Potential Use Of Mesenchymal Stem Cells Research Articles

MICROSCOPIC CHANGES IN MUSCLES OF RABBITS WITH EXPERIMENTALLY DAMAGED MUSCLE TISSUE UNDER THE INFLUENCE OF TRANSPLANTED MESENCHYMAL STEM CELLS

Due to the high level of activity of some animals, particularly sports and working animals, muscle injuries are becoming a serious and urgent problem for veterinarians. Sporting events, training and work duties can lead to tears, strains and other injuries to skeletal muscle tissue. Muscle injuries in sports and working animals are a complex problem that requires a careful and comprehensive approach to treatment. These injuries can lead to pain, restricted movement and loss of performance. Traditional treatments, while effective, are often lengthy and not always successful. Therefore, scientists and veterinarians are constantly looking for new and more effective ways to treat and rehabilitate animals to help them recover from injuries faster and more fully. The main purpose of this article is to review, summarise and analyse histological studies investigating the use of allogeneic mesenchymal stem cells in veterinary medicine for regenerative therapy. An additional goal of the article is to review the results of these studies and highlight the main conclusions regarding the potential use of MSCs in veterinary practice. The main role in cell therapy is played by allogeneic mesenchymal stem cells (MSCs). These cells, which do not have a specific differentiation, can independently renew themselves and develop into cells with specific functions, making them effective for tissue repair. It is especially important to note that mesenchymal stem cells are promising for veterinary medicine because they are easy to isolate and cultivate. The article discusses the use of allogeneic mesenchymal stem cells for tissue repair in veterinary medicine in experimental animals, taking into account the results of scientific research conducted by the authors of the article. The use of a new and promising method of treating animals with damaged muscle tissue based on cellular regeneration can significantly accelerate the recovery of animals after injury and avoid side effects that often occur with traditional treatments.

Therapeutic Effects of Insulin-Producing Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Type 1 Diabetes Mouse Model.

In patients with type 1 diabetes (T1D), compromised pancreatic β-cell functions are compensated through daily insulin injections or the transplantation of pancreatic tissue or islet cells. However, both approaches are associated with specific challenges. The transplantation of mesenchymal stem cells (MSCs) represents a potential alternative, as MSCs have tissue-forming capacity and can be isolated from various tissues. The human umbilical cord (hUC) is a good source of freely available MSCs, which can be collected through pain-free, non-invasive methods subject to minimal ethical concerns. We sought to develop a method for the in vitro generation of insulin-producing cells (IPCs) using MSCs. We examined the potential therapeutic uses and efficacy of IPCs generated from hUC-derived MSCs (hUC-IPCs) and human adipose tissue (hAD)-derived MSCs (hAD-IPCs) through in vitro experiments and streptozotocin (STZ)-induced C57BL/6 T1D mouse models. We discovered that compared to hAD-IPCs, hUC-IPCs exhibited a superior insulin secretion capacity. Therefore, hUC-IPCs were selected as candidates for T1D cell therapy in mice. Fasting glucose and intraperitoneal glucose tolerance test levels were lower in hUC-IPC-transplanted mice than in T1D control mice and hAD-IPC-transplanted mice. Our findings support the potential use of MSCs for the treatment of T1D.

Recent Progress in Engineering Mesenchymal Stem Cell Differentiation.

Due to the ability to differentiate into variety of cell types, mesenchymal stem cells (MSCs) hold promise as source in cell-based therapy for treating injured tissue and degenerative diseases. The potential use of MSCs to replace or repair damaged tissues may depend on the efficient differentiation protocols to derive specialized cells without any negative side effects. Identification of appropriate cues that support the lineage-specific differentiation of stem cells is critical for tissue healing and cellular therapy. Recently, a number of stimuli have been utilized to direct the differentiation of stem cells. Biochemical stimuli such as small molecule, growth factor and miRNA have been traditionally used to regulate the fate of stem cells. In recent years, many studies have reported that biophysical stimuli including cyclic mechanical strain, fluid shear stress, microgravity, electrical stimulation, matrix stiffness and topography can also be sensed by stem cells through mechanical receptors, thus affecting the stem cell behaviors including their differentiation potential. In this paper, we review all the most recent literature on the application of biochemical and biophysical cues on regulating MSC differentiation. An extensive literature search was done using electronic database (Medline/Pubmed). Although there are still some challenges that need to be taken into consideration before translating these methods into clinics, biochemical and biophysical stimulation appears to be an attractive method to manipulate the lineage commitment of MSCs.

Stem cells and respiratory disease

Stem cells and respiratory disease

The effect of PEGylated hollow gold nanoparticles on stem cell migration: potential application in tissue regeneration.

Mesenchymal stem cells (MSCs) not only can be differentiated into different cell types but also have tropism towards injured or inflamed tissues serving as repair cells. Here we have demonstrated that MSCs containing gold nanoparticles (GNPs) whose surface has been functionalized with PEG show accelerated cell migration, successful scaffold colonization and regeneration. We report the impact of GNPs on the migration (by the wound healing assay), and proliferation (by flow cytometry analysis and by the detection of metabolic mitochondrial activity) on the behaviour of different cell lines including MSCs, HeLa cells, and human dermal fibroblasts. We conclude that GNPs are easily internalized by MSCs causing an increase in their migration rate, mediated by actin and tubulin with a 4-fold increased expression level of those proteins. We also demonstrate that MSCs containing GNPs are able to successfully colonize fibrin and PCL-based scaffolds and that an enhanced osteoblastic differentiation is reached when using the nanoparticle-laden cells compared to untreated cells used as a control. These results highlight the potential use of MSCs as therapeutic nanoparticle-carriers in regenerative medicine.

Immunosuppressive effects of mesenchymal stem cells on tacrolimus therapy in rat heart transplant model

Introduction: Mesenchymal stem cells (MSCs) are used in various clinical settings for effective cell therapy by taking advantage of their immunomodulatory, regenerative, and anti-inflammatory properties. We previously investigated the effects of the regenerative and anti-inflammatory properties of MSCs for consideration of their clinical application in organ transplantation. Since immunosuppressant agents are administered in nearly all clinical cases of organ transplantation, clarification of the immunological interaction between MSCs and the calcineurin inhibitor tacrolimus (TAC) is needed.Aim: Due to potential use of MSCs in organ transplantation, we assessed immunological interactions between TAC and MSCs in vivo.Methods: Adipose tissue-derived MSCs (AT-MSCs) were obtained from wild-type Lewis rats. We then used a rat heart transplantation model to observe the immunosuppressive effects of AT-MSCs, TAC, and those in combination. Following allogeneic heterotopic heart transplantation from ACI rats to Lewis rats, graft survival was assessed in groups treated with AT-MSCs, TAC, both, or neither.Results: Median survival of the allograft was 14.5 days in the TAC-alone group and 11 days in the MSC+TAC group. Although the difference between those groups was not significant, the survival periods of both were significantly longer as compared to that of the control (median survival =5 days, P<0.05) and MSC-alone (median survival =5 days, P<0.05) groups.Conclusions: Administration of AT-MSCs did not decrease the beneficial immunosuppressive effect of TAC on heart graft survival. TAC appears to be compatible and effective for clinical use as an immunosuppressant with AT-MSCs.

Canine mesenchymal stem cells are neurotrophic and angiogenic: An in vitro assessment of their paracrine activity

Mesenchymal stem cells (MSCs) have been used in cell replacement therapies for connective tissue damage, but also can stimulate wound healing through paracrine activity. In order to further understand the potential use of MSCs to treat dogs with neurological disorders, this study examined the paracrine action of adipose-derived canine MSCs on neuronal and endothelial cell models. The culture-expanded MSCs exhibited a MSC phenotype according to plastic adherence, cell morphology, CD profiling and differentiation potential along mesenchymal lineages. Treating the SH-SY5Y neuronal cell line with serum-free MSC culture-conditioned medium (MSC CM) significantly increased SH-SY5Y cell proliferation (P < 0.01), neurite outgrowth (P = 0.0055) and immunopositivity for the neuronal marker βIII-tubulin (P = 0.0002). Treatment of the EA.hy926 endothelial cell line with MSC CM significantly increased the rate of wound closure in endothelial cell scratch wound assays (P = 0.0409), which was associated with significantly increased endothelial cell proliferation (P < 0.05) and migration (P = 0.0001). Furthermore, canine MSC CM induced endothelial tubule formation in EA.hy926 cells in a soluble basement membrane matrix. Hence, this study has demonstrated that adipose-derived canine MSC CM stimulated neuronal and endothelial cells probably through the paracrine activity of MSC-secreted factors. This supports the use of canine MSC transplants or their secreted products in the clinical treatment of dogs with neurological disorders and provides some insight into possible mechanisms of action.

Human Adipose Tissue-Derived Mesenchymal Stem Cells Target Brain Tumor-Initiating Cells.

In neuro-oncology, the biology of neural stem cells (NSCs) has been pursued in two ways: as tumor-initiating cells (TICs) and as a potential cell-based vehicle for gene therapy. NSCs as well as mesenchymal stem cells (MSCs) have been reported to possess tumor tropism capacities. However, there is little data on the migratory capacity of MSCs toward brain tumor-initiating cells (BTICs). This study focuses on the ability of human adipose tissue derived MSCs (hAT-MSCs) to target BTICs and their crosstalk in the microenvironment. BTICs were isolated from three different types of brain tumors. The migration capacities of hAT-MSCs toward BTICs were examined using an in vitro migration assay and in vivo bioluminescence imaging analysis. To investigate the crosstalk between hAT-MSCs and BTICs, we analyzed the mRNA expression patterns of cyto-chemokine receptors by RT-qPCR and the protein level of their ligands in co-cultured medium. The candidate cyto-chemokine receptors were selectively inhibited using siRNAs. Both in vitro and in vivo experiments showed that hAT-MSCs possess migratory abilities to target BTICs isolated from medulloblastoma, atypical teratoid/rhabdoid tumors (AT/RT) and glioblastoma. Different types of cyto-chemokines are involved in the crosstalk between hAT-MSCs and BTICs (medulloblastoma and AT/RT: CXCR4/SDF-1, CCR5/RANTES, IL6R/IL-6 and IL8R/IL8; glioblastoma: CXCR4/SDF-1, IL6R/IL-6, IL8R/IL-8 and IGF1R/IGF-1). Our findings demonstrated the migratory ability of hAT-MSCs for BTICs, implying the potential use of MSCs as a delivery vehicle for gene therapy. This study also confirmed the expression of hAT-MSCs cytokine receptors and the BTIC ligands that play roles in their crosstalk.

Effects of Intravenous Human Umbilical Cord Blood Mesenchymal Stem Cell Therapy versus Gabapentin in Pentylenetetrazole-Induced Chronic Epilepsy in Rats

Aim: The identification and application of stem cells to treat central nervous system disorders represent a dramatic evolution and expansion into the realms of neurorestoration and neuroregeneration. The aim of this study was to assess the possible ameliorative effect of mesenchymal stem cells (MSCs) in comparison to gabapentin on pentylenetetrazole (PTZ)-induced epileptogenesis and its consequences. Methods: Thirty-two rats were divided into 4 equal groups; group I: saline-injected group, group II: PTZ group, which received 13 intraperitoneal (i.p.) injections of PTZ (30 mg/kg) 3 times/week, groups III and IV: groups received PTZ and were treated with i.p. gabapentin (200 mg/kg) 60 min before each PTZ injection (group III) or a single intravenous injection of 10⁶ MSCs/rat at day 22 (group IV). Results: Treatment with either gabapentin or MSCs demonstrated a significant improvement in the PTZ-induced epileptogenesis and its severe consequences, i.e. oxidative stress damage, motor and cognitive impairments. Moreover, they enhanced the GABA neurotransmitter levels. Meanwhile, MSC administration to chronic epileptic rats afforded more ameliorative effects on PTZ-induced epileptogenesis and its severe consequences in comparison to gabapentin. Conclusion: These data indicate that MSCs were superior to gabapentin in ameliorating PTZ-induced epileptogenesis and verified the potential use of MSCs in seizure control, motor and cognitive impairments, oxidative stress, and the impairing GABA level in experimentally induced epilepsy.

The potential of mesenchymal stem cell in prion research.

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.

Stem cells: innovations in clinical applications.

The use of mesenchymal stem cells (MSCs) as clinical therapeutics is a relatively new avenue of study for treatment of a variety of diseases. The therapeutic impact of the MSCs is based upon their multiplicities of function and interaction with host tissues. MSCs can be anti-inflammatory, antifibrotic, antimicrobial, and regenerative, all which may improve outcomes in scenarios of damaged tissues and inflammation. Although most studies focus on utilizing MSCs to direct clinical efficacy, it is the ability to orchestrate host response in surrounding tissue that is especially unique and versatile. This orchestration of host response can be applied to a variety of clinical scenarios not only through cell-cell interactions but also through production of bioactive secreted factors. These bioactive factors include small proteins, chemokines, cytokines, and other cellular regulators. These factors have the capacity to induce angiogenesis or blood vessel development, be chemotactic, and induce cellular recruitment. MSCs also have the capacity to differentiate with the implicated environment to regenerate tissue or accommodate host tissue in a cell specific manner. The differentiation cannot only be done in vivo but also can be optimized in vitro prior to in vivo administration, potentiating the versatility of the MSCs and opening avenues for corrective therapy and cell delivery of genes. The differentiation process depends on the environment with which the MSCs are put and results in active communication between the newly administered cells host tissue. Since these properties have been identified, there are a variety of clinical trials and studies being conducted on MSCs ability to treat human disease. This review outlines the potential use of MSCs, the types of tissue, and the innovative applications of MSCs for the treatment of diseases.

Recovery of Fertility in Azoospermia Rats after Injection of Adipose-Tissue-Derived Mesenchymal Stem Cells: The Sperm Generation

The recent reports on the treatment of azoospermia patients, in which spermatozoa could not be traced in their testes, are focused more on the potential use of adult stem cells, like mesenchymal stem cells (MSCs). The aim of this study was to demonstrate the potential use of MSCs derived from adipose tissue in the treatment of azoospermia using rat disease models. After busulfan application, the rats (n = 20) were injected with the GFP+ MSCs into left rete testes. After 12 weeks, the testes with cell injection (right testes) were compared to control (left testes) after dimensional and immunohistochemical analyses. Testes treated with MSCs appeared morphologically normal, but they were atrophic in rats without stem cell treatment, in which the seminiferous tubules were empty. Spermatogenesis was detected, not in every but in some tubules of cell-treated testes. GFP+/VASA+ and GFP+/SCP1+ cells in testes indicated the transdifferentiation of MSCs into spermatogenetic cells in the appropriate microenvironment. Rats with cell treatment were mated to show the full recovery of spermatogenesis, and continuous generations were obtained. The expression of GFP was detected in the mesenchymal stem cells derived from adipose tissue and bone marrow and also in the sperms of offspring. In conclusion, MSCs might be studied for the same purpose in humans in future.

The potential use of mesenchymal stem cells in hematopoietic stem cell transplantation

In the last 10 years, mesenchymal stem cells (MSCs) have emerged as a therapeutic approach to regenerative medicine, cancer, autoimmune diseases, and many more due to their potential to differentiate into various tissues, to repair damaged tissues and organs, and also for their immunomodulatory properties. Findings in vitro and in vivo have demonstrated immune regulatory function of MSCs and have facilitated their application in clinical trials, such as those of autoimmune diseases and chronic inflammatory diseases. There has been an increasing interest in the role of MSCs in allogeneic hematopoietic stem cell transplantation (HSCT), including hematopoietic stem cell engraftment and the prevention and treatment of graft-versus-host disease (GVHD), and their therapeutic potential has been reported in numerous clinical trials. Although the safety of clinical application of MSCs is established, further modifications to improve their efficacy are required. In this review, we summarize advances in the potential use of MSCs in HSCT. In addition, we discuss their use in clinical trials of the treatment of GVHD following HSCT, the immunomodulatory capacity of MSCs, and their regenerative and therapeutic potential in the field of HSCT.

Mesenchymal Stem Cells Prime Proliferating Adult Neural Progenitors Toward an Oligodendrocyte Fate

Oligodendrogenesis encompasses lineage specification of neural progenitor cells (NPCs) and differentiation into oligodendrocytes that ultimately culminates in the myelination of central nervous system axons. Each individual process must be tightly regulated by extracellular and cell-intrinsic mechanisms, whose identities are barely understood. We had previously demonstrated that soluble factors derived from rat mesenchymal stem cells (MSCs) induce oligodendrogenesis in differentiating adult NPCs under differentiation conditions. However, since lineage specification predominantly occurs in proliferating progenitors and not necessarily during early differentiation, we investigated if soluble factors derived from MSCs are able to prime NPCs to the oligodendroglial fate already under proliferation conditions. Therefore, we analyzed the effects of a 3 weeks stimulation of adult NPCs under proliferation conditions with conditioned media derived from MSCs (MSC-CM) in terms of cell morphology, proliferation, cell-specific marker expression profile, response to growth factor withdrawal (GFW), cell-lineage restriction, and expression of glial fate determinants. While MSC-CM did not affect the proliferation rate of NPCs, it boosted the formation of 2', 3'-cyclic-nucleotide-3'-phosphodieesterase (CNPase)- and myelin basic protein-expressing oligodendrocytes after GFW, even when cells were exposed to an astrogenic milieu. Moreover, it reinforced the proper development of oligodendrocytes, since it ensured a sustained expression of the functional marker CNPase. Finally, the presence of MSC-CM reduced the anti-oligodendrogenic determinant Id2 in proliferating NPCs, thus increasing the relative proportion of the pro-oligodendrogenic factor Olig2 expression. In summary, MSCs prime proliferating progenitors and, thus, reinforce cell fate choice and accelerate differentiation toward the oligodendrocyte lineage. The present findings underscore the potential use of MSCs in cell therapies for remyelination such as in multiple sclerosis and spinal cord injury. Moreover, they urge the identification of the oligodendrogenic activity(ies) derived from MSCs to develop novel molecular therapies for demyelinating diseases.

