Co-transplantation Of Mesenchymal Stem Cells Research Articles

Alternative therapeutic strategies in diabetes management.

Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreatic β cells, insulin resistance in peripheral tissues, or both, and results in a non-sufficient production of insulin. To adjust blood glucose levels, diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity. With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities, different strategies have been investigated. The first approaches included enhancing endogenous β cell activity or transplanting new islets. The protocol for this kind of intervention has recently been optimized, leading to standardized procedures. It is indicated for diabetic patients with severe hypoglycemia, complicated by impaired hypoglycemia awareness or exacerbated glycemic lability. Transplantation has been associated with improvement in all comorbidities associated with diabetes, quality of life, and survival. However, different trials are ongoing to further improve the beneficial effects of transplantation. Furthermore, to overcome some limitations associated with the availability of islets/pancreas, alternative therapeutic strategies are under evaluation, such as the use of mesenchymal stem cells (MSCs) or induced pluripotent stem cells for transplantation. The cotransplantation of MSCs with islets has been successful, thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms, including exosome release. The use of induced pluripotent stem cells is recent and requires further investigation. The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities, such as wound healing. Despite the number of advantages of the direct injection of MSCs, new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results. In conclusion, this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.

Strategy for Clinical Setting of Co-transplantation of Mesenchymal Stem Cells and Pancreatic Islets.

Islet transplantation may be the most efficient therapeutic technique for patients with type 1 diabetes mellitus (T1DM). However, the clinical application of this method is faced with numerous limitations, including isolated islet apoptosis, recipient rejection, and graft vascular reconstruction. Mesenchymal stem cells (MSCs) possess anti-apoptotic, immunomodulatory, and angiogenic properties. Here, we review recent studies on co-culture and co-transplantation of islets with MSCs. We have summarized the methods of preparation of co-transplantation, especially the merits of co-culture, and the effects of co-transplantation. Accumulating experimental evidence shows that co-culture of islets with MSCs promotes islet survival, enhances islet secretory function, and prevascularizes islets through various pretransplant preparations. This review is expected to provide a reference for exploring the use of MSCs for clinical islet co-transplantation.

Advancements in innate immune regulation strategies in islet transplantation.

As a newly emerging organ transplantation technique, islet transplantation has shown the advantages of minimal trauma and high safety since it was first carried out. The proposal of the Edmonton protocol, which has been widely applied, was a breakthrough in this method. However, direct contact between islets and portal vein blood will cause a robust innate immune response leading to massive apoptosis of the graft, and macrophages play an essential role in the innate immune response. Therefore, therapeutic strategies targeting macrophages in the innate immune response have become a popular research topic in recent years. This paper will summarize and analyze recent research on strategies for regulating innate immunity, primarily focusing on macrophages, in the field of islet transplantation, including drug therