Mesenchymal Stem Cell Transplantation Therapy Research Articles

HGF Facilitates the Repair of Spinal Cord Injuries by Driving the Chemotactic Migration of MSCs Through the β-Catenin/TCF4/Nedd9 Signaling Pathway.

Transplanted mesenchymal stem cells (MSCs) can significantly aid in repairing spinal cord injuries (SCI) by migrating to and settling at the injury site. However, this process is typically inefficient, as only a small fraction of MSCs successfully reach the target lesion area. During SCI, the increased expression and secretion of hepatocyte growth factor (HGF) act as a chemoattractant that guides MSC migration. Nonetheless, the precise mechanisms by which HGF influences MSC migration are not fully understood. This study focused on unraveling the molecular pathways that drive MSC migration towards the SCI site in response to HGF. It was found that HGF can activate β-catenin signaling in MSCs either by phosphorylating LRP6 or by suppressing GSK3β phosphorylation through the AKT and ERK1/2 pathways, or by enhancing the expression and nuclear translocation of TCF4. This activation leads to elevated Nedd9 expression, which promotes focal adhesion formation and F-actin polymerization, facilitating chemotactic migration. Transplanting MSCs during peak HGF expression in injured tissues substantially improves nerve regeneration, reduces scarring, and enhances hind limb mobility. Additionally, prolonging HGF release can further boost MSC migration and engraftment, thereby amplifying regenerative outcomes. However, inhibiting HGF/Met or interfering with β-catenin or Nedd9 signaling significantly impairs MSC engraftment, obstructing tissue repair and functional recovery. Together, these findings provide a theoretical basis and practical strategy for MSC transplantation therapy in SCI, highlighting the specific molecular mechanisms by which HGF regulates β-catenin signaling in MSCs, ultimately triggering their chemotactic migration.

Activation of Mitochondria in Mesenchymal Stem Cells by Mitochondrial Delivery of Coenzyme Q10.

The efficacy of mesenchymal stem cell (MSC) transplantation has been reported for various diseases. We previously developed a drug delivery system targeting mitochondria (MITO-Porter) by using a microfluidic device to encapsulate Coenzyme Q10 (CoQ10) on a large scale. The current study aimed to confirm if treatment with CoQ10 encapsulated by MITO-Porter enhanced mitochondrial functions in MSCs, with the potential to improve MSC transplantation therapy. We used highly purified human bone marrow-derived MSCs, described as rapidly expanding clones (RECs), and attempted to control and increase the amount of CoQ10 encapsulated in the MITO-Porter using microfluidic device system. We treated these RECs with CoQ10 encapsulated MITO-Porter, and evaluated its cellular uptake, co-localization with mitochondria, changes in mitochondrial respiratory capacity, and cellular toxicity. There was no significant change in mitochondrial respiratory capacity following treatment with the previous CoQ10 encapsulated MITO-Porter; however, mitochondrial respiratory capacity in RECs was significantly increased by treatment with CoQ10-rich MITO-Porter. Utilization of a microfluidic device enabled the amount of CoQ10 encapsulated in MITO-Porter to be controlled, and treatment with CoQ10-rich MITO-Porter successfully activated mitochondrial functions in MSCs. The MITO-Porter system thus provides a promising tool to improve MSC cell transplantation therapy.

The Effect of Exercise on Mesenchymal Stem Cells and their Application in Obesity Treatment.

Mesenchymal stem cells (MSCs) have demonstrated considerable potential in tissue repair and the treatment of immune-related diseases, but there are problems with homing efficiency during MSCs transplantation. Exercise, as an intervention, has been shown to have an important impact on the properties of MSCs. This review summarizes the effects of exercise on the properties (including proliferation, apoptosis, differentiation, and homing) of bone marrow-derived MSCs and adipose-derived MSCs. Studies indicated that exercise enhances bone marrow-derived MSCs proliferation, osteogenic differentiation, and homing while reducing adipogenic differentiation. For adipose-derived MSCs, exercise enhances proliferation and reduces adipogenic differentiation. In addition, studies have investigated the therapeutic effects of combined therapy of MSCs transplantation with exercise on diseases of the bone, cardiac, and nervous systems. The combined therapy improves tissue repair by increasing the homing of transplanted MSCs and cytokine secretion (such as neurotrophin 4). Furthermore, MSCs transplantation also has potential for the treatment of obesity. Although the effect is not significant in weight loss, MSCs transplantation shows effects in controlling blood glucose, improving dyslipidemia, reducing inflammation, and improving liver disease. Finally, the potential role of combined MSCs transplantation and exercise therapy in addressing obesity is discussed.

Mesenchymal Stem Cell Senescence during Aging:From Mechanisms to Rejuvenation Strategies.

In cell transplantation therapy, mesenchymal stem cells(MSCs)are ideal seed cells due to their easy acquisition and cultivation, strong regenerative capacity, multi-directional differentiation abilities, and immunomodulatory effects. Autologous MSCs are better applicable compared with allogeneic MSCs in clinical practice. The elderly are the main population for cell transplantation therapy, but as donor aging, MSCs in the tissue show aging-related changes. When the number of generations of in vitro expansion is increased, MSCs will also exhibit replicative senescence. The quantity and quality of MSCs decline during aging, which limits the efficacy of autologous MSCs transplantation therapy. In this review, we examine the changes in MSC senescence as a result of aging, discuss the progress of research on mechanisms and signalling pathways of MSC senescence, and discuss possible rejuvenation strategies of aged MSCs to combat senescence and enhance the health and therapeutic potential of MSCs.

Jujuboside A inhibits oxidative stress damage and enhances immunomodulatory capacity of human umbilical cord mesenchymal stem cells through up-regulating IDO expression.

Impaired immunomodulatory capacity and oxidative stress are the key factors limiting the effectiveness of mesenchymal stem cell transplantation therapy. The present study was aimed to investigate the effects of jujuboside A (JuA) on the protective effect and immunomodulatory capacity of human umbilical cord mesenchymal stem cells (hUC-MSCs). Hydrogen peroxide was used to establish an oxidative damage model of hUC-MSCs, while PBMCs isolated from rats were used to evaluate the effect of JuA pre-treatment on the immunomodulatory capacity of hUC-MSCs. Furthermore, Hoechst 33258 staining, lactate dehydrogenase test, measurement of malondialdehyde, Western blot, high-performance liquid chromatography; and flow cytometry were performed. Our results indicated that JuA (25 μmol·L-1) promoted the proliferation of hUC-MSCs, but did not affect the differentiating capability of these cells. JuA pre-treatment inhibited apoptosis, prevented oxidative damage, and up-regulated the protein expression of nuclear factor-erythroid factor 2-related factor 2 and heme oxygenase 1 in hUC-MSCs in which oxidative stress was induced with H2O2. In addition, JuA pre-treatment enhanced the inhibitory effect of hUC-MSCs against abnormally activated PBMCs, which was related to stimulation of the expression and activity of indoleamine 2,3-dioxygenase. In conclusion, our results demonstrate that JuA pre-treatment can enhance the survival and immunomodulatory ability through pathways related to oxidative stress, providing a new option for the improvement of hUC-MSCs in the clinical setting.

Classification and Characteristics of Mesenchymal Stem Cells and Its Potential Therapeutic Mechanisms and Applications against Ischemic Stroke.

Ischemic stroke is a serious cerebral disease that often induces death and long-term disability. As a currently available therapy for recanalization after ischemic stroke, thrombolysis, including intravenous thrombolysis and endovascular therapy, still cannot be applicable to all patients due to the narrow time window. Mesenchymal stem cell (MSC) transplantation therapy, which can trigger neuronal regeneration and repair, has been considered as a significant advance in treatment of ischemic stroke. MSC transplantation therapy has exhibited its potential to improve the neurological function in ischemic stroke. Our review describes the current progress and future perspective of MSC transplantation therapy in ischemic stroke treatment, including cell types, transplantation approaches, therapeutic mechanisms, and preliminary clinical trials of MSC transplantation, for providing us an update role of MSC transplantation in ischemic stroke treatment.

The Comparative Effects of Mesenchymal Stem Cell Transplantation Therapy for Spinal Cord Injury in Humans and Animal Models: A Systematic Review and Meta-Analysis.

Simple SummaryThe effects of mesenchymal stem cell (MSC) transplants on functional recovery after spinal cord injury have been compared in humans and animal models. Data show that MSC transplants increase functional outcomes across species. However, modes and timings of MSC delivery mean that the animal studies cannot be used to predict outcome, suggesting that alternative models are required to improve translation of research to clinical trial.Animal models have been used in preclinical research to examine potential new treatments for spinal cord injury (SCI), including mesenchymal stem cell (MSC) transplantation. MSC transplants have been studied in early human trials. Whether the animal models represent the human studies is unclear. This systematic review and meta-analysis has examined the effects of MSC transplants in human and animal studies. Following searches of PubMed, Clinical Trials and the Cochrane Library, published papers were screened, and data were extracted and analysed. MSC transplantation was associated with significantly improved motor and sensory function in humans, and significantly increased locomotor function in animals. However, there are discrepancies between the studies of human participants and animal models, including timing of MSC transplant post-injury and source of MSCs. Additionally, difficulty in the comparison of functional outcome measures across species limits the predictive nature of the animal research. These findings have been summarised, and recommendations for further research are discussed to better enable the translation of animal models to MSC-based human clinical therapy.

Evaluation of the effects of immunotherapy and mesenchymal stem cells transplantation in the treatment of critically ill coronavirus disease 2019 patients

To analyze the immunotherapy and clinical characteristics of coronavirus disease 2019 (COVID-19) patients, and focus on exploring the effects of immunotherapy and mesenchymal stem cells (MSC) transplantation in the critically ill patients' treatment. Fity-five COVID-19 patients were admitted to the Fifth People's Hospital of Wuxi from January 23rd to March 31st, 2020 as the research object. The demographic characteristics of the cases and the methods of immunotherapy were analyzed, focusing on the immunized indicators, positivity of pathogens and clinical indicators of critically ill COVID-19 patient, and the effects of immunotherapy and stem cell transplantation were evaluated. Aged, male and people with comorbidities were the main risk factors in the development of severe and critical COVID-19. All of confirmed COVID-19 cases (n = 55) had been treated with interferon-α (IFN-α), of which 81.8% (n = 45, mild and ordinary) of the patients were recovered, 14.6% (n = 8) of the patients were converted to severe, 3.6% (n = 2) of the patients were converted to critical, and some severe patients were treated with gamma globulin and albumin as adjuvant treatment. Critically ill patients were not only treated with IFN-α, gamma globulin and albumin, but also treated with convalescent plasma and MSC transplantation. Due to pulmonary hemorrhage and persistently low blood oxygen saturation, terminal lung transplantation therapy was implemented. The total number of lymphocytes, CD4+, CD8+ T lymphocytes, natural killer (NK) cells and B cells in peripheral blood of the two critical COVID-19 patients were significantly reduced, and the functions of lung, liver, and kidney were severely damaged on admission, manifested as significant increase of the levels of blood C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood urea nitrogen (BUN), etc. and decrease of blood oxygen saturation, and type I respiratory failure, and the noninvasive assisted ventilation was needed to improve. After adjuvant immunotherapy such as gamma globulin, the nucleic acid of 2019 novel coronavirus (2019-nCoV) turned into negative. The CRP of one critically ill patient was significantly lower than the value at admission (minimum of 21 mg/L). But the lung inflammation progressed rapidly, and the pathological results of the lung tissue from the lung transplantation showed hemorrhage and irreversible fibrosis. The ability to secrete immunoglobulin A (IgA) was significantly reduced. Liver function had been significantly improved and stabilized after treatment with convalescent plasma during the recovery period. MSC transplantation treatment reduced the BUN level by > 50% compared with the previous period, and the total number of lymphocytes in the patient increased by more than 2 times (rose from 0.23×109/L to 0.57×109/L), but the total amount of lymphocytes was still lower than the normal reference value (< 1.1×109/L). The lung inflammation lesions were obviously absorbed, and the vital signs were stable. In addition to IFN, gamma globulin, antiserum and MSC transplantation therapy can help clear the virus and reduce inflammation. Although MSC transplantation fail to completely change the immunecompromised state of critically ill patients, it controlled the progression of inflammation in the liver and kidneys.

Neovascularization: The Main Mechanism of MSCs in Ischemic Heart Disease Therapy.

Mesenchymal stem cell (MSC) transplantation after myocardial infarction (MI) has been shown to effectively limit the infarct area in numerous clinical and preclinical studies. However, the primary mechanism associated with this activity in MSC transplantation therapy remains unclear. Blood supply is fundamental for the survival of myocardial tissue, and the formation of an efficient vascular network is a prerequisite for blood flow. The paracrine function of MSCs, which is throughout the neovascularization process, including MSC mobilization, migration, homing, adhesion and retention, regulates angiogenesis and vasculogenesis through existing endothelial cells (ECs) and endothelial progenitor cells (EPCs). Additionally, MSCs have the ability to differentiate into multiple cell lineages and can be mobilized and migrate to ischemic tissue to differentiate into ECs, pericytes and smooth muscle cells in some degree, which are necessary components of blood vessels. These characteristics of MSCs support the view that these cells improve ischemic myocardium through angiogenesis and vasculogenesis. In this review, the results of recent clinical and preclinical studies are discussed to illustrate the processes and mechanisms of neovascularization in ischemic heart disease.

The Systematic Effect of Mesenchymal Stem Cell Therapy in Critical COVID-19 Patients: A Prospective Double Controlled Trial

The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-β, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.

Recruitment of Mesenchymal Stem Cells to Damaged Sites by Plant-Derived Components.

Mesenchymal stem cells (MSCs) are capable of differentiating into a limited number of diverse cells and secrete regenerative factors that contribute to the repair of damaged tissue. In response to signals emitted by tissue damage, MSCs migrate from the bone marrow and area surrounding blood vessels within tissues into the circulating blood, and accumulate at the site of damage. Hence, MSC transplantation therapy is beginning to be applied to the treatment of various intractable human diseases. Recent medicinal plants studies have shown that plant-derived components can activate cell functions. For example, several plant-derived components activate cell signaling pathways, such as phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK), enhance expression of the CXCL12/CXCR4 axis, stimulate extracellular matrix remodeling, and consequently, promote cell migration of MSCs. Moreover, plant-derived components have been shown to promote recruitment of MSCs to damaged tissues and enhance healing in disease models, potentially advancing their therapeutic use. This article provides a comprehensive review of several plant-derived components that activate MSC migration and homing to damaged sites to promote tissue repair.

Cxcr6-Based Mesenchymal Stem Cell Gene Therapy Potentiates Skin Regeneration in Murine Diabetic Wounds.

Mesenchymal stem cell (MSC) therapies for wound healing are often compromised due to low recruitment and engraftment of transplanted cells, as well as delayed differentiation into cell lineages for skin regeneration. An increased expression of chemokine ligand CXCL16 in wound bed and its cognate receptor, CXCR6, on murine bone-marrow-derived MSCs suggested a putative therapeutic relevance of exogenous MSC transplantation therapy. Induction of the CXCL16-CXCR6 axis led to activation of focal adhesion kinase (FAK), Src, and extracellular signal-regulated kinases 1/2 (ERK1/2)-mediated matrix metalloproteinases (MMP)-2 promoter regulation and expression, the migratory signaling pathways in MSC. CXCL16 induction also increased the transdifferentiation of MSCs into endothelial-like cells and keratinocytes. Intravenous transplantation of allogenic stable MSCs with Cxcr6 gene therapy potentiated skin tissue regeneration by increasing recruitment and engraftment as well as neovascularization and re-epithelialization at the wound site in excisional splinting wounds of type I and II diabetic mice. This study suggests that activation of the CXCL16-CXCR6 axis in bioengineered MSCs with Cxcr6 overexpression provides a promising therapeutic approach for the treatment of diabetic wounds.

Encapsulation of Mesenchymal Stem Cells: Dissecting the Underlying Mechanism of Mesenchymal Stem Cell Transplantation Therapy.

Mesenchymal stem cells (MSCs) are widely considered good candidates for cell transplantation therapy. Various central nervous system disorders have been suggested as suitable targets for MSC transplantation therapy. In this context, a great deal of basic and clinical research has been conducted to explore its clinical uses. Although depression is one of the most common diseases in the world, the response rate to the currently available treatment is insufficient and new treatments are much needed. Despite the fact that MSC transplantation therapy has the potential to elicit an antidepressant effect, few studies have been conducted on this topic to date and the underlying mechanism remains poorly understood. To address the development of a new treatment for depression, we evaluated the effect of MSCs using the encapsulation technique and Wistar-Kyoto rats. Encapsulation enables dissection of the complicated underlying mechanism of MSC transplantation therapy. Wistar-Kyoto rats that exhibit treatment-resistant depressive-like behaviors allow us to compare the effect of MSCs with that of conventional antidepressant treatment. In this commentary, we briefly summarize our recent published results and discuss future research prospects.

Synovial fluid-derived mesenchymal cells have non-inferior chondrogenic potential and can be utilized for regenerative therapy as substitute for synovium-derived cells

Recent progress in the field of mesenchymal stem cell (MSC) biology has enabled their clinical application. In the autologous cell transplantation therapy, the source of MSCs are quite important to reduce patients’ physical burden. In this study, we isolated MSCs from the synovial fluid (SF) and synovial membrane (Syn) of the same patients and compared the biological characteristics of them. In vitro and in vivo experiments indicated the non-inferior chondrocytic differentiation and articular cartilage regeneration potential of SF-MSCs compared to that of Syn-MSCs; however, SF-MSCs showed less proliferative potential than Syn-MSCs in vitro. Flow cytometry-based multiplex surface antigen expression analyses indicated that SF-MSCs exhibit fewer cells positive for CD140, which is a functional growth factor receptor for MSCs. Nevertheless, we obtained enough SF-MSCs for transplantation within several passages. Since arthrocentesis is routinely performed during outpatient care in the consultation room and is less invasive than synovial biopsy, MSC derived from synovial fluid could be considered an attractive cell source for cartilage regenerative therapy as a substitute for Syn-MSC. Developing these cells for clinical application may greatly benefit patients undergoing autologous MSC transplantation therapy.

Characteristics and usefulness of synovial fluid-derived stem cells compared with synovium-derived stem cells

Purpose: Recent progresses in the field of mesenchymal stem cells (MSCs) have brought us to apply them for clinical applications. In the autologous MSC transplantation therapy, the selection of donor tissues for the isolation of MSCs is quite important to obtain better clinical outcomes and to reduce patient's physical burden. We have started clinical trials to regenerate intra-articular cartilagenous tissues using MSCs derived from autologous synovial membrane (Syn-MSCs). In these trials, patients must suffer synovial biopsy to prepare autologous MSCs before transplantation. We considered that synovial fluid can be another good supplier for autologous MSCs for cartilage regeneration therapy since arthrocentesis is usually performed during the normal medical examinations in the consultation rooms. We have isolated MSCs from synovial fluid (SF-MSCs) and reported that these cells also have great potential to differentiate into chondrocytic lineage in vitro. However, it is still unrevealed whether SF-MSCs have comparable potential in cartilagenous tissue regeneration with those of Syn-MSCs. This study was aimed to compare proliferation and differentiation capacity of SF-MSCs and Syn-MSCs from the same patient. Methods: Synovial membrane (Syn) and synovial fluid (SF) were harvested from the same patient who underwent total knee arthroplasty at our hospital with approval and permission (n = 14, male = 1, female = 13, average 73.0 year-old). Isolated cells were maintained upto passage 10 to compare their proliferation ability. In vitro differentiation assay was performed using passage 3 cells. Flowcytometric analyses were performed to detect distinct surface antigen expression profiles between Syn- and SF-MSCs (FACS Verse, BD Bioscience). In order to compare the cartilage repair ability of SF-MSCs and Syn-MSCs, MSCs from the same patient were transplanted to osteochondral defects created in the trochlear groove of the femur of 10-week-old Lewis Rat, and histological assessments were performed at 4 weeks and 8 weeks. Results: Proliferation rate of SF-MSCs was much slower than that of Syn-MSC, however, they continued proliferating by 70 days in culture and needed for almost 3 weeks (passage 3) to become 1 × 107 cells, which is currently required for clinical application. In vitro differentiation assays indicated that there were subtle differences in chondrogenic-, osteogenic-, and adipogenic- differentiation ability between SF- and Syn-MSCs. Flowcytometric analyses indicated that the expression of MSC-related surface antigens (CD73, CD90, and CD105) was comparable between the groups. In contrast, expressions of certain sets of cell adhesion molecules (CD51/61) and growth factor receptors (CD140a) tended to decrease in SF-MSCs. In in vivo study, there was no significant difference in ICRS score (respectively SF 3.4, Syn 3.4 at 4weeks (P = 1.0), SF 6.8, Syn 5.4 at 8weeks (P = 0.798). Both MSCs groups showed good cartilage repair and there was no significant difference in histological grading scale modified from that of Pineda et al, and Wakitani et al(respectively SF 9.8, Syn 10.2 at 4weeks (P = 0.854), SF 7.4, Syn 7.4 at 8weeks (P = 0.446)). Conclusions: In this study, we showed that SF-MSCs could be the replacement of Syn-MSCs for cartilagenous tissue regeneration therapy. Surface antigen expression analyses and in vitro differentiation assays indicated that phenotypes of SF-MSCs are quite similar with those of Syn-MSCs and have characteristics of MSCs. However, proliferation rate was lower in SF-MSCs if compared to that of Syn-MSCs (n = 12). We consider that the down-regulation of cell adhesion molecules (CD51/61; Integrin alpha v/beta 3) and a growth factor receptor (CD140a/PDGFR alpha) might be possible reasons for that (n = 2). In spite of the less proliferation ability in vitro, cartilagenous tissue regeneration ability was quite comparable between SF-MSCs and Syn-MSCs. Since arthrocentesis is less invasive than synovial biopsy, it is much advantageous to reduce patient's physical burden in transplantation therapy.

Sustained benefit from combined plasmapheresis and allogeneic mesenchymal stem cells transplantation therapy in systemic sclerosis

BackgroundSystemic sclerosis (SSc) is an autoimmune disease involving the skin and several internal organs. Most therapies available for this disease are symptomatic. Given the difficulty in treating SSc, we conducted this study to investigate the effect of combined plasmapheresis (PE) and allogeneic mesenchymal stem cells transplantation (MSCT) therapy on SSc.MethodsFourteen patients underwent three repeated PE treatments with subsequent pulse cyclophosphamide on days 1, 3 and 5. Patients received a single MSCT (1 × 106 cells/kg of body weight) on day 8. During follow up, evaluations performed included complete physical examination, serologic testing, and organ function.ResultsThe mean modified Rodnan skin score (MRSS) improved from 20.1 ± 3.1 to 13.8 ± 10.2 (P < 0.001) at 12 months of follow up. Three patients had interstitial lung disease, all had improvement of lung function and improved computed tomography (CT) images after 12 months of combined therapy. This combined treatment also significantly decreased the anti-Scl70 autoantibody titer and serum transforming growth factor-β and vascular endothelial growth factor levels during follow up.ConclusionThe results indicate that PE combined with MSCT is a feasible treatment associated with possible clinical benefit for SSc patients.Trial registrationClinicalTrials.gov, NCT00962923. Registered on 19 August 2009.

Endothelial growth medium suppresses apoptosis of mesenchymal stem cells in vitro via decrease of miR‑29a.

The administration of mesenchymal stem cells (MSCs) in cases of cardiac ischemia/reperfusion injury (IRI) has been associated with a significant reduction of myocardial cell death and an effective improvement in cardiac function. However, one major limiting factor in MSCs transplantation therapy is the low survival rate of the transplanted cells. The present study aimed to demonstrate that human amnion-derived mesenchymal stem cells (hAMSCs) cultured with endothelial growth medium (EGM-2) exhibited reduced apoptosis when exposed to serum-free and hypoxic conditions; and that the expression of microRNA (miR)-29a decreased significantly. Furthermore, miR-29a knockdown resulted in decreased apoptosis of hAMSCs and increased myeloid cell leukemia (MCL)-1 at the mRNA and protein levels. These results suggested that EGM-2 promoted survival of hAMSCs partly through the regulation of miR-29a and MCL-1 expression levels. These findings may provide a novel understanding of a potential effective therapeutic strategy for cardiac IRI.

Therapeutic effects of stem cells on ischemic stroke were confirmed in an improved photothrombotic mouse model.

See accompanying article by Yun-Kyong Choi et al. DOI 10.1002/biot.201600057 Photothrombosis models with well-defined infarcts in specific regions of the cortex were developed by adjusting the intensity, duration and field of light/laser of irradiation. Infarct sizes, cellular and motor behaviors were observed. Optimal operation parameters were determined to create suitable lesions that mimic stroke. The model was used in the study of bone marrow-derived mesenchymal stem cells transplantation therapy. Neurogenesis and behavior recovery were observed after transplantation. Ischemic stroke is becoming a major cause of serious brain damage with enormous cost to the society in aftercare 1 and the loss of productivity in developed countries. Effective animal models for ischemic stroke are very important to improve our understanding to the pathophysiologic mechanism, treatment and prognosis of this complicated disease. However, the actual applicability of the animal study data on human treatment of various aspects of stroke-related symptoms is not all satisfactory. For example, the most common technique 2 used to induce ischemic stroke, middle cerebral artery occlusion (MCAO) produces significant edema and size variability which bring forth uncertainty in the interpretation of the observed behavior. The photothrombotic ischemia model 3, on the other hand, is more reproducible and reliable due to its much milder damages to the brain. Furthermore, as shown in Fig. 1, well-defined infarcts can be made to have more precise volume and location, with optimized operation parameters such as irradiation intensity, field and duration. In the current paper 4, a study to improve the method by determining better operation parameters for the photothrombotic method was conducted. The usefulness of a particular model for scientific studies resides closely with how much the model resembles human conditions, at molecular, cellular, physiological and systemic levels, of the studied disease or symptoms. Cerebral vasculature is one of the most important factors that affect the selection of proper models for specific stroke study. The ability to observe partial or complete recovery in brain tissue or motor function of a particular model is also important for developing treatment. In those areas, the well-controlled photothrombotic model presents a good opportunity for the medical research community. Laser is used to create thrombotic clots in specific regions of the brain, in order to produce well-controlled mimics of ischemic stroke in animal models. The authors present their results of stem-cell therapy 5 based on this model, as an example of the applicability of their improved method. In their results of transplantation of bone marrow-derived mesenchymal stem cells, significant improvement in neurogenesis with high reliability was reported. A stable animal model by the current method will benefit future researchers in ischemic brain diseases. The author declares no financial or commercial conflict of interest.

Activation of Wnt3a signaling promotes myogenic differentiation of mesenchymal stem cells in mdx mice.

Duchenne muscular dystrophy (DMD) is an X-linked genetic muscular disorder with no effective treatment at present. Mesenchymal stem cell (MSC) transplantation has been used to treat DMD, but the efficiency is low. Our previous studies show that activation of Wnt3a signaling promotes myogenic differentiation of MSCs in vitro. Here we report an effective MSC transplantation therapy in mdx mice by activation of Wnt3a signaling. MSCs were isolated from mouse bone marrow, and pretreated with Wnt3a-conditioned medium (Wnt3a-CM), then transplanted into mdx mice. The recipient mice were euthanized at 4, 8, 12, 16 weeks after the transplantation, and muscle pathological changes were examined. The expression of dystrophin in muscle was detected using immunofluorescence staining, RT-PCR and Western blotting. Sixteen weeks later, transplantation of Wnt3a-pretreated MSCs in mdx mice improved the characteristics of dystrophic muscles evidenced by significant reductions in centrally nucleated myofibers, the variability range of cross-sectional area (CSA) and the connective tissue area of myofibers. Furthermore, transplantation of Wnt3a-pretreated MSCs in mdx mice gradually and markedly increased the expression of dystrophin in muscle, and improved the efficiency of myogenic differentiation. Transplantation of Wnt3a-pretreated MSCs in mdx mice results in long-term amelioration of the dystrophic phenotype and restores dystrophin expression in muscle. The results suggest that Wnt3a may be a promising candidate for the treatment of DMD.

Protective Effect of Sinapine against Hydroxyl Radical-Induced Damage to Mesenchymal Stem Cells and Possible Mechanisms.

As a phenolic alkaloid occurring in Cruciferous plants, sinapine was observed to protect mesenchymal stem cells (MSCs) against ·OH-induced damage in this study. It was also found to prevent DNA from damage, to scavenge various free radicals (·OH, ·O2(-), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid diammonium salt) (ABTS)(+·), and 1,1-diphenyl-2-picrylhydrazyl radical (DPPH·)), and to reduce Cu(2+) to Cu(+). To further explore the mechanism, the end-product of sinapine reaction with DPPH· was determined using HPLC-electrospray ionization (ESI)-MS/MS and HPLC-diode array detector (DAD). Four molecular ion peaks (m/z 701, 702, 703, and 351) in HPLC-ESI-MS/MS analysis indicated a radical adduct formation (RAF) pathway; while a bathochromic shift (λ(max) 334→475 nm) in HPLC-DAD indicated the formation of quinone as the oxidized product of the phenolic -OH group. Based on these results, it may be concluded that, (i) sinapine can effectively protect against ·OH-induced damage to DNA and MSCs; such protective effect may provide evidence for a potential role for sinapine in MSC transplantation therapy, and be responsible for the beneficial effects of Cruciferous plants. (ii) The possible mechanism for sinapine to protect against ·OH-induced oxidative damage is radical-scavenging, which is thought to be via hydrogen atom (H·) transfer (HAT) (or sequential electron (e) proton transfer (SEPT))→RAF pathways.