

  17. Mesenchymal stem cell-derived exosomes facilitate nasopharyngeal carcinoma progression

    PubMed Central

    Shi, Si; Zhang, Qicheng; Xia, Yunfei; You, Bo; Shan, Ying; Bao, Lili; Li, Li; You, Yiwen; Gu, Zhifeng

    2016-01-01

    Mesenchymal stem cells (MSCs), which are capable of differentiating into multiple cell types, are reported to exert multiple effects on tumor development. However, the relationship between MSCs and nasopharyngeal carcinoma (NPC) cells remains unclear. Exosomes are small membrane vesicles that can be released by several cell types, including MSCs. Exosomes, which can carry membrane and cytoplasmic constituents, have been described as participants in a novel mechanism of cell-to-cell communication. In the present study, we investigated the mechanisms underlying the interaction between MSCs and NPC cells. The data showed that MSCs secreted 40-100 nm heterogeneous small vesicles, which were defined as exosomes. Incubation of NPC cells with MSC-derived exosomes resulted in the uptake of exosomes by the cells, which promoted their proliferation, migration and tumorigenesis. After an extended treatment duration, the tumor cells showed morphological changes and significant changes in the expression of epithelial-mesenchymal transition (EMT) markers. Moreover, we found that FGF19 was highly expressed in MSC-exosomes and that exosomes stimulated NPC progression by activating the FGF19-FGFR4-dependent ERK signaling cascade and by modulating the EMT. All of these data indicated that exosomes participate in a novel mechanism by which MSCs influence NPC progression. PMID:27186416

  18. Mesenchymal stem cells protect from hypoxia-induced alveolar epithelial-mesenchymal transition.

    PubMed

    Uzunhan, Yurdagül; Bernard, Olivier; Marchant, Dominique; Dard, Nicolas; Vanneaux, Valérie; Larghero, Jérôme; Gille, Thomas; Clerici, Christine; Valeyre, Dominique; Nunes, Hilario; Boncoeur, Emilie; Planès, Carole

    2016-03-01

    Administration of bone marrow-derived human mesenchymal stem cells (hMSC) reduces lung inflammation, fibrosis, and mortality in animal models of lung injury, by a mechanism not completely understood. We investigated whether hMSC would prevent epithelial-mesenchymal transition (EMT) induced by hypoxia in primary rat alveolar epithelial cell (AEC). In AEC cultured on semipermeable filters, prolonged hypoxic exposure (1.5% O2 for up to 12 days) induced phenotypic changes consistent with EMT, i.e., a change in cell morphology, a decrease in transepithelial resistance (Rte) and in the expression of epithelial markers [zonula occludens-1 (ZO-1), E-cadherin, AQP-5, TTF-1], together with an increase in mesenchymal markers [vimentin, α-smooth muscle actin (α-SMA)]. Expression of transcription factors driving EMT such as SNAIL1, ZEB1, and TWIST1 increased after 2, 24, and 48 h of hypoxia, respectively. Hypoxia also induced TGF-β1 mRNA expression and the secretion of active TGF-β1 in apical medium, and the expression of connective tissue growth factor (CTGF), two inducers of EMT. Coculture of AEC with hMSC partially prevented the decrease in Rte and in ZO-1, E-cadherin, and TTF-1 expression, and the increase in vimentin expression induced by hypoxia. It also abolished the increase in TGF-β1 expression and in TGF-β1-induced genes ZEB1, TWIST1, and CTGF. Finally, incubation with human recombinant KGF at a concentration similar to what was measured in hMSC-conditioned media restored the expression of TTF-1 and prevented the increase in TWIST1, TGF-β1, and CTGF in hypoxic AEC. Our results indicate that hMSC prevent hypoxia-induced alveolar EMT through the paracrine modulation of EMT signaling pathways and suggest that this effect is partly mediated by KGF. PMID:26702148

  19. Immunomodulatory functions of mesenchymal stem cells and possible mechanisms.

    PubMed

    Wang, Qing; Ding, Gang; Xu, Xin

    2016-09-01

    In addition to their well-studied self-renewal capabilities and multipotent differentiation properties, mesenchymal stem cells (MSCs) have been reported to possess profound immunomodulatory functions both in vitro and in vivo. More and more studies have shown that MSCs are capable of interacting closely with almost all subsets of immune cells, such as T cells, B cells, dendritic cells, natural killer cells, macrophages, and neutrophils etc. The immunomodulatory property of MSCs may shed light on the treatment of a variety of autoimmune and inflammation-related diseases. In this article, we will review the studies on the immunomodulatory and anti-inflammatory functions of MSCs and the mechanisms responsible for the interaction between immune cells and MSCs, which could improve the development of promising approaches for cell-mediated immune therapies. PMID:26932157

  20. The Modulatory Effects of Mesenchymal Stem Cells on Osteoclastogenesis

    PubMed Central

    Sharaf-Eldin, Wessam E.; Abu-Shahba, Nourhan; Mahmoud, Marwa; El-Badri, Nagwa

    2016-01-01

    The effect of mesenchymal stem cells (MSCs) on bone formation has been extensively demonstrated through several in vitro and in vivo studies. However, few studies addressed the effect of MSCs on osteoclastogenesis and bone resorption. Under physiological conditions, MSCs support osteoclastogenesis through producing the main osteoclastogenic cytokines, RANKL and M-CSF. However, during inflammation, MSCs suppress osteoclast formation and activity, partly via secretion of the key anti-osteoclastogenic factor, osteoprotegerin (OPG). In vitro, co-culture of MSCs with osteoclasts in the presence of high concentrations of osteoclast-inducing factors might reflect the in vivo inflammatory pathology and prompt MSCs to exert an osteoclastogenic suppressive effect. MSCs thus seem to have a dual effect, by stimulating or inhibiting osteoclastogenesis, depending on the inflammatory milieu. This effect of MSCs on osteoclast formation seems to mirror the effect of MSCs on other immune cells, and may be exploited for the therapeutic potential of MSCs in bone loss associated inflammatory diseases. PMID:26823668

  1. VEGF improves survival of mesenchymal stem cells in infarcted hearts

    SciTech Connect

    Pons, Jennifer; Huang Yu; Arakawa-Hoyt, Janice; Washko, Daniel; Takagawa, Junya; Ye, Jianqin; Grossman, William; Su Hua

    2008-11-14

    Bone marrow-derived mesenchymal stem cells (MSC) are a promising source for cell-based treatment of myocardial infarction (MI), but existing strategies are restricted by low cell survival and engraftment. We examined whether vascular endothelial growth factor (VEGF) improve MSC viability in infracted hearts. We found long-term culture increased MSC-cellular stress: expressing more cell cycle inhibitors, p16{sup INK}, p21 and p19{sup ARF}. VEGF treatment reduced cellular stress, increased pro-survival factors, phosphorylated-Akt and Bcl-xL expression and cell proliferation. Co-injection of MSCs with VEGF to MI hearts increased cell engraftment and resulted in better improvement of cardiac function than that injected with MSCs or VEGF alone. In conclusion, VEGF protects MSCs from culture-induce cellular stress and improves their viability in ischemic myocardium, which results in improvements of their therapeutic effect for the treatment of MI.

  2. Proangiogenic Features of Mesenchymal Stem Cells and Their Therapeutic Applications

    PubMed Central

    Tao, Hongyan; Han, Zhibo; Han, Zhong Chao; Li, Zongjin

    2016-01-01

    Mesenchymal stem cells (MSCs) have shown their therapeutic potency for treatment of cardiovascular diseases owing to their low immunogenicity, ease of isolation and expansion, and multipotency. As multipotent progenitors, MSCs have revealed their ability to differentiate into various cell types and could promote endogenous angiogenesis via microenvironmental modulation. Studies on cardiovascular diseases have demonstrated that transplanted MSCs could engraft at the injured sites and differentiate into cardiomyocytes and endothelial cells as well. Accordingly, several clinical trials using MSCs have been performed and revealed that MSCs may improve relevant clinical parameters in patients with vascular diseases. To fully comprehend the characteristics of MSCs, understanding their intrinsic property and associated modulations in tuning their behaviors as well as functions is indispensable for future clinical translation of MSC therapy. This review will focus on recent progresses on endothelial differentiation and potential clinical application of MSCs, with emphasis on therapeutic angiogenesis for treatment of cardiovascular diseases. PMID:26880933

  3. Separation of Mesenchymal Stem Cells Through a Strategic Centrifugation Protocol.

    PubMed

    Ferlin, Kimberly M; Kaplan, David S; Fisher, John P

    2016-04-01

    Despite great promise surrounding mesenchymal stem cells (MSCs), their implementation for tissue engineering strategies remains in the development phases. Many of the concerns regarding the clinical use of MSCs originate from population heterogeneity, during both isolation and differentiation. In this study, we utilize our previously developed centrifugation cell adhesion protocol for the separation of MSCs. Our findings reveal that MSCs can be isolated from whole bone marrow using a 200 g (700 pN) centrifugal force after 24 h of culture on polystyrene with cell surface marker expression equivalent to positive controls. During differentiation, a centrifugation protocol with identical force parameters could be applied 14 days into chondrogenic differentiation to isolate differentiated chondrocytes, which exhibited increased expression of chondrogenic markers compared to controls. In summary, the use of our developed centrifugation cell adhesion protocol has proven to be an effective means to separate MSC populations, decreasing the heterogeneity of subsequent cell therapy products. PMID:26797048

  4. Mesenchymal stem cells: immune evasive, not immune privileged

    PubMed Central

    Ankrum, James A.; Ong, Joon Faii; Karp, Jeffrey M.

    2014-01-01

    The diverse immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) may be exploited for treatment of a multitude of inflammatory conditions. MSCs have long been reported to be hypoimmunogenic or ‘immune privileged’; this property is thought to enable MSC transplantation across major histocompatibility barriers and the creation of off-the-shelf therapies consisting of MSCs grown in culture. However, recent studies describing generation of antibodies against and immune rejection of allogeneic donor MSCs suggest that MSCs may not actually be immune privileged. Nevertheless, whether rejection of donor MSCs influences the efficacy of allogeneic MSC therapies is not known, and no definitive clinical advantage of autologous MSCs over allogeneic MSCs has been demonstrated to date. Although MSCs may exert therapeutic function through a brief ‘hit and run’ mechanism, protecting MSCs from immune detection and prolonging their persistence in vivo may improve clinical outcomes and prevent patient sensitization toward donor antigens. PMID:24561556

  5. [Immunomodulatory properties of stem mesenchymal cells in autoimmune diseases].

    PubMed

    Sánchez-Berná, Isabel; Santiago-Díaz, Carlos; Jiménez-Alonso, Juan

    2015-01-20

    Autoimmune diseases are a cluster of disorders characterized by a failure of the immune tolerance and a hyperactivation of the immune system that leads to a chronic inflammation state and the damage of several organs. The medications currently used to treat these diseases usually consist of immunosuppressive drugs that have significant systemic toxic effects and are associated with an increased risk of opportunistic infections. Recently, several studies have demonstrated that mesenchymal stem cells have immunomodulatory properties, a feature that make them candidates to be used in the treatment of autoimmune diseases. In the present study, we reviewed the role of this therapy in the treatment of systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Crohn's disease and multiple sclerosis, as well as the potential risks associated with its use. PMID:24636281

  6. Flexible polymeric ultrathin film for mesenchymal stem cell differentiation.

    PubMed

    Pensabene, Virginia; Taccola, Silvia; Ricotti, Leonardo; Ciofani, Gianni; Menciassi, Arianna; Perut, Francesca; Salerno, Manuela; Dario, Paolo; Baldini, Nicola

    2011-07-01

    Ultrathin films (also called nanofilms) are two-dimensional (2-D) polymeric structures with potential application in biology, biotechnology, cosmetics and tissue engineering. Since they can be handled in liquid form with micropipettes or tweezers they have been proposed as flexible systems for cell adhesion and proliferation. In particular, with the aim of designing a novel patch for bone or tendon repair and healing, in this work the biocompatibility, adhesion and proliferation activity of Saos-2, MRC-5 and human and rat mesenchymal stem cells on poly(lactic acid) nanofilms were evaluated. The nanofilms did not impair the growth and differentiation of osteoblasts and chondrocytes. Moreover, nanofilm adhesion to rabbit joints was evident under ex vivo conditions. PMID:21421086

  7. Mesenchymal Stem Cells after Polytrauma: Actor and Target

    PubMed Central

    Wiegner, Rebecca; Lampl, Lorenz; Brenner, Rolf E.

    2016-01-01

    Mesenchymal stem cells (MSCs) are multipotent cells that are considered indispensable in regeneration processes after tissue trauma. MSCs are recruited to damaged areas via several chemoattractant pathways where they function as “actors” in the healing process by the secretion of manifold pro- and anti-inflammatory, antimicrobial, pro- and anticoagulatory, and trophic/angiogenic factors, but also by proliferation and differentiation into the required cells. On the other hand, MSCs represent “targets” during the pathophysiological conditions after severe trauma, when excessively generated inflammatory mediators, complement activation factors, and damage- and pathogen-associated molecular patterns challenge MSCs and alter their functionality. This in turn leads to complement opsonization, lysis, clearance by macrophages, and reduced migratory and regenerative abilities which culminate in impaired tissue repair. We summarize relevant cellular and signaling mechanisms and provide an up-to-date overview about promising future therapeutic MSC strategies in the context of severe tissue trauma. PMID:27340408

  8. Secretome From Mesenchymal Stem Cells Induces Angiogenesis Via Cyr61

    PubMed Central

    ESTRADA, ROSENDO; LI, NA; SAROJINI, HARSHINI; AN, JIN; LEE, MENQ-JER; WANG, EUGENIA

    2010-01-01

    It is well known that bone marrow-derived mesenchymal stem cells (MSCs) are involved in wound healing and regeneration responses. In this study, we globally profiled the proteome of MSCs to investigate critical factor(s) that may promote wound healing. Cysteine-rich protein 61 (Cyr61) was found to be abundantly present in MSCs. The presence of Cyr61 was confirmed by immunofluorescence staining and immunoblot analysis. Moreover, we showed that Cyr61 is present in the culture medium (secretome) of MSCs. The secretome of MSCs stimulates angiogenic response in vitro, and neovascularization in vivo. Depletion of Cyr61 completely abrogates the angiogenic-inducing capability of the MSC secretome. Importantly, addition of recombinant Cyr61 polypeptides restores the angiogenic activity of Cyr61-depleted secretome. Collectively, these data demonstrate that Cyr61 polypeptide in MSC secretome contributes to the angiogenesis-promoting activity, a key event needed for regeneration and repair of injured tissues. PMID:19170074

  9. Adult Mesenchymal Stem Cells: When, Where, and How

    PubMed Central

    Caplan, Arnold I.

    2015-01-01

    Adult mesenchymal stem cells (MSCs) have profound medicinal effects at body sites of tissue injury, disease, or inflammation as either endogenously or exogenously supplied. The medicinal effects are either immunomodulatory or trophic or both. When to deliver these mediators of regeneration, where, and by what delivery apparatus or mechanism will directly determine their medical efficacy. The MSCs help manage the innate regenerative capacity of almost every body tissue and the MSCs have only recently been fully appreciated. Perhaps the most skilled physician-manager of the body's innate regenerative capacity is in orthopedics where the vigorous regeneration and repair capacity of bone through local MSCs-titers is expertly managed by the orthopaedic physician. The challenge is to extend MSCs expertise to address other tissue dysfunctions and diseases. The medicine of tomorrow will encompass optimizing the tissues' intrinsic regenerative potential through management of local MSCs. PMID:26273305

  10. Mesenchymal Stem Cells after Polytrauma: Actor and Target.

    PubMed

    Huber-Lang, Markus; Wiegner, Rebecca; Lampl, Lorenz; Brenner, Rolf E

    2016-01-01

    Mesenchymal stem cells (MSCs) are multipotent cells that are considered indispensable in regeneration processes after tissue trauma. MSCs are recruited to damaged areas via several chemoattractant pathways where they function as "actors" in the healing process by the secretion of manifold pro- and anti-inflammatory, antimicrobial, pro- and anticoagulatory, and trophic/angiogenic factors, but also by proliferation and differentiation into the required cells. On the other hand, MSCs represent "targets" during the pathophysiological conditions after severe trauma, when excessively generated inflammatory mediators, complement activation factors, and damage- and pathogen-associated molecular patterns challenge MSCs and alter their functionality. This in turn leads to complement opsonization, lysis, clearance by macrophages, and reduced migratory and regenerative abilities which culminate in impaired tissue repair. We summarize relevant cellular and signaling mechanisms and provide an up-to-date overview about promising future therapeutic MSC strategies in the context of severe tissue trauma. PMID:27340408

  11. Prenatal transplantation of mesenchymal stem cells to treat osteogenesis imperfecta

    PubMed Central

    Chan, Jerry K. Y.; Götherström, Cecilia

    2014-01-01

    Osteogenesis imperfecta (OI) can be a severe disorder that can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure, growth, and fracture healing. In this review, we give an introduction to OI and MSC, and the basis for pre- and postnatal transplantation in OI. We also summarize the two patients with OI who have received pre- and postnatal transplantation of MSC. The findings suggest that prenatal transplantation of allogeneic MSC in OI is safe. The cell therapy is of likely clinical benefit with improved linear growth, mobility, and reduced fracture incidence. Unfortunately, the effect is transient. For this reason, postnatal booster infusions using same-donor MSC have been performed with clinical benefit, and without any adverse events. So far there is limited experience in this specific field and proper studies are required to accurately conclude on clinical benefits of MSC transplantation to treat OI. PMID:25346689

  12. Mesenchymal stem cells are highly resistant to sulfur mustard.

    PubMed

    Schmidt, Annette; Scherer, Michael; Thiermann, Horst; Steinritz, Dirk

    2013-12-01

    The effect of sulfur mustard (SM) to the direct injured tissues of the skin, eyes and airways is well investigated. Little is known about the effect of SM to mesenchymal stem cells (MSC). However, this is an interesting aspect. Comparing the clinical picture of SM it is known today that MSC play an important role e.g. in chronic impaired wound healing. Therefore we wanted to get an understanding about how SM affects MSC and if these findings might become useful to get a better understanding of the effect of sulfur mustard gas with respect to skin wounds. We used mesenchymal stem cells, isolated from femoral heads from healthy donors and treated them with a wide range of SM to ascertain the dose-response-curve. With the determined inhibitory concentrations IC1 (1μM), IC5 (10μM), IC10 (20μM) and IC25 (40μM) we did further investigations. We analyzed the migratory ability and the differentiation capacity under influence of SM. Already very low concentrations of SM demonstrated a strong effect to the migratory activity whereas the differentiation capacity seemed not to be affected. Putting these findings together it seems to be likely that a link between MSC and the impaired wound healing after SM exposure might exist. Same as in patients with chronic impaired wound healing MSC had shown a reduced migratory activity. The fact that MSC are able to tolerate very high concentrations of SM and still do not lose their differentiation capacity may reveal new ways of treating wounds caused by sulfur mustard. PMID:23933411

  13. Generation of induced pluripotent stem cells from human mesenchymal stem cells of parotid gland origin

    PubMed Central

    Yan, Xing; Xu, Nuo; Meng, Cen; Wang, Bianhong; Yuan, Jinghong; Wang, Caiyun; Li, Yang

    2016-01-01

    The technology to reprogram human somatic cells to pluripotent state allows the generation of patient-specific induced pluripotent stem cells (iPSCs) and holds a great promise for regenerative medicine and autologous transplantation. Here we, for the first time, identified mesenchymal stem cells isolated from parotid gland (hPMSCs) as a suitable candidate for iPSC production. In the present study, hPMSCs were isolated from parotid gland specimens in patients with squamous cell carcinoma of the oral cavity. The mesenchymal stem cell properties of cultured hPMSCs were confirmed by expression of surface markers and induced differentiation into osteogenic, chondrogenic and adipogenic cell lineages. hPMSCs were then reprogrammed to pluripotent cells by episomal vector-mediated transduction of reprogramming factors (OCT3/4, SOX2, KLF4, c-MYC, LIN28 and TP53 shRNA). The resulting hPMSC-iPSCs showed similar characteristics as human embryonic stem cells (ESCs) with regard to morphology, pluripotent markers, global gene expression, and methylation status of pluripotent cell-specific genes OCT4 and NANOG. These hPMSC-iPSCs were able to differentiate into cells of all three germ layers both in vitro and in vivo. Our results indicate that hPMSCs could be an alternative cell source for generation of iPSCs and have the potential to be used in cell-based regenerative medicine. PMID:27158336

  14. Citalopram increases the differentiation efficacy of bone marrow mesenchymal stem cells into neuronal-like cells

    PubMed Central

    Verdi, Javad; Mortazavi-Tabatabaei, Seyed Abdolreza; Sharif, Shiva; Verdi, Hadi; Shoae-Hassani, Alireza

    2014-01-01

    Several studies have demonstrated that selective serotonin reuptake inhibitor antidepressants can promote neuronal cell proliferation and enhance neuroplasticity both in vitro and in vivo. It is hypothesized that citalopram, a selective serotonin reuptake inhibitor, can promote the neuronal differentiation of adult bone marrow mesenchymal stem cells. Citalopram strongly enhanced neuronal characteristics of the cells derived from bone marrow mesenchymal stem cells. The rate of cell death was decreased in citalopram-treated bone marrow mesenchymal stem cells than in control cells in neurobasal medium. In addition, the cumulative population doubling level of the citalopram-treated cells was significantly increased compared to that of control cells. Also BrdU incorporation was elevated in citalopram-treated cells. These findings suggest that citalopram can improve the neuronal-like cell differentiation of bone marrow mesenchymal stem cells by increasing cell proliferation and survival while maintaining their neuronal characteristics. PMID:25206899

  15. Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell.

    PubMed

    Inamdar, Ajinkya C; Inamdar, Arati A

    2013-10-01

    Lung disorders such as asthma, acute respiratory distress syndrome (ARDS), chronic obstructive lung disease (COPD), and interstitial lung disease (ILD) show a few common threads of pathogenic mechanisms: inflammation, aberrant immune activity, infection, and fibrosis. Currently no modes of effective treatment are available for ILD or emphysema. Being anti-inflammatory, immunomodulatory, and regenerative in nature, the administration of mesenchymal stem cells (MSCs) has shown the capacity to control immune dysfunction and inflammation in the lung. The intravenous infusion of MSCs, the common mode of delivery, is followed by their entrapment in lung vasculature before MSCs reach to other organ systems thus indicating the feasible and promising approach of MSCs therapy for lung diseases. In this review, we discuss the mechanistic basis for MSCs therapy for asthma, ARDS, COPD, and ILD. PMID:23992090

  16. Eccentric exercise facilitates mesenchymal stem cell appearance in skeletal muscle.

    PubMed

    Valero, M Carmen; Huntsman, Heather D; Liu, Jianming; Zou, Kai; Boppart, Marni D

    2012-01-01

    Eccentric, or lengthening, contractions result in injury and subsequently stimulate the activation and proliferation of satellite stem cells which are important for skeletal muscle regeneration. The discovery of alternative myogenic progenitors in skeletal muscle raises the question as to whether stem cells other than satellite cells accumulate in muscle in response to exercise and contribute to post-exercise repair and/or growth. In this study, stem cell antigen-1 (Sca-1) positive, non-hematopoetic (CD45⁻) cells were evaluated in wild type (WT) and α7 integrin transgenic (α7Tg) mouse muscle, which is resistant to injury yet liable to strain, 24 hr following a single bout of eccentric exercise. Sca-1⁺CD45⁻ stem cells were increased 2-fold in WT muscle post-exercise. The α7 integrin regulated the presence of Sca-1⁺ cells, with expansion occurring in α7Tg muscle and minimal cells present in muscle lacking the α7 integrin. Sca-1⁺CD45⁻ cells isolated from α7Tg muscle following exercise were characterized as mesenchymal-like stem cells (mMSCs), predominantly pericytes. In vitro multiaxial strain upregulated mMSC stem cells markers in the presence of laminin, but not gelatin, identifying a potential mechanistic basis for the accumulation of these cells in muscle following exercise. Transplantation of DiI-labeled mMSCs into WT muscle increased Pax7⁺ cells and facilitated formation of eMHC⁺DiI⁻ fibers. This study provides the first demonstration that mMSCs rapidly appear in skeletal muscle in an α7 integrin dependent manner post-exercise, revealing an early event that may be necessary for effective repair and/or growth following exercise. The results from this study also support a role for the α7 integrin and/or mMSCs in molecular- and cellular-based therapeutic strategies that can effectively combat disuse muscle atrophy. PMID:22253772

  17. Mesenchymal Stem Cells as Cellular Vectors for Pediatric Neurological Disorders

    PubMed Central

    Phinney, Donald G.; Isakova, Iryna A.

    2014-01-01

    Lysosomal storage diseases are a heterogeneous group of hereditary disorders characterized by a deficiency in lysosomal function. Although these disorders differ in their etiology and phenotype those that affect the nervous system generally manifest as a profound deterioration in neurologic function with age. Over the past several decades implementation of various treatment regimens including bone marrow and cord blood cell transplantation, enzyme replacement, and substrate reduction therapy have proved effective for managing some clinical manifestations of these diseases but their ability to ameliorate neurologic complications remains unclear. Consequently, there exists a need to develop alternative therapies that more effectively target the central nervous system. Recently, direct intracranial transplantation of tissue-specific stem and progenitor cells has been explored as a means to reconstitute metabolic deficiencies in the CNS. In this chapter we discuss the merits of bone marrow-derived mesenchymal stem cells (MSCs) for this purpose. Originally identified as progenitors of connective tissue cell lineages, recent findings have revealed several novel aspects of MSC biology that make them attractive as therapeutic agents in the CNS. We relate these advances in MSC biology to their utility as cellular vectors for treating neurologic sequelae associated with pediatric neurologic disorders. PMID:24858930

  18. Aging alters tissue resident mesenchymal stem cell properties.

    PubMed

    Alt, Eckhard U; Senst, Christiane; Murthy, Subramanyam N; Slakey, Douglas P; Dupin, Charles L; Chaffin, Abigail E; Kadowitz, Philip J; Izadpanah, Reza

    2012-03-01

    Tissue resident mesenchymal stem cells (MSCs) are known to participate in tissue regeneration that follows cell turnover, apoptosis, or necrosis. It has been long known that aging impedes an organism's repair/regeneration capabilities. In order to study the age associated changes, the molecular characteristics of adipose tissue derived MSCs (ASCs) from three age groups of healthy volunteers, i.e., young, middle aged, and aged were investigated. The number and multilineage differentiation potential of ASCs declined with age. Aging reduces the proliferative capacity along with increases in cellular senescence. A significant increase in quiescence of G2 and S phase was observed in ASCs from aged donors. The expression of genes related to senescence such as CHEK1 and cyclin-dependent kinase inhibitor p16(ink4a) was increased with age, however genes of apoptosis were downregulated. Further, an age-dependent abnormality in the expression of DNA break repair genes was observed. Global microRNA analysis revealed an abnormal expression of mir-27b, mir-106a, mir-199a, and let-7. In ubiquitously distributed adipose tissue (and ASCs), aging brings about important alterations, which might be critical for tissue regeneration and homeostasis. Our findings therefore provide a better understanding of the mechanism(s) involved in stem cell aging and regenerative potential, and this in turn may affect tissue repair that declines with aging. PMID:22265741

  19. Epac Activation Regulates Human Mesenchymal Stem Cells Migration and Adhesion.

    PubMed

    Yu, Jiao-Le; Deng, Ruixia; Chung, Sookja K; Chan, Godfrey Chi-Fung

    2016-04-01

    How to enhance the homing of human mesenchymal stem cells (hMSCs) to the target tissues remains a clinical challenge nowadays. To overcome this barrier, the mechanism responsible for the hMSCs migration and engraftment has to be defined. Currently, the exact mechanism involved in migration and adhesion of hMSCs remains unknown. Exchange protein directly activated by cAMP (Epac), a novel protein discovered in cAMP signaling pathway, may have a potential role in regulating cells adhesion and migration by triggering the downstream Rap family signaling cascades. However, the exact role of Epac in cells homing is elusive. Our study evaluated the role of Epac in the homing of hMSCs. We confirmed that hMSCs expressed functional Epac and its activation enhanced the migration and adhesion of hMSCs significantly. The Epac activation was further found to be contributed directly to the chemotactic responses induced by stromal cell derived factor-1 (SDF-1) which is a known chemokine in regulating hMSCs homing. These findings suggested Epac is connected to the SDF-1 signaling cascades. In conclusion, our study revealed that Epac plays a role in hMSCs homing by promoting adhesion and migration. Appropriate manipulation of Epac may enhance the homing of hMSCs and facilitate their future clinical applications. Stem Cells 2016;34:948-959. PMID:26727165

  20. Mesenchymal Stem Cells Derived from Dental Pulp: A Review

    PubMed Central

    Santiago-Osorio, Edelmiro

    2016-01-01

    The mesenchymal stem cells of dental pulp (DPSCs) were isolated and characterized for the first time more than a decade ago as highly clonogenic cells that were able to generate densely calcified colonies. Now, DPSCs are considered to have potential as stem cell source for orthopedic and oral maxillofacial reconstruction, and it has been suggested that they may have applications beyond the scope of the stomatognathic system. To date, most studies have shown that, regardless of their origin in third molars, incisors, or exfoliated deciduous teeth, DPSCs can generate mineralized tissue, an extracellular matrix and structures type dentin, periodontal ligament, and dental pulp, as well as other structures. Different groups worldwide have designed and evaluated new efficient protocols for the isolation, expansion, and maintenance of clinically safe human DPSCs in sufficient numbers for various therapeutics protocols and have discussed the most appropriate route of administration, the possible contraindications to their clinical use, and the parameters to be considered for monitoring their clinical efficacy and proper biological source. At present, DPSC-based therapy is promising but because most of the available evidence was obtained using nonhuman xenotransplants, it is not a mature technology. PMID:26779263

  1. Clinical Applications of Mesenchymal Stem Cells in Laryngotracheal Reconstruction

    PubMed Central

    Hanson, Summer; Thibeault, Susan L.; Hematti, Peiman

    2011-01-01

    Abstract / Summary During the past several years, mesenchymal stem cells (MSCs) derived from adult tissue have rapidly moved from in vitro and animal studies into clinical trials as a therapeutic modality for a diverse group of clinical applications, including head and neck reconstruction. For many diseases, cell therapy could affect the underlying pathophysiologic processes through multiple pathways providing an advantage over current treatment modalities. There is an emerging body of evidence that MSCs have unique immunomodulatory properties in addition to the ability to differentiate into multiple tissue lineages which make them even more attractive for regenerative medicine. A variety of pre-clinical and clinical studies have shown that MSCs may have a useful role in tissue repair as well as engineering strategies in head and neck reconstructive surgery. Clinically, this has ranged from injection laryngoplasty to the implantation of a tracheal construct seeded with MSC-derived chondrocytes. Recent advances in stem cell immunobiology can offer insight to the multiple mechanisms through which MSCs could affect underlying pathophysiologic processes ranging from vocal fold scarring to composite tissue defects. Thorough evaluation of the current literature is necessary in understanding how MSCs could potentially revolutionize our approach to head and neck defects. The purpose of this review is to highlight the advances in MSC-based therapies in head and neck surgery, specifically laryngotracheal reconstruction. The clinical role of tissue-derived MSCs, though not well understood, holds promise for many therapeutic applications in regenerative medicine and reconstruction. PMID:19951250

  2. Clinical Applications of Mesenchymal Stem Cells in Chronic Diseases

    PubMed Central

    Sitzia, Clementina; Erratico, Silvia; Torrente, Yvan

    2014-01-01

    Extraordinary progress in understanding several key features of stem cells has been made in the last ten years, including definition of the niche, and identification of signals regulating mobilization and homing as well as partial understanding of the mechanisms controlling self-renewal, commitment, and differentiation. This progress produced invaluable tools for the development of rational cell therapy protocols that have yielded positive results in preclinical models of genetic and acquired diseases and, in several cases, have entered clinical experimentation with positive outcome. Adult mesenchymal stem cells (MSCs) are nonhematopoietic cells with multilineage potential to differentiate into various tissues of mesodermal origin. They can be isolated from bone marrow and other tissues and have the capacity to extensively proliferate in vitro. Moreover, MSCs have also been shown to produce anti-inflammatory molecules which can modulate humoral and cellular immune responses. Considering their regenerative potential and immunoregulatory effect, MSC therapy is a promising tool in the treatment of degenerative, inflammatory, and autoimmune diseases. It is obvious that much work remains to be done to increase our knowledge of the mechanisms regulating development, homeostasis, and tissue repair and thus to provide new tools to implement the efficacy of cell therapy trials. PMID:24876848

  3. Mesenchymal Stem Cells Derived from Dental Pulp: A Review.

    PubMed

    Ledesma-Martínez, Edgar; Mendoza-Núñez, Víctor Manuel; Santiago-Osorio, Edelmiro

    2016-01-01

    The mesenchymal stem cells of dental pulp (DPSCs) were isolated and characterized for the first time more than a decade ago as highly clonogenic cells that were able to generate densely calcified colonies. Now, DPSCs are considered to have potential as stem cell source for orthopedic and oral maxillofacial reconstruction, and it has been suggested that they may have applications beyond the scope of the stomatognathic system. To date, most studies have shown that, regardless of their origin in third molars, incisors, or exfoliated deciduous teeth, DPSCs can generate mineralized tissue, an extracellular matrix and structures type dentin, periodontal ligament, and dental pulp, as well as other structures. Different groups worldwide have designed and evaluated new efficient protocols for the isolation, expansion, and maintenance of clinically safe human DPSCs in sufficient numbers for various therapeutics protocols and have discussed the most appropriate route of administration, the possible contraindications to their clinical use, and the parameters to be considered for monitoring their clinical efficacy and proper biological source. At present, DPSC-based therapy is promising but because most of the available evidence was obtained using nonhuman xenotransplants, it is not a mature technology. PMID:26779263

  4. Impairment of mesenchymal stem cells derived from oral leukoplakia

    PubMed Central

    Zhang, Zhihui; Song, Jiangyuan; Han, Ying; Mu, Dongdong; Su, Sha; Ji, Xiaoli; Liu, Hongwei

    2015-01-01

    Oral leukoplakia is one of the common precancerous lesions in oral mucosa. To compare the biological characteristics and regenerative capacities of mesenchymal stem cells (MSCs) from oral leukoplakia (epithelial hyperplasia and dysplasia) and normal oral mucosa, MSCs were isolated by enzyme digestion. Then these cells were identified by the expression of MSC related markers, STRO-1, CD105 and CD90, with the absent for the hematopoietic stem cell marker CD34 by flow cytometric detection. The self-renewal ability of MSCs from oral leukoplakia was enhanced, while the multipotent differentiation was descended, compared with MSCs from normal oral mucosa. Fibrin gel was used as a carrier for MSCs transplanted into immunocompromised mice to detect their regenerative capacity. The regenerative capacities of MSCs from oral leukoplakia became impaired partly. Collagen IV (Col IV) and matrix metalloproteinases-9 (MMP-9) were selected to analyze the potential mechanism for the functional changes of MSCs from oral leukoplakia by immunochemical and western blot analysis. The expression of Col IV was decreased and that of MMP-9 was increased by MSCs with the progression of oral leukoplakia, especially in MSCs from epithelial dysplasia. The imbalance between regenerative and metabolic self-regulatory functions of MSCs from oral leukoplakia may be related to the progression of this premalignant disorder. PMID:26617710

  5. Mesenchymal stem cell therapy for cirrhosis: Present and future perspectives.

    PubMed

    Eom, Young Woo; Kim, Gaeun; Baik, Soon Koo

    2015-09-28

    Cirrhosis occurs as a result of various chronic liver injuries, which may be caused by viral infections, alcohol abuse and the administration of drugs and chemicals. Recently, bone marrow cells (BMCs), hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) have been used for developing treatments for cirrhosis. Clinical trials have investigated the therapeutic potential of BMCs, HSCs and MSCs for the treatment of cirrhosis based on their potential to differentiate into hepatocytes. Although the therapeutic mechanisms of BMC, HSC and MSC treatments are still not fully characterized, the evidence thus far has indicated that the potential therapeutic mechanisms of MSCs are clearer than those of BMCs or HSCs with respect to liver regenerative medicine. MSCs suppress inflammatory responses, reduce hepatocyte apoptosis, increase hepatocyte regeneration, reverse liver fibrosis and enhance liver functionality. This paper summarizes the clinical studies that have used BMCs, HSCs and MSCs in patients with liver failure or cirrhosis. We also present the potential therapeutic mechanisms of BMCs, HSCs and MSCs for the improvement of liver function. PMID:26420953

  6. Bile acids induce hepatic differentiation of mesenchymal stem cells

    PubMed Central

    Sawitza, Iris; Kordes, Claus; Götze, Silke; Herebian, Diran; Häussinger, Dieter

    2015-01-01

    Mesenchymal stem cells (MSC) have the potential to differentiate into multiple cell lineages and their therapeutic potential has become obvious. In the liver, MSC are represented by stellate cells which have the potential to differentiate into hepatocytes after stimulation with growth factors. Since bile acids can promote liver regeneration, their influence on liver-resident and bone marrow-derived MSC was investigated. Physiological concentrations of bile acids such as tauroursodeoxycholic acid were able to initiate hepatic differentiation of MSC via the farnesoid X receptor and transmembrane G-protein-coupled bile acid receptor 5 as investigated with knockout mice. Notch, hedgehog, transforming growth factor-β/bone morphogenic protein family and non-canonical Wnt signalling were also essential for bile acid-mediated differentiation, whereas β-catenin-dependent Wnt signalling was able to attenuate this process. Our findings reveal bile acid-mediated signalling as an alternative way to induce hepatic differentiaion of stem cells and highlight bile acids as important signalling molecules during liver regeneration. PMID:26304833

  7. Genetic Engineering of Mesenchymal Stem Cells for Regenerative Medicine.

    PubMed

    Nowakowski, Adam; Walczak, Piotr; Janowski, Miroslaw; Lukomska, Barbara

    2015-10-01

    Mesenchymal stem cells (MSCs), which can be obtained from various organs and easily propagated in vitro, are one of the most extensively used types of stem cells and have been shown to be efficacious in a broad set of diseases. The unique and highly desirable properties of MSCs include high migratory capacities toward injured areas, immunomodulatory features, and the natural ability to differentiate into connective tissue phenotypes. These phenotypes include bone and cartilage, and these properties predispose MSCs to be therapeutically useful. In addition, MSCs elicit their therapeutic effects by paracrine actions, in which the metabolism of target tissues is modulated. Genetic engineering methods can greatly amplify these properties and broaden the therapeutic capabilities of MSCs, including transdifferentiation toward diverse cell lineages. However, cell engineering can also affect safety and increase the cost of therapy based on MSCs; thus, the advantages and disadvantages of these procedures should be discussed. In this review, the latest applications of genetic engineering methods for MSCs with regenerative medicine purposes are presented. PMID:26140302

  8. Mesenchymal stem cell therapy for osteoarthritis: current perspectives

    PubMed Central

    Wyles, Cody C; Houdek, Matthew T; Behfar, Atta; Sierra, Rafael J

    2015-01-01

    Osteoarthritis (OA) is a painful chronic condition with a significant impact on quality of life. The societal burden imposed by OA is increasing in parallel with the aging population; however, no therapies have demonstrated efficacy in preventing the progression of this degenerative joint disease. Current mainstays of therapy include activity modification, conservative pain management strategies, weight loss, and if necessary, replacement of the affected joint. Mesenchymal stem cells (MSCs) are a multipotent endogenous population of progenitors capable of differentiation to musculoskeletal tissues. MSCs have a well-documented immunomodulatory role, managing the inflammatory response primarily through paracrine signaling. Given these properties, MSCs have been proposed as a potential regenerative cell therapy source for patients with OA. Research efforts are focused on determining the ideal source for derivation, as MSCs are native to several tissues. Furthermore, optimizing the mode of delivery remains a challenge both for appropriate localization of MSCs and for directed guidance toward stemming the local inflammatory process and initiating a regenerative response. Scaffolds and matrices with growth factor adjuvants may prove critical in this effort. The purpose of this review is to summarize the current state of MSC-based therapeutics for OA and discuss potential barriers that must be overcome for successful implementation of cell-based therapy as a routine treatment strategy in orthopedics. PMID:26357483

  9. Cancer-associated mesenchymal stem cells aggravate tumor progression

    PubMed Central

    Kudo-Saito, Chie

    2015-01-01

    Mesenchymal stem cells (MSCs) have both stemness and multi-modulatory activities on other cells, and the immunosuppressive and tumor-promotive mechanisms have been intensively investigated in cancer. The role of MSCs appears to be revealed in tumor aggravation, and targeting MSCs seems to be a promising strategy for treating cancer patients. However, it is still impractical in clinical therapy, since the precise MSCs are poorly understood in the in vivo setting. In previous studies, MSCs were obtained from different sources, and were prepared by ex vivo expansion for a long term. The inconsistent experimental conditions made the in vivo MSCs obscure. To define the MSCs in the host is a priority issue for targeting MSCs in cancer therapy. We recently identified a unique subpopulation of MSCs increasing in mice and human with cancer metastasis. These MSCs are specifically expanded by metastatic tumor cells, and promote tumor progression and dissemination accompanied by immune suppression and dysfunction in the host, more powerfully than normal MSCs growing without interference of cancer. In this review, we summarize current knowledge of the role of MSCs in tumor aggravation, along with our new findings of the bizarre MSCs. PMID:25883937

  10. Suitability of human mesenchymal stem cells for gene therapy depends on the expansion medium

    SciTech Connect

    Apel, Anja; Groth, Ariane; Schlesinger, Sabine; Bruns, Helge; Schemmer, Peter; Buechler, Markus W.; Herr, Ingrid

    2009-02-01

    Great hope is set in the use of mesenchymal stem cells for gene therapy and regenerative medicine. Since the frequency of this subpopulation of stem cells in bone marrow is low, mesenchymal stem cells are expanded ex vivo and manipulated prior to experimental or clinical use. Different methods for isolation and expansion are available, but the particular effect on the stem cell character is unclear. While the isolation of mesenchymal stem cells by density centrifugation followed by selection of the plastic adherent fraction is frequently used, the composition of expansion media differs. Thus, in the present study we cultured mesenchymal stem cells isolated from five healthy young volunteers in three widely used expansion media and performed a detailed analysis of the effect on morphology, proliferation, clonogenicity, passaging, differentiation and senescence. By this way we clearly show that the type of expansion medium used determines the stem cell character and time of senescence which is critical for future gene therapeutic and regenerative approaches using mesenchymal stem cells.

  11. Body Management: Mesenchymal Stem Cells Control the Internal Regenerator

    PubMed Central

    Hariri, Robert

    2015-01-01

    Summary It has been assumed that adult tissues cannot regenerate themselves. With the current understanding that every adult tissue has its own intrinsic progenitor or stem cell, it is now clear that almost all tissues have regenerative potential partially related to their innate turnover dynamics. Moreover, it appears that a separate class of local cells originating as perivascular cells appears to provide regulatory oversight for localized tissue regeneration. The management of this regeneration oversight has a profound influence on the use of specific cells for cell therapies as a health care delivery tool set. The multipotent mesenchymal stem cell (MSC), now renamed the medicinal signaling cell, predominantly arises from pericytes released from broken and inflamed blood vessels and appears to function as both an immunomodulatory and a regeneration mediator. MSCs are being tested for their management capabilities to produce therapeutic outcomes in more than 480 clinical trials for a wide range of clinical conditions. Local MSCs function by managing the body’s primary repair and regeneration activities. Supplemental MSCs can be provided from either endogenous or exogenous sources of either allogeneic or autologous origin. This MSC-based therapy has the potential to change how health care is delivered. These medicinal cells are capable of sensing their surroundings. Also, by using its complex signaling circuitry, these cells organize site-specific regenerative responses as if these therapeutic cells were well-programmed modern computers. Given these facts, it appears that we are entering a new age of cellular medicine. Significance This report is a perspective from an active scientist and an active entrepreneur and commercial leader. It is neither a comprehensive review nor a narrowly focused treatise. The broad themes and the analogy to the working component of a computer and that of a cell are meant to draw several important scientific principles and health

  12. The potential of mesenchymal stem cells in the management of radiation enteropathy

    PubMed Central

    Chang, P-Y; Qu, Y-Q; Wang, J; Dong, L-H

    2015-01-01

    Although radiotherapy is effective in managing abdominal and pelvic malignant tumors, radiation enteropathy is still unavoidable. This disease severely affects the quality of life of cancer patients due to some refractory lesions, such as intestinal ischemia, mucositis, ulcer, necrosis or even perforation. Current drugs or prevailing therapies are committed to alleviating the symptoms induced by above lesions. But the efficacies achieved by these interventions are still not satisfactory, because the milieus for tissue regeneration are not distinctly improved. In recent years, regenerative therapy for radiation enteropathy by using mesenchymal stem cells is of public interests. Relevant results of preclinical and clinical studies suggest that this regenerative therapy will become an attractive tool in managing radiation enteropathy, because mesenchymal stem cells exhibit their pro-regenerative potentials for healing the injuries in both epithelium and endothelium, minimizing inflammation and protecting irradiated intestine against fibrogenesis through activating intrinsic repair actions. In spite of these encouraging results, whether mesenchymal stem cells promote tumor growth is still an issue of debate. On this basis, we will discuss the advances in anticancer therapy by using mesenchymal stem cells in this review after analyzing the pathogenesis of radiation enteropathy, introducing the advances in managing radiation enteropathy using regenerative therapy and exploring the putative actions by which mesenchymal stem cells repair intestinal injuries. At last, insights gained from the potential risks of mesenchymal stem cell-based therapy for radiation enteropathy patients may provide clinicians with an improved awareness in carrying out their studies. PMID:26247725

  13. Glial cell derived neurotrophic factor induces spermatogonial stem cell marker genes in chicken mesenchymal stem cells.

    PubMed

    Boozarpour, Sohrab; Matin, Maryam M; Momeni-Moghaddam, Madjid; Dehghani, Hesam; Mahdavi-Shahri, Naser; Sisakhtnezhad, Sajjad; Heirani-Tabasi, Asieh; Irfan-Maqsood, Muhammad; Bahrami, Ahmad Reza

    2016-06-01

    Mesenchymal stem cells (MSCs) are known with the potential of multi-lineage differentiation. Advances in differentiation technology have also resulted in the conversion of MSCs to other kinds of stem cells. MSCs are considered as a suitable source of cells for biotechnology purposes because they are abundant, easily accessible and well characterized cells. Nowadays small molecules are introduced as novel and efficient factors to differentiate stem cells. In this work, we examined the potential of glial cell derived neurotrophic factor (GDNF) for differentiating chicken MSCs toward spermatogonial stem cells. MSCs were isolated and characterized from chicken and cultured under treatment with all-trans retinoic acid (RA) or glial cell derived neurotrophic factor. Expression analysis of specific genes after 7days of RA treatment, as examined by RT-PCR, proved positive for some germ cell markers such as CVH, STRA8, PLZF and some genes involved in spermatogonial stem cell maintenance like BCL6b and c-KIT. On the other hand, GDNF could additionally induce expression of POU5F1, and NANOG as well as other genes which were induced after RA treatment. These data illustrated that GDNF is relatively more effective in diverting chicken MSCs towards Spermatogonial stem cell -like cells in chickens and suggests GDNF as a new agent to obtain transgenic poultry, nevertheless, exploitability of these cells should be verified by more experiments. PMID:27026484

  14. The Endometrium as a Source of Mesenchymal Stem Cells for Regenerative Medicine1

    PubMed Central

    Mutlu, Levent; Hufnagel, Demetra; Taylor, Hugh S.

    2015-01-01

    Stem cell therapies have opened new frontiers in medicine with the possibility of regenerating lost or damaged cells. Embryonic stem cells, induced pluripotent stem cells, hematopoietic stem cells, and mesenchymal stem cells have been used to derive mature cell types for tissue regeneration and repair. However, the endometrium has emerged as an attractive, novel source of adult stem cells that are easily accessed and demonstrate remarkable differentiation capacity. In this review, we summarize our current understanding of endometrial stem cells and their therapeutic potential in regenerative medicine. PMID:25904012

  15. Clinical Trials With Mesenchymal Stem Cells: An Update.

    PubMed

    Squillaro, Tiziana; Peluso, Gianfranco; Galderisi, Umberto

    2016-01-01

    In the last year, the promising features of mesenchymal stem cells (MSCs), including their regenerative properties and ability to differentiate into diverse cell lineages, have generated great interest among researchers whose work has offered intriguing perspectives on cell-based therapies for various diseases. Currently the most commonly used adult stem cells in regenerative medicine, MSCs, can be isolated from several tissues, exhibit a strong capacity for replication in vitro, and can differentiate into osteoblasts, chondrocytes, and adipocytes. However, heterogeneous procedures for isolating and cultivating MSCs among laboratories have prompted the International Society for Cellular Therapy (ISCT) to issue criteria for identifying unique populations of these cells. Consequently, the isolation of MSCs according to ISCT criteria has produced heterogeneous, nonclonal cultures of stromal cells containing stem cells with different multipotent properties, committed progenitors, and differentiated cells. Though the nature and functions of MSCs remain unclear, nonclonal stromal cultures obtained from bone marrow and other tissues currently serve as sources of putative MSCs for therapeutic purposes, and several findings underscore their effectiveness in treating different diseases. To date, 493 MSC-based clinical trials, either complete or ongoing, appear in the database of the US National Institutes of Health. In the present article, we provide a comprehensive review of MSC-based clinical trials conducted worldwide that scrutinizes biological properties of MSCs, elucidates recent clinical findings and clinical trial phases of investigation, highlights therapeutic effects of MSCs, and identifies principal criticisms of the use of these cells. In particular, we analyze clinical trials using MSCs for representative diseases, including hematological disease, graft-versus-host disease, organ transplantation, diabetes, inflammatory diseases, and diseases in the liver, kidney

  16. The potential of mesenchymal stem cell in prion research.

    PubMed

    Mediano, D R; Sanz-Rubio, D; Ranera, B; Bolea, R; Martín-Burriel, I

    2015-05-01

    Scrapie and bovine spongiform encephalopathy are fatal neurodegenerative diseases caused by the accumulation of a misfolded protein (PrP(res)), the pathological form of the cellular prion protein (PrP(C)). For the last decades, prion research has greatly progressed, but many questions need to be solved about prion replication mechanisms, cell toxicity, differences in genetic susceptibility, species barrier or the nature of prion strains. These studies can be developed in murine models of transmissible spongiform encephalopathies, although development of cell models for prion replication and sample titration could reduce economic and timing costs and also serve for basic research and treatment testing. Some murine cell lines can replicate scrapie strains previously adapted in mice and very few show the toxic effects of prion accumulation. Brain cell primary cultures can be more accurate models but are difficult to develop in naturally susceptible species like humans or domestic ruminants. Stem cells can be differentiated into neuron-like cells and be infected by prions. However, the use of embryo stem cells causes ethical problems in humans. Mesenchymal stem cells (MSCs) can be isolated from many adult tissues, including bone marrow, adipose tissue or even peripheral blood. These cells differentiate into neuronal cells, express PrP(C) and can be infected by prions in vitro. In addition, in the last years, these cells are being used to develop therapies for many diseases, including neurodegenerative diseases. We review here the use of cell models in prion research with a special interest in the potential use of MSCs. PMID:24854140

  17. Stem cell transplantation and mesenchymal cells to treat autoimmune diseases.

    PubMed

    Tyndall, Alan; van Laar, Jacob M

    2016-06-01

    Since the start of the international stem cell transplantation project in 1997, over 2000 patients have received a haematopoietic stem cell transplant (HSCT), mostly autologous, as treatment for a severe autoimmune disease, the majority being multiple sclerosis (MS), systemic sclerosis (SSc) and Crohn's disease. There was an overall 85% 5-year survival and 43% progression-free survival. Around 30% of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many cases, e.g. systemic sclerosis, morphological improvement such as reduction of skin collagen and normalization of microvasculature was documented, beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of the three running large prospective randomized controlled trials will allow modification of the protocols to reduce the high transplant-related mortality which relates to regimen intensity, age of patient, and comorbidity. Mesenchymal stromal cells (MSC), often incorrectly called stem cells, have been the intense focus of in vitro studies and animal models of rheumatic and other diseases over more than a decade. Despite multiple plausible mechanisms of action and a plethora of positive in vivo animal studies, few randomised controlled clinical trials have demonstrated meaningful clinical benefit in any condition so far. This could be due to confusion in cell product terminology, complexity of clinical study design and execution or agreement on meaningful outcome measures. Within the rheumatic diseases, SLE and rheumatoid arthritis (RA) have received most attention. Uncontrolled multiple trial data from over 300 SLE patients have been published from one centre suggesting a positive outcome; one single centre comparative study in 172 RA was positive. In addition, small numbers of patients with Crohn's disease, multiple sclerosis, primary Sjögren's disease, polymyositis/dermatomyositis and type II diabetes

  18. Epigenetic modulators promote mesenchymal stem cell phenotype switches.

    PubMed

    Alexanian, Arshak R

    2015-07-01

    Discoveries in recent years have suggested that some tissue specific adult stem cells in mammals might have the ability to differentiate into cell types from different germ layers. This phenomenon has been referred to as stem cell transdifferentiation or plasticity. Despite controversy, the current consensus holds that transdifferentiation does occur in mammals, but only within a limited range. Understanding the mechanisms that underlie the switches in phenotype and development of the methods that will promote such type of conversions can open up endless possibilities for regenerative medicine. Epigenetic control contributes to various processes that lead to cellular plasticity and DNA and histone covalent modifications play a key role in these processes. Recently, we have been able to convert human mesenchymal stem cells (hMSCs) into neural-like cells by exposing cells to epigenetic modifiers and neural inducing factors. The goal of this study was to investigate the stability and plasticity of these transdifferentiated cells. To this end, neurally induced MSCs (NI-hMSCs) were exposed to adipocyte inducing factors. Grown for 24-48 h in fat induction media NI-hMSCs reversed their morphology into fibroblast-like cells and regained their proliferative properties. After 3 weeks approximately 6% of hMSCs differentiated into multilocular or plurivacuolar adipocyte cells that demonstrated by Oil Red O staining. Re-exposure of these cultures or the purified adipocytes to neural induction medium induced the cells to re-differentiate into neuronal-like cells. These data suggest that cell plasticity can be manipulated by the combination of small molecule modulators of chromatin modifying enzymes and specific cell signaling pathways. PMID:25936755

  19. Therapeutic application of mesenchymal stem cell-derived exosomes: A promising cell-free therapeutic strategy in regenerative medicine.

    PubMed

    Motavaf, M; Pakravan, K; Babashah, S; Malekvandfard, F; Masoumi, M; Sadeghizadeh, M

    2016-01-01

    Mesenchymal stem cells have emerged as promising therapeutic candidates in regenerative medicine. The mechanisms underlying mesenchymal stem cells regenerative properties were initially attributed to their engraftment in injured tissues and their subsequent transdifferentiation to repair and replace damaged cells. However, studies in animal models and patients indicated that the low number of transplanted mesenchymal stem cells localize to the target tissue and transdifferentiate to appropriate cell lineage. Instead the regenerative potential of mesenchymal stem cells has been found - at least in part - to be mediated via their paracrine actions. Recently, a secreted group of vesicles, called "exosome" has been identified as major mediator of mesenchymal stem cells therapeutic efficacy. In this review, we will summarize the current literature on administration of exosomes released by mesenchymal stem cells in regenerative medicine and suggest how they could help to improve tissue regeneration following injury. PMID:27453276

  20. Parkinson's Disease and Mesenchymal Stem Cells: Potential for Cell-Based Therapy

    PubMed Central

    Kitada, Masaaki; Dezawa, Mari

    2012-01-01

    Cell transplantation is a strategy with great potential for the treatment of Parkinson's disease, and many types of stem cells, including neural stem cells and embryonic stem cells, are considered candidates for transplantation therapy. Mesenchymal stem cells are a great therapeutic cell source because they are easy accessible and can be expanded from patients or donor mesenchymal tissues without posing serious ethical and technical problems. They have trophic effects for protecting damaged tissues as well as differentiation ability to generate a broad spectrum of cells, including dopamine neurons, which contribute to the replenishment of lost cells in Parkinson's disease. This paper focuses mainly on the potential of mesenchymal stem cells as a therapeutic cell source and discusses their potential clinical application in Parkinson's disease. PMID:22530164

  1. Therapeutic Effects of CUR-Activated Human Umbilical Cord Mesenchymal Stem Cells on 1-Methyl-4-phenylpyridine-Induced Parkinson's Disease Cell Model

    PubMed Central

    Jinfeng, Li; Yunliang, Wang; Xinshan, Liu; Yutong, Wang; Shanshan, Wang; Peng, Xue; Xiaopeng, Yang; Zhixiu, Xu; Qingshan, Lu; Honglei, Yin; Xia, Cao; Hongwei, Wang; Bingzhen, Cao

    2016-01-01

    The purpose of this study is to evaluate the therapeutic effects of human umbilical cord-derived mesenchymal stem cells (hUC-MSC) activated by curcumin (CUR) on PC12 cells induced by 1-methyl-4-phenylpyridinium ion (MPP+), a cell model of Parkinson's disease (PD). The supernatant of hUC-MSC and hUC-MSC activated by 5 µmol/L CUR (hUC-MSC-CUR) were collected in accordance with the same concentration. The cell proliferation and differentiation potential to dopaminergic neuronal cells and antioxidation were observed in PC12 cells after being treated with the above two supernatants and 5 µmol/L CUR. The results showed that the hUC-MSC-CUR could more obviously promote the proliferation and the expression of tyrosine hydroxylase (TH) and microtubule associated protein-2 (MAP2) and significantly decreased the expression of nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in PC12 cells. Furtherly, cytokines detection gave a clue that the expression of IL-6, IL-10, and NGF was significantly higher in the group treated with the hUC-MSC-CUR compared to those of other two groups. Therefore, the hUC-MSC-CUR may be a potential strategy to promote the proliferation and differentiation of PD cell model, therefore providing new insights into a novel therapeutic approach in PD. PMID:27340670

  2. Transcriptional Dynamics of Immortalized Human Mesenchymal Stem Cells during Transformation

    PubMed Central

    Hori, Yutaro; Koshiba-Takeuchi, Kazuko; Makino, Hatsune; Monobe, Yoko; Kishida, Marina; Adachi, Jun; Takeuchi, Jun; Tomonaga, Takeshi; Umezawa, Akihiro; Kameoka, Yosuke; Akagi, Ken-ichi

    2015-01-01

    Comprehensive analysis of alterations in gene expression along with neoplastic transformation in human cells provides valuable information about the molecular mechanisms underlying transformation. To further address these questions, we performed whole transcriptome analysis to the human mesenchymal stem cell line, UE6E7T-3, which was immortalized with hTERT and human papillomavirus type 16 E6/E7 genes, in association with progress of transformation in these cells. At early stages of culture, UE6E7T-3 cells preferentially lost one copy of chromosome 13, as previously described; in addition, tumor suppressor genes, DNA repair genes, and apoptosis-activating genes were overexpressed. After the loss of chromosome 13, additional aneuploidy and genetic alterations that drove progressive transformation, were observed. At this stage, the cell line expressed oncogenes as well as genes related to anti-apoptotic functions, cell-cycle progression, and chromosome instability (CIN); these pro-tumorigenic changes were concomitant with a decrease in tumor suppressor gene expression. At later stages after prolong culture, the cells exhibited chromosome translocations, acquired anchorage-independent growth and tumorigenicity in nude mice, (sarcoma) and exhibited increased expression of genes encoding growth factor and DNA repair genes, and decreased expression of adhesion genes. In particular, glypican-5 (GPC5), which encodes a cell-surface proteoglycan that might be a biomarker for sarcoma, was expressed at high levels in association with transformation. Patched (Ptc1), the cell surface receptor for hedgehog (Hh) signaling, was also significantly overexpressed and co-localized with GPC5. Knockdown of GPC5 expression decreased cell proliferation, suggesting that it plays a key role in growth in U3-DT cells (transformants derived from UE6E7T-3 cells) through the Hh signaling pathway. Thus, the UE6E7T-3 cell culture model is a useful tool for assessing the functional contribution of

  3. Oxygen Tension Regulates Human Mesenchymal Stem Cell Paracrine Functions

    PubMed Central

    Deschepper, Mickael; Moya, Adrien; Logeart-Avramoglou, Delphine; Boisson-Vidal, Catherine; Petite, Hervé

    2015-01-01

    Mesenchymal stem cells (MSCs) have captured the attention and research endeavors of the scientific world because of their differentiation potential. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly due to the multitude of bioactive mediators secreted by these cells. Because the paracrine potential of MSCs is closely related to their microenvironment, the present study investigated and characterized select aspects of the human MSC (hMSC) secretome and assessed its in vitro and in vivo bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. In contrast to supernatant conditioned media (CM) obtained from hMSCs cultured at either 5% or 21% of O2, CM from hMSCs cultured under near anoxia exhibited significantly (p < .05) enhanced chemotactic and proangiogenic properties and a significant (p < .05) decrease in the inflammatory mediator content. An analysis of the hMSC secretome revealed a specific profile under near anoxia: hMSCs increase their paracrine expression of the angiogenic mediators vascular endothelial growth factor (VEGF)-A, VEGF-C, interleukin-8, RANTES, and monocyte chemoattractant protein 1 but significantly decrease expression of several inflammatory/immunomodulatory mediators. These findings provide new evidence that elucidates aspects of great importance for the use of MSCs in regenerative medicine and could contribute to improving the efficacy of such therapies. Significance The present study investigated and characterized select aspects of the human mesenchymal stem cell (hMSC) secretome and assessed its in vitro and in vivo biological bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. The present study

  4. Transcriptional Dynamics of Immortalized Human Mesenchymal Stem Cells during Transformation.

    PubMed

    Takeuchi, Masao; Higashino, Atsunori; Takeuchi, Kikuko; Hori, Yutaro; Koshiba-Takeuchi, Kazuko; Makino, Hatsune; Monobe, Yoko; Kishida, Marina; Adachi, Jun; Takeuchi, Jun; Tomonaga, Takeshi; Umezawa, Akihiro; Kameoka, Yosuke; Akagi, Ken-Ichi

    2015-01-01

    Comprehensive analysis of alterations in gene expression along with neoplastic transformation in human cells provides valuable information about the molecular mechanisms underlying transformation. To further address these questions, we performed whole transcriptome analysis to the human mesenchymal stem cell line, UE6E7T-3, which was immortalized with hTERT and human papillomavirus type 16 E6/E7 genes, in association with progress of transformation in these cells. At early stages of culture, UE6E7T-3 cells preferentially lost one copy of chromosome 13, as previously described; in addition, tumor suppressor genes, DNA repair genes, and apoptosis-activating genes were overexpressed. After the loss of chromosome 13, additional aneuploidy and genetic alterations that drove progressive transformation, were observed. At this stage, the cell line expressed oncogenes as well as genes related to anti-apoptotic functions, cell-cycle progression, and chromosome instability (CIN); these pro-tumorigenic changes were concomitant with a decrease in tumor suppressor gene expression. At later stages after prolong culture, the cells exhibited chromosome translocations, acquired anchorage-independent growth and tumorigenicity in nude mice, (sarcoma) and exhibited increased expression of genes encoding growth factor and DNA repair genes, and decreased expression of adhesion genes. In particular, glypican-5 (GPC5), which encodes a cell-surface proteoglycan that might be a biomarker for sarcoma, was expressed at high levels in association with transformation. Patched (Ptc1), the cell surface receptor for hedgehog (Hh) signaling, was also significantly overexpressed and co-localized with GPC5. Knockdown of GPC5 expression decreased cell proliferation, suggesting that it plays a key role in growth in U3-DT cells (transformants derived from UE6E7T-3 cells) through the Hh signaling pathway. Thus, the UE6E7T-3 cell culture model is a useful tool for assessing the functional contribution of

  5. Mesenchymal Stem Cells Retain Their Defining Stem Cell Characteristics After Exposure to Ionizing Radiation

    SciTech Connect

    Nicolay, Nils H.; Sommer, Eva; Lopez, Ramon; Wirkner, Ute; Trinh, Thuy; Sisombath, Sonevisay; Debus, Jürgen; Ho, Anthony D.; Saffrich, Rainer; Huber, Peter E.

    2013-12-01

    Purpose: Mesenchymal stem cells (MSCs) have the ability to migrate to lesion sites and undergo differentiation into functional tissues. Although this function may be important for tissue regeneration after radiation therapy, the influence of ionizing radiation (IR) on cellular survival and the functional aspects of differentiation and stem cell characteristics of MSCs have remained largely unknown. Methods and Materials: Radiation sensitivity of human primary MSCs from healthy volunteers and primary human fibroblast cells was examined, and cellular morphology, cell cycle effects, apoptosis, and differentiation potential after exposure to IR were assessed. Stem cell gene expression patterns after exposure to IR were studied using gene arrays. Results: MSCs were not more radiosensitive than human primary fibroblasts, whereas there were considerable differences regarding radiation sensitivity within individual MSCs. Cellular morphology, cytoskeletal architecture, and cell motility were not markedly altered by IR. Even after high radiation doses up to 10 Gy, MSCs maintained their differentiation potential. Compared to primary fibroblast cells, MSCs did not show an increase in irradiation-induced apoptosis. Gene expression analyses revealed an upregulation of various genes involved in DNA damage response and DNA repair, but expression of established MSC surface markers appeared only marginally influenced by IR. Conclusions: These data suggest that human MSCs are not more radiosensitive than differentiated primary fibroblasts. In addition, upon photon irradiation, MSCs were able to retain their defining stem cell characteristics both on a functional level and regarding stem cell marker expression.

  6. Titanium phosphate glass microcarriers induce enhanced osteogenic cell proliferation and human mesenchymal stem cell protein expression

    PubMed Central

    Lakhkar, Nilay J; M Day, Richard; Kim, Hae-Won; Ludka, Katarzyna; Mordan, Nicola J; Salih, Vehid; Knowles, Jonathan C

    2015-01-01

    In this study, we have developed 50- to 100-µm-sized titanium phosphate glass microcarriers (denoted as Ti5) that show enhanced proliferation of human mesenchymal stem cells and MG63 osteosarcoma cells, as well as enhanced human mesenchymal stem cell expression of bone differentiation markers, in comparison with commercially available glass microspheres at all time points. We also demonstrate that these microcarriers provide superior human mesenchymal stem cell proliferation with conventional Dulbecco’s Modified Eagle medium than with a specially developed commercial stem cell medium. The microcarrier proliferative capacity is revealed by a 24-fold increase in MG63 cell numbers in spinner flask bioreactor studies performed over a 7-day period, versus only a 6-fold increase in control microspheres under the same conditions; the corresponding values of Ti5 and control microspheres under static culture are 8-fold and 7-fold, respectively. The capability of guided osteogenic differentiation is confirmed by ELISAs for bone morphogenetic protein-2 and osteopontin, which reveal significantly greater expression of these markers, especially osteopontin, by human mesenchymal stem cells on the Ti5 microspheres than on the control. Scanning electron microscopy and confocal laser scanning microscopy images reveal favorable MG63 and human mesenchymal stem cell adhesion on the Ti5 microsphere surfaces. Thus, the results demonstrate the suitability of the developed microspheres for use as microcarriers in bone tissue engineering applications. PMID:26668711

  7. Visual bone marrow mesenchymal stem cell transplantation in the repair of spinal cord injury

    PubMed Central

    Zhang, Rui-ping; Xu, Cheng; Liu, Yin; Li, Jian-ding; Xie, Jun

    2015-01-01

    An important factor in improving functional recovery from spinal cord injury using stem cells is maximizing the number of transplanted cells at the lesion site. Here, we established a contusion model of spinal cord injury by dropping a weight onto the spinal cord at T7-8. Superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells were transplanted into the injured spinal cord via the subarachnoid space. An outer magnetic field was used to successfully guide the labeled cells to the lesion site. Prussian blue staining showed that more bone marrow mesenchymal stem cells reached the lesion site in these rats than in those without magnetic guidance or superparamagnetic iron oxide labeling, and immunofluorescence revealed a greater number of complete axons at the lesion site. Moreover, the Basso, Beattie and Bresnahan (BBB) locomotor rating scale scores were the highest in rats with superparamagnetic labeling and magnetic guidance. Our data confirm that superparamagnetic iron oxide nanoparticles effectively label bone marrow mesenchymal stem cells and impart sufficient magnetism to respond to the external magnetic field guides. More importantly, superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells can be dynamically and non-invasively tracked in vivo using magnetic resonance imaging. Superparamagnetic iron oxide labeling of bone marrow mesenchymal stem cells coupled with magnetic guidance offers a promising avenue for the clinical treatment of spinal cord injury. PMID:25878588

  8. Osteogenic Potency of Nacre on Human Mesenchymal Stem Cells

    PubMed Central

    Green, David W.; Kwon, Hyuk-Jae; Jung, Han-Sung

    2015-01-01

    Nacre seashell is a natural osteoinductive biomaterial with strong effects on osteoprogenitors, osteoblasts, and osteoclasts during bone tissue formation and morphogenesis. Although nacre has shown, in one study, to induce bridging of new bone across large non-union bone defects in 8 individual human patients, there have been no succeeding human surgical studies to confirm this outstanding potency. But the molecular mechanisms associated with nacre osteoinduction and the influence on bone marrow-derived mesenchymal stem cells (BMSC’s), skeletal stem cells or bone marrow stromal cells remain elusive. In this study we highlight the phenotypic and biochemical effects of Pinctada maxima nacre chips and the global nacre soluble protein matrix (SPM) on primary human bone marrow-derived stromal cells (hBMSCs) in vitro. In static co-culture with nacre chips, the hBMSCs secreted Alkaline phosphatase (ALP) at levels that exceeded bone morphogenetic protein (rhBMP-2) treatment. Concentrated preparation of SPM applied to Stro-1 selected hBMSC’s led to rapid ALP secretions, at concentrations exceeding the untreated controls even in osteogenic conditions. Within 21 days the same population of Stro-1 selected hBMSCs proliferated and secreted collagens I–IV, indicating the premature onset of an osteoblast phenotype. The same SPM was found to promote unselected hBMSC differentiation with osteocalcin detected at 7 days, and proliferation increased at 7 days in a dose-dependent manner. In conclusion, nacre particles and nacre SPM induced the early stages of human bone cell differentiation, indicating that they may be promising soluble factors with osteoinductive capacity in primary human bone cell progenitors such as, hBMSC’s. PMID:25666352

  9. Mesenchymal stem cell characteristics of dental pulp and periodontal ligament stem cells after in vivo transplantation.

    PubMed

    Lei, Ming; Li, Kun; Li, Bei; Gao, Li-Na; Chen, Fa-Ming; Jin, Yan

    2014-08-01

    Mesenchymal stem cells (MSCs) isolated from human postnatal dental pulp and periodontal ligament (PDL) tissues can give rise to multilineage differentiation in vitro and generate related dental tissues in vivo. However, the cell properties of human dental pulp stem cells (DPSCs) and PDL stem cells (PDLSCs) after in vivo implantation remain largely unidentified. In this study, cells were re-isolated from in vivo-generated dental pulp-like and PDL-like tissues (termed re-DPCs and re-PDLCs, respectively) as a result of ectopic transplantation of human DPSC and PDLSC sheets. The cell characteristics in terms of colony-forming ability, cell surface antigens and multi-differentiation potentials were all evaluated before and after implantation. It was found that re-DPCs and re-PDLCs were of human and mesenchymal origin and positive for MSC markers such as STRO-1, CD146, CD29, CD90 and CD105; and, to some extent, re-DPCs could maintain their colony forming abilities. Moreover, both cell types were able to form mineral deposits and differentiate into adipocytes and chondrocytes; however, quantitative analysis and related gene expression determination showed that the osteo-/chondro-differentiation capabilities of re-DPCs and re-PDLCs were significantly reduced compared to those of DPSCs and PDLSCs, respectively (P < 0.05); re-PDLCs showed a greater reduction potential than re-DPCs. We conclude that DPSCs and PDLSCs may maintain their MSC characteristics after in vivo implantation and, compared to PDLSCs, DPSCs appear much more stable under in vivo conditions. These findings provide additional cellular and molecular evidence that supports expanding the use of dental tissue-derived stem cells in cell therapy and tissue engineering. PMID:24824581

  10. Markers of stemness in equine mesenchymal stem cells: a plea for uniformity.

    PubMed

    De Schauwer, Catharina; Meyer, Evelyne; Van de Walle, Gerlinde R; Van Soom, Ann

    2011-05-01

    Mesenchymal stromal cells (MSC) are a very promising subpopulation of adult stem cells for cell-based regenerative therapies in veterinary medicine. Despite major progress in the knowledge on adult stem cells during recent years, a proper identification of MSC remains a challenge. In human medicine, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) recently proposed three criteria to define MSC. Firstly, cells must be plastic-adherent when maintained under standard culture conditions. Secondly, MSC must express CD73, CD90 and CD105, and lack expression of CD34, CD45, CD14 or CD11b, CD79α or CD19 and MHC class II antigens. Thirdly, MSC must be able to differentiate into osteoblasts, adipocytes and chondroblasts in vitro. Successful isolation and differentiation of equine MSC from different sources such as bone marrow, fat tissue, umbilical cord blood, Wharton's Jelly or peripheral blood has been widely reported. However, their unequivocal immunophenotyping is hampered by the lack of a single specific marker and the limited availability of monoclonal anti-horse antibodies, which are two major factors complicating successful research on equine MSC. Detection of gene expression on mRNA level is hereby a valuable alternative, although the need still exists to test several antibody clones in search for cross-reactivity. To date, commercial antibodies recognizing equine epitopes are only available for CD13, CD44 and MHC-II. Moreover, as the expression of certain adult stem cell markers may differ between species, it is mandatory to define a set of CD markers which can be uniformly applied for the identification of equine MSC. PMID:21196039

  11. Mesenchymal stem cells inhibit complement activation by secreting factor H.

    PubMed

    Tu, Zhidan; Li, Qing; Bu, Hong; Lin, Feng

    2010-11-01

    Mesenchymal stem cells (MSCs) possess potent and broad immunosuppressive capabilities, and have shown promise in clinical trials treating many inflammatory diseases. Previous studies have found that MSCs inhibit dendritic cell, T-cell, and B-cell activities in the adaptive immunity; however, whether MSCs inhibit complement in the innate immunity, and if so, by which mechanism, have not been established. In this report, we found that MSCs constitutively secrete factor H, which potently inhibits complement activation. Depletion of factor H in the MSC-conditioned serum-free media abolishes their complement inhibitory activities. In addition, production of factor H by MSCs is augmented by inflammatory cytokines TNF-α and interferon-γ (IFN-γ) in dose- and time-dependent manners, while IL-6 does not have a significant effect. Furthermore, the factor H production from MSCs is significantly suppressed by the prostaglandin E2 (PGE2) synthesis inhibitor indomethacin and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-d-tryptophan (1-MT), both of which inhibitors are known to efficiently dampen MSCs immunosuppressive activity. These results indicate that MSCs inhibit complement activation by producing factor H, which could be another mechanism underlying MSCs broad immunosuppressive capabilities. PMID:20163251

  12. Mesenchymal Stem Cells Respond to Hypoxia by Increasing Diacylglycerols.

    PubMed

    Lakatos, Kinga; Kalomoiris, Stefanos; Merkely, Béla; Nolta, Jan A; Fierro, Fernando A

    2016-02-01

    Mesenchymal stem cells (MSC) are currently being tested clinically for a plethora of conditions, with most approaches relying on the secretion of paracrine signals by MSC to modulate the immune system, promote wound healing, and induce angiogenesis. Hypoxia has been shown to affect MSC proliferation, differentiation, survival and secretory profile. Here, we investigate changes in the lipid composition of human bone marrow-derived MSC after exposure to hypoxia. Using mass spectrometry, we compared the lipid profiles of MSC derived from five different donors, cultured for two days in either normoxia (control) or hypoxia (1% oxygen). Hypoxia induced a significant increase of total triglycerides, fatty acids and diacylglycerols (DG). Remarkably, reduction of DG levels using the phosphatidylcholine-specific phospholipase C inhibitor D609 inhibited the secretion of VEGF and Angiopoietin-2, but increased the secretion of interleukin-8, without affecting significantly their respective mRNA levels. Functionally, incubation of MSC in hypoxia with D609 inhibited the potential of the cells to promote migration of human endothelial cells in a wound/scratch assay. Hence, we show that hypoxia induces in MSC an increase of DG that may affect the angiogenic potential of these cells. PMID:26212931

  13. Mesenchymal Stem Cell (MSC) Aggregate Formation in vivo

    PubMed Central

    Bartosh, Thomas J.; Ylostalo, Joni H.