Bone Marrow Derived Mesenchymal Stem Cells Inhibit Inflammation and Preserve Vascular Endothelial Integrity in the Lungs after Hemorrhagic Shock

Hemorrhagic shock (HS) and trauma is currently the leading cause of death in young adults worldwide. Morbidity and mortality after HS and trauma is often the result of multi-organ failure such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), conditions with few therapeutic options. Bone marrow derived mesenchymal stem cells (MSCs) are a multipotent stem cell population that has shown therapeutic promise in numerous pre-clinical and clinical models of disease. In this paper, in vitro studies with pulmonary endothelial cells (PECs) reveal that conditioned media (CM) from MSCs and MSC-PEC co-cultures inhibits PEC permeability by preserving adherens junctions (VE-cadherin and β-catenin). Leukocyte adhesion and adhesion molecule expression (VCAM-1 and ICAM-1) are inhibited in PECs treated with CM from MSC-PEC co-cultures. Further support for the modulatory effects of MSCs on pulmonary endothelial function and inflammation is demonstrated in our in vivo studies on HS in the rat. In a rat “fixed volume” model of mild HS, we show that MSCs administered IV potently inhibit systemic levels of inflammatory cytokines and chemokines in the serum of treated animals. In vivo MSCs also inhibit pulmonary endothelial permeability and lung edema with concurrent preservation of the vascular endothelial barrier proteins: VE-cadherin, Claudin-1, and Occludin-1. Leukocyte infiltrates (CD68 and MPO positive cells) are also decreased in lungs with MSC treatment. Taken together, these data suggest that MSCs, acting directly and through soluble factors, are potent stabilizers of the vascular endothelium and inflammation. These data are the first to demonstrate the therapeutic potential of MSCs in HS and have implications for the potential use of MSCs as a cellular therapy in HS-induced lung injury.

Treatment Outcomes of Alginate-Embedded Allogenic Mesenchymal Stem Cells Versus Autologous Chondrocytes for the Repair of Focal Articular Cartilage Defects in a Rabbit Model

Background: Mesenchymal stem cells (MSCs) represent a promising alternative form of cell-based therapy for cartilage injury. However, the capacity of MSCs for chondrogenesis has not been fully explored. In particular, there is presently a lack of studies comparing the effectiveness of MSCs to conventional autologous chondrocyte (autoC) treatment for regeneration of full-thickness cartilage defects in vivo. Hypothesis: Treatment with allogenic undifferentiated MSCs (alloMSCs) results in superior cartilage tissue regeneration profiles when compared with autoC for repair of focal articular cartilage defects. Study Design: Controlled laboratory study. Methods: Full-thickness articular cartilage defects were created on the weightbearing surface of the medial femoral condyles in both knees of New Zealand White rabbits (N = 30). Six weeks after the defect was induced, the right knee was treated with either alloMSCs (n = 12) or autoC (n = 18), while the left knee remained untreated (control). The rabbits were sacrificed at 6 months after treatment for assessment of cartilage tissue regeneration, which included the Brittberg morphologic score, histologic grading by O’Driscoll score, and quantitative analysis of glycosaminoglycans per total protein content. Results: Apart from significantly higher Brittberg scores in the alloMSC treatment group (8.8 ± 0.8) versus the autoC treatment group (6.6 ± 0.8) (P = .04), both treatments showed similar cartilage regenerative profiles. All outcome measures were significantly higher in the treatment groups compared with their respective controls (P < .05). Conclusion: AlloMSCs have similar effectiveness as autoC for repair of focal cartilage defects. Both treatments resulted in superior tissue regeneration compared with untreated defects. Clinical Relevance: The results have an implication of supporting the potential use of MSCs for cartilage repair after sports injuries or diseases, in view of similar efficacy but less patient morbidity and potential cost savings as compared with conventional autoC therapy.

Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications

Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitor cells that are isolated from many adult tissues, in particular from the bone marrow and adipose tissue. Along with their capacity for differentiating into cells of mesodermal lineage, such as adipocytes, osteoblasts and chondrocytes, these cells have also generated great interest for their ability to display immunomodulatory capacities. Indeed, a major breakthrough came with the finding that they are able to induce peripheral tolerance, suggesting they may be used as therapeutic tools in immune-mediated disorders. The present review aims at discussing the current knowledge on the targets and mechanisms of MSC-mediated immunosuppression as well as the potential use of MSCs as modulators of immune responses in a variety of diseases related to alloreactive immunity or autoimmunity

Cardiac Differentiation Is Driven by NKX2.5 and GATA4 Nuclear Translocation in Tissue-Specific Mesenchymal Stem Cells

Myocardial infarction is a major public health problem that causes significant mortality despite recent advances in its prevention and treatment. Therefore, approaches based on adult stem cells represent a promising alternative to conventional therapies for this life-threatening condition. Mesenchymal stem cells (MSCs) are self-renewing pluripotent cells that have been isolated from multiple tissues and differentiate to various cell types. Here we have analyzed the capacity of MSCs from human bone marrow (BMSC), adipose tissue (ATSC), and dental pulp (DPSC) to differentiate to cells with a cardiac phenotype. Differentiation of MSCs was induced by long-term co-culture with neonatal rat cardiomyocytes (CMs). Shortly after the establishment of MSC-CM co-cultures, expression of connexin 43 and the cardiac-specific markers troponin I, beta-myosin heavy chain, atrial natriuretic peptide, and alpha-sarcomeric actinin was detected in BMSCs, ATSCs, and DPSCs. Expression of differentiation markers increased over time in the co-cultures, reaching the highest levels at 4 weeks. Translocation of the transcription factors NKX2.5 and GATA4 to the nucleus was observed in all three cultures of MSCs during the differentiation process; moreover, nuclear localization of NKX2.5 and GATA4 correlated with expression of alpha-sarcomeric actinin. These changes were accompanied by an increase in myofibril organization in the resulting CM-like cells as analyzed by electron microscopy. Thus, our results provide novel information regarding the differentiation of tissue-specific MSCs to cardiomyocytes and support the potential use of MSCs in cell-based cardiac therapies.

A Role for Mesenchymal Stem Cells in the Control of Graft-Versus-Host Disease

Several reports have demonstrated the ability of mesenchymal stem cells (MSCs) to enhance hemopoietic engraftment and to exert a profound inhibitory effect on T-cell proliferation in vitro, making them a candidate for the prevention/treatment of graft-versus-host disease. Recent publications have highlighted the underlying mechanisms of the immunosuppressive function of MSCs, elicited by proinflammatory cytokines, such as interferon-gamma and tumor necrosis factor-alpha. These new findings have lead to a better understanding of the biology of MSCs, the outcome of graft-versus-host disease clinical trials and the conflicting results of preclinical T-cell-dependent pathologies. The potential use of MSCs as immunosuppressive elements in allogeneic stem-cell transplantation settings is thus discussed below.

Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells Do Not Differentiate Into Neural Cell Types or Integrate Into the Retina After Intravitreal Grafting in Neonatal Rats

This study investigated the ability of mesenchymal stem cells (MSCs) derived from full-term human umbilical cord blood to survive, integrate and differentiate after intravitreal grafting to the degenerating neonatal rat retina following intracranial optic tract lesion. MSCs survived for 1 week in the absence of immunosuppression. When host animals were treated with cyclosporin A and dexamethasone to suppress inflammatory and immune responses, donor cells survived for at least 3 weeks, and were able to spread and cover the entire vitreal surface of the host retina. However, MSCs did not significantly integrate into or migrate through the retina. They also maintained their human antigenicity, and no indication of neural differentiation was observed in retinas where retinal ganglion cells either underwent severe degeneration or were lost. These results have provided the first in vivo evidence that MSCs derived from human umbilical cord blood can survive for a significant period of time when the host rat response is suppressed even for a short period. These results, together with the observation of a lack of neuronal differentiation and integration of MSCs after intravitreal grafting, has raised an important question as to the potential use of MSCs for neural repair through the replacement of lost neurons in the mammalian retina and central nervous system.