    2016-01-01

    Human mesenchymal stem/progenitor cells (MSCs) isolated from various adult tissues show remarkable therapeutic potential and are being employed in clinical trials for the treatment of numerous diseases (Prockop et al., 2010). While routes of cell administration vary, profound beneficial effects of MSCs in animal models have been observed following intraperitoneal injections of the cells (Roddy et al., 2011). Similar to MSC spheres formed in culture under conditions where attachment to plastic is not permitted (Bartosh et al., 2010), MSCs injected into the peritoneum of mice spontaneously aggregate into 3D sphere-like structures (Bartosh et al., 2013). During the process of sphere assembly and compaction, MSCs upregulate expression of numerous therapeutic anti-inflammatory and immune modulatory factors. Here we describe the method we previously used for the generation of human bone marrow-derived MSC aggregates/spheres in vivo (Bartosh et al., 2013). By tagging the MSCs with green fluorescent protein (GFP), the aggregates formed can be easily visualized, collected and analyzed for changes in cellular properties and interactions with host immune cells.

  14. Current Methods of Adipogenic Differentiation of Mesenchymal Stem Cells

    PubMed Central

    Scott, Michelle A.; Nguyen, Virginia T.; Levi, Benjamin

    2011-01-01

    There has been a recent increase in our understanding in the isolation, culture, and differentiation of mesenchymal stem cells (MSCs). Concomitantly, the availability of MSCs has increased, with cells now commercially available, including human MSCs from adipose tissue and bone marrow. Despite an increased understanding of MSC biology and an increase in their availability, standardization of techniques for adipogenic differentiation of MSCs is lacking. The following review will explore the variability in adipogenic differentiation in vitro, specifically in 3T3-L1 and primary MSCs derived from both adipose tissue and bone marrow. A review of alternative methods of adipogenic induction is also presented, including the use of specific peroxisome proliferator-activated receptor-gamma agonists as well as bone morphogenetic proteins. Finally, we define a standard, commonly used adipogenic differentiation medium in the hopes that this will be adopted for the future standardization of laboratory techniques—however, we also highlight the essentially arbitrary nature of this decision. With the current, rapid pace of electronic publications, it becomes imperative for standardization of such basic techniques so that interlaboratory results may be easily compared and interpreted. PMID:21526925

  15. Human Mesenchymal Stem Cell Morphology and Migration on Microtextured Titanium.

    PubMed

    Banik, Brittany L; Riley, Thomas R; Platt, Christina J; Brown, Justin L

    2016-01-01

    The implant used in spinal fusion procedures is an essential component to achieving successful arthrodesis. At the cellular level, the implant impacts healing and fusion through a series of steps: first, mesenchymal stem cells (MSCs) need to adhere and proliferate to cover the implant; second, the MSCs must differentiate into osteoblasts; third, the osteoid matrix produced by the osteoblasts needs to generate new bone tissue, thoroughly integrating the implant with the vertebrate above and below. Previous research has demonstrated that microtextured titanium is advantageous over smooth titanium and PEEK implants for both promoting osteogenic differentiation and integrating with host bone tissue; however, no investigation to date has examined the early morphology and migration of MSCs on these surfaces. This study details cell spreading and morphology changes over 24 h, rate and directionality of migration 6-18 h post-seeding, differentiation markers at 10 days, and the long-term morphology of MSCs at 7 days, on microtextured, acid-etched titanium (endoskeleton), smooth titanium, and smooth PEEK surfaces. The results demonstrate that in all metrics, the two titanium surfaces outperformed the PEEK surface. Furthermore, the rough acid-etched titanium surface presented the most favorable overall results, demonstrating the random migration needed to efficiently cover a surface in addition to morphologies consistent with osteoblasts and preosteoblasts. PMID:27243001

  16. Isolation of Mouse Bone Marrow Mesenchymal Stem Cells.

    PubMed

    Boregowda, Siddaraju V; Krishnappa, Veena; Phinney, Donald G

    2016-01-01

    Mesenchymal stem cells (MSCs) were initially characterized as connective tissue progenitors resident in bone marrow, but have now been isolated from a variety of tissues and organs and shown to also exhibit potent tissue regenerative properties mediated largely via paracrine actions. These findings have spurred the development of MSC-based therapies for treating a diverse array of nonskeletal diseases. Although genetic and experimental rodent models of disease represent important tools for developing efficacious MSC-based therapies, development of reliable methods to isolate MSCs from mouse bone marrow has been hampered by the unique biological properties of these cells. Indeed, few isolation schemes afford high yields and purity while maintaining the genomic integrity of cells. We recently demonstrated that mouse MSCs are highly sensitive to oxidative stress, and long-term expansion of these cells in atmospheric oxygen selects for immortalized clones that lack a functional p53 protein. Herein, we describe a protocol for the isolation of primary MSCs from mouse bone marrow that couples immunodepletion with culture in a low-oxygen environment and affords high purity and yield while preserving p53 function. PMID:27236673

  17. Human umbilical cord mesenchymal stem cell transplantation restores damaged ovaries

    PubMed Central

    Zhu, Shao-Fang; Hu, Hong-Bo; Xu, Hong-Yan; Fu, Xia-Fei; Peng, Dong-Xian; Su, Wei-Yan; He, Yuan-Li

    2015-01-01

    Ovarian injury because of chemotherapy can decrease the levels of sexual hormones and potentia generandi of patients, thereby greatly reducing quality of life. The goal of this study was to investigate which transplantation method for human umbilical cord mesenchymal stem cells (HUMSCs) can recover ovarian function that has been damaged by chemotherapy. A rat model of ovarian injury was established using an intraperitoneal injection of cyclophosphamide. Membrane-labelled HUMSCs were subsequently injected directly into ovary tissue or tail vein. The distribution of fluorescently labelled HUMSCs, estrous cycle, sexual hormone levels, and potentia generandi of treated and control rats were then examined. HUMSCs injected into the ovary only distributed to the ovary and uterus, while HUMSCs injected via tail vein were detected in the ovary, uterus, kidney, liver and lung. The estrous cycle, levels of sex hormones and potentia generandi of the treated rats were also recovered to a certain degree. Moreover, in some transplanted rats, fertility was restored and their offspring developed normally. While ovary injection could recover ovarian function faster, both methods produced similar results in the later stages of observation. Therefore, our results suggest that transplantation of HUMSCs by tail vein injection represents a minimally invasive and effective treatment method for ovarian injury. PMID:25922900

  18. Mesenchymal stem cells (MSCs) as skeletal therapeutics - an update.

    PubMed

    Saeed, Hamid; Ahsan, Muhammad; Saleem, Zikria; Iqtedar, Mehwish; Islam, Muhammad; Danish, Zeeshan; Khan, Asif Manzoor

    2016-01-01

    Mesenchymal stem cells hold the promise to treat not only several congenital and acquired bone degenerative diseases but also to repair and regenerate morbid bone tissues. Utilizing MSCs, several lines of evidences advocate promising clinical outcomes in skeletal diseases and skeletal tissue repair/regeneration. In this context, both, autologous and allogeneic cell transfer options have been utilized. Studies suggest that MSCs are transplanted either alone by mixing with autogenous plasma/serum or by loading onto repair/induction supportive resorb-able scaffolds. Thus, this review is aimed at highlighting a wide range of pertinent clinical therapeutic options of MSCs in the treatment of skeletal diseases and skeletal tissue regeneration. Additionally, in skeletal disease and regenerative sections, only the early and more recent preclinical evidences are discussed followed by all the pertinent clinical studies. Moreover, germane post transplant therapeutic mechanisms afforded by MSCs have also been conversed. Nonetheless, assertive use of MSCs in the clinic for skeletal disorders and repair is far from a mature therapeutic option, therefore, posed challenges and future directions are also discussed. Importantly, for uniformity at all instances, term MSCs is used throughout the review. PMID:27084089

  19. Cell Fate and Differentiation of Bone Marrow Mesenchymal Stem Cells

    PubMed Central

    Jimi, Eijiro

    2016-01-01

    Osteoblasts and bone marrow adipocytes originate from bone marrow mesenchymal stem cells (BMMSCs) and there appears to be a reciprocal relationship between adipogenesis and osteoblastogenesis. Alterations in the balance between adipogenesis and osteoblastogenesis in BMMSCs wherein adipogenesis is increased relative to osteoblastogenesis are associated with decreased bone quality and quantity. Several proteins have been reported to regulate this reciprocal relationship but the exact nature of the signals regulating the balance between osteoblast and adipocyte formation within the bone marrow space remains to be determined. In this review, we focus on the role of Transducin-Like Enhancer of Split 3 (TLE3), which was recently reported to regulate the balance between osteoblast and adipocyte formation from BMMSCs. We also discuss evidence implicating canonical Wnt signalling, which plays important roles in both adipogenesis and osteoblastogenesis, in regulating TLE3 expression. Currently, there is demand for new effective therapies that target the stimulation of osteoblast differentiation to enhance bone formation. We speculate that reducing TLE3 expression or activity in BMMSCs could be a useful approach towards increasing osteoblast numbers and reducing adipogenesis in the bone marrow environment. PMID:27298623

  20. The Effect of Hypoxia on Mesenchymal Stem Cell Biology

    PubMed Central

    Ejtehadifar, Mostafa; Shamsasenjan, Karim; Movassaghpour, Aliakbar; Akbarzadehlaleh, Parvin; Dehdilani, Nima; Abbasi, Parvaneh; Molaeipour, Zahra; Saleh, Mahshid

    2015-01-01

    Although physiological and pathological role of hypoxia have been appreciated in mammalians for decades however the cellular biology of hypoxia more clarified in the past 20 years. Discovery of the transcription factor hypoxia-inducible factor (HIF)-1, in the 1990s opened a new window to investigate the mechanisms behind hypoxia. In different cellular contexts HIF-1 activation show variable results by impacting various aspects of cell biology such as cell cycle, apoptosis, differentiation and etc. Mesenchymal stem cells (MSC) are unique cells which take important role in tissue regeneration. They are characterized by self-renewal capacity, multilineage potential, and immunosuppressive property. Like so many kind of cells, hypoxia induces different responses in MSCs by HIF- 1 activation. The activation of this molecule changes the growth, multiplication, differentiation and gene expression profile of MSCs in their niche by a complex of signals. This article briefly discusses the most important effects of hypoxia in growth kinetics, signalling pathways, cytokine secretion profile and expression of chemokine receptors in different conditions. PMID:26236651

  1. Mesenchymal Stem Cells Ameliorated Glucolipotoxicity in HUVECs through TSG-6

    PubMed Central

    An, Xingxing; Li, Lan; Chen, Younan; Luo, Ai; Ni, Zuyao; Liu, Jingping; Yuan, Yujia; Shi, Meimei; Chen, Bo; Long, Dan; Cheng, Jingqiu; Lu, Yanrong

    2016-01-01

    Glucolipotoxicity is one of the critical causal factors of diabetic complications. Whether mesenchymal stem cells (MSCs) have effects on glucolipotoxicity in human umbilical vein endothelial cells (HUVECs) and mechanisms involved are unclear. Thirty mM glucose plus 100 μM palmitic acid was used to induce glucolipotoxicity in HUVECs. MSCs and HUVECs were co-cultured at the ratio of 1:5 via Transwell system. The mRNA expressions of inflammatory factors were detected by RT-qPCR. The productions of reactive oxygen species (ROS), cell cycle and apoptosis were analyzed by flow cytometry. The tumor necrosis factor-α stimulated protein 6 (TSG-6) was knockdown in MSCs by RNA interference. High glucose and palmitic acid remarkably impaired cell viability and tube formation capacity, as well as increased the mRNA expression of inflammatory factors, ROS levels, and cell apoptosis in HUVECs. MSC co-cultivation ameliorated these detrimental effects in HUVECs, but no effect on ROS production. Moreover, TSG-6 was dramatically up-regulated by high glucose and fatty acid stimulation in both MSCs and HUVECs. TSG-6 knockdown partially abolished the protection mediated by MSCs. MSCs had protective effects on high glucose and palmitic acid induced glucolipotoxicity in HUVECs, and TSG-6 secreted by MSCs was likely to play an important role in this process. PMID:27043548

  2. [Immunoregulatory role of mesenchymal stem cells in bone reparation processes].

    PubMed

    Zubov, D O

    2008-01-01

    Bone marrow contains mesenchymal stem cells (MSC) including osteoblast progenitor cells. When culturedunder conditions promoting an osteoblastic phenotype,MSC proliferate to form colonies that produce alkaline phosphatase and, subsequently, a mature osteoblastic phenotype. Transplantation of cultured autologous MSC to patients with non-healing bone fractures gives a good result leading to complete bone fracture consolidation. The aim of the study is to determine a quantitative production of IL-1beta, IL-2, IL-4, IL-6, IL-8 and TNF-alpha by cultured uncommitted and committed osteogenic MSC. The results showed that the cytokine profile consisting of IL-1beta, IL-2, IL-4, IL-6, IL-8 and TNF-alpha is secreted by cultured MSC. The secretion of IL-1beta and IL-2 by cultured MSC together with hyper production of IL-6 (up to 276.5 pg/ml, p<0.05) and IL-8 (up to 106.6 ng/ml, p<0.05) by osteoinducted MSC are firstly shown. The immunoregulatory role of transplanted autologous cells in inflammation and own bone reparation processes during posttraumatic bone fracture healing is highlighted. In conclusion, the data obtained allow examining of cultured autologous MSC as effective activators of bone resorption, inflammation and some immunological reactions in the process of altered osteoreparation. PMID:18756772

  3. Chondrogenic Differentiation of Mesenchymal Stem Cells: Challenges and Unfulfilled Expectations

    PubMed Central

    Somoza, Rodrigo A.; Welter, Jean F.; Correa, Diego

    2014-01-01

    Articular cartilage repair and regeneration provides a substantial challenge in Regenerative Medicine because of the high degree of morphological and mechanical complexity intrinsic to hyaline cartilage due, in part, to its extracellular matrix. Cartilage remains one of the most difficult tissues to heal; even state-of-the-art regenerative medicine technology cannot yet provide authentic cartilage resurfacing. Mesenchymal stem cells (MSCs) were once believed to be the panacea for cartilage repair and regeneration, but despite years of research, they have not fulfilled these expectations. It has been observed that MSCs have an intrinsic differentiation program reminiscent of endochondral bone formation, which they follow after exposure to specific reagents as a part of current differentiation protocols. Efforts have been made to avoid the resulting hypertrophic fate of MSCs; however, so far, none of these has recreated a fully functional articular hyaline cartilage without chondrocytes exhibiting a hypertrophic phenotype. We reviewed the current literature in an attempt to understand why MSCs have failed to regenerate articular cartilage. The challenges that must be overcome before MSC-based tissue engineering can become a front-line technology for successful articular cartilage regeneration are highlighted. PMID:24749845

  4. Ion channels in mesenchymal stem cells from rat bone marrow.

    PubMed

    Li, Gui-Rong; Deng, Xiu-Ling; Sun, Haiying; Chung, Stephen S M; Tse, Hung-Fat; Lau, Chu-Pak

    2006-06-01

    Mesenchymal stem cells (MSCs) from bone marrow are believed to be an ideal cell source for cardiomyoplasty; however, cellular electrophysiology is not understood. The present study was designed to investigate ion channels in undifferentiated rat MSCs. It was found that three types of outward currents were present in rat MSCs, including a small portion of Ca(2+)-activated K(+) channel (I(KCa)) sensitive to inhibition by iberiotoxin and/or clotromazole, a delayed rectifier K(+) current (IK(DR)), and a transient outward K(+) current (I(to)). In addition, tetrodotoxin (TTX)-sensitive sodium current (I(Na.TTX)) and nifedipine-sensitive L-type Ca(2+) current (I(Ca.L)) were found in a small population of rat MSCs. Moreover, reverse transcription-polymerase chain reaction revealed the molecular evidence of mRNA for the functional ionic currents, including Slo and KCNN4 for I(KCa); Kv1.4 for I(to); Kv1.2 and Kv2.1 for IK(DR); SCN2a1 for I(Na.TTX); and CCHL2a for I(Ca.L). These results demonstrate for the first time that multiple functional ion channel currents (i.e., I(KCa), I(to), IK(DR), I(Na.TTX), and I(Ca.L)) are present in rat MSCs from bone marrow; however, physiological roles of these ion channels remain to be studied. PMID:16484345

  5. Mesenchymal stem cells as mediators of neural differentiation.

    PubMed

    Hardy, Steven A; Maltman, Daniel J; Przyborski, Stefan A

    2008-01-01

    Mesenchymal stem cells (MSCs) represent a promising source of material for autologous cell transplantation therapies, in particular, their potential use for the treatment of damaged nervous tissue. Much of the work in this area has focused on the transplantation of MSCs into animal models of neurological disorders, including stroke and spinal cord injury. Although numerous studies have reported significant functional improvements in these systems, the exact mechanism(s) by which MSCs elicit recovery remains largely undefined. While it has been proposed that 'trans'-differentiation and/or cell fusion events underly MSC-mediated neural repair, there is considerable doubt that the low frequency of these phenomena is sufficient to account for the observed levels of recovery. Furthermore, in vitro studies call into question the ability of MSCs to produce authentic neural derivatives. In this review we focus on recent evidence indicating that transplanted MSCs promote endogenous repair of neurologically damaged areas via the release of soluble trophic factors and cytokines. Through the modern analysis of MSC-conditioned media it is becoming possible to gain new insight into the release and interplay of these soluble factors and their neurogenic effects. Ultimately this understanding may lead to the rational design of new therapies for the treatment of neurological and neurodegenerative disorders. PMID:18220922

  6. Mechanisms of mesenchymal stem/stromal cell function.

    PubMed

    Spees, Jeffrey L; Lee, Ryang Hwa; Gregory, Carl A

    2016-01-01

    The past decade has seen an explosion of research directed toward better understanding of the mechanisms of mesenchymal stem/stromal cell (MSC) function during rescue and repair of injured organs and tissues. In addition to delineating cell-cell signaling and molecular controls for MSC differentiation, the field has made particular progress in defining several other mechanisms through which administered MSCs can promote tissue rescue/repair. These include: 1) paracrine activity that involves secretion of proteins/peptides and hormones; 2) transfer of mitochondria by way of tunneling nanotubes or microvesicles; and 3) transfer of exosomes or microvesicles containing RNA and other molecules. Improved understanding of MSC function holds great promise for the application of cell therapy and also for the development of powerful cell-derived therapeutics for regenerative medicine. Focusing on these three mechanisms, we discuss MSC-mediated effects on immune cell responses, cell survival, and fibrosis and review recent progress with MSC-based or MSC-derived therapeutics. PMID:27581859

  7. Oxidative stress induces senescence in human mesenchymal stem cells

    SciTech Connect

    Brandl, Anita; Meyer, Matthias; Bechmann, Volker; Nerlich, Michael; Angele, Peter

    2011-07-01

    Mesenchymal stem cells (MSCs) contribute to tissue repair in vivo and form an attractive cell source for tissue engineering. Their regenerative potential is impaired by cellular senescence. The effects of oxidative stress on MSCs are still unknown. Our studies were to investigate into the proliferation potential, cytological features and the telomere linked stress response system of MSCs, subject to acute or prolonged oxidant challenge with hydrogen peroxide. Telomere length was measured using the telomere restriction fragment assay, gene expression was determined by rtPCR. Sub-lethal doses of oxidative stress reduced proliferation rates and induced senescent-morphological features and senescence-associated {beta}-galactosidase positivity. Prolonged low dose treatment with hydrogen peroxide had no effects on cell proliferation or morphology. Sub-lethal and prolonged low doses of oxidative stress considerably accelerated telomere attrition. Following acute oxidant insult p21 was up-regulated prior to returning to initial levels. TRF1 was significantly reduced, TRF2 showed a slight up-regulation. SIRT1 and XRCC5 were up-regulated after oxidant insult and expression levels increased in aging cells. Compared to fibroblasts and chondrocytes, MSCs showed an increased tolerance to oxidative stress regarding proliferation, telomere biology and gene expression with an impaired stress tolerance in aged cells.

  8. Model microgravity enhances endothelium differentiation of mesenchymal stem cells

    NASA Astrophysics Data System (ADS)

    Zhang, Xiaofeng; Nan, Yayun; Wang, Huan; Chen, Jun; Wang, Nanding; Xie, Juan; Ma, Jing; Wang, Zongren

    2013-02-01

    Mesenchymal stem cells (MSCs) are capable of differentiation into multilineage cell types under certain induction conditions. Previous studies have demonstrated that physical environments and mechanical force can influence MSC fate, indicating that these factors may be favorable inducers for clinical treatment. Our previous study found that MSCs are spread with a spindle shape when cultured in normal gravity (NG), and under modeled microgravity (MMG) for 72 h, they become unspread and round and their cytoskeleton fibers are reorganized. These morphological changes affected the function of MSCs through the activity of RhoA. We examined the responses of MSCs under MMG stimulation, followed with VEGF differentiation. We found that MSCs under MMG for 72 h were differentiated into endothelial-like cells by detecting the expression of endothelial-specific molecules (Flk-1 and vWF), which were also able to form a capillary network. Their endothelial differentiation potential was improved under MMG compared with that under NG. We believe that this method is a novel choice of MMG stimulation for neovascularization. This phenomenon may increase the potential of MSC differentiation, which might be a new strategy for the treatment of various vascular diseases and improve vascularization in tissue engineering.

  9. Engineering Mesenchymal Stem Cells for Regenerative Medicine and Drug Delivery

    PubMed Central

    Park, Ji Sun; Suryaprakash, Smruthi; Lao, Yeh-Hsing; Leong, Kam W.

    2015-01-01

    Researchers have applied mesenchymal stem cells (MSC) to a variety of therapeutic scenarios by harnessing their multipotent, regenerative, and immunosuppressive properties with tropisms toward inflamed, hypoxic, and cancerous sites. Although MSC-based therapies have been shown to be safe and effective to a certain degree, the efficacy remains low in most cases when MSC are applied alone. To enhance their therapeutic efficacy, researchers have equipped MSC with targeted delivery functions using genetic engineering, therapeutic agent incorporation, and cell surface modification. MSC can be genetically modified virally or non-virally to overexpress therapeutic proteins that complement their innate properties. MSC can also be primed with non-peptidic drugs or magnetic nanoparticles for enhanced efficacy and externally regulated targeting, respectively. Furthermore, MSC can be functionalized with targeting moieties to augment their homing toward therapeutic sites using enzymatic modification, chemical conjugation, or non-covalent interactions. These engineering techniques are still works in progress, requiring optimization to improve the therapeutic efficacy and targeting effectiveness while minimizing any loss of MSC function. In this review, we will highlight the advanced techniques of engineering MSC, describe their promise and the challenges of translation into clinical settings, and suggest future perspectives on realizing their full potential for MSC-based therapy. PMID:25770356

  10. Mesenchymal stem cell mechanobiology and emerging experimental platforms

    PubMed Central

    MacQueen, Luke; Sun, Yu; Simmons, Craig A.

    2013-01-01

    Experimental control over progenitor cell lineage specification can be achieved by modulating properties of the cell's microenvironment. These include physical properties of the cell adhesion substrate, such as rigidity, topography and deformation owing to dynamic mechanical forces. Multipotent mesenchymal stem cells (MSCs) generate contractile forces to sense and remodel their extracellular microenvironments and thereby obtain information that directs broad aspects of MSC function, including lineage specification. Various physical factors are important regulators of MSC function, but improved understanding of MSC mechanobiology requires novel experimental platforms. Engineers are bridging this gap by developing tools to control mechanical factors with improved precision and throughput, thereby enabling biological investigation of mechanics-driven MSC function. In this review, we introduce MSC mechanobiology and review emerging cell culture platforms that enable new insights into mechanobiological control of MSCs. Our main goals are to provide engineers and microtechnology developers with an up-to-date description of MSC mechanobiology that is relevant to the design of experimental platforms and to introduce biologists to these emerging platforms. PMID:23635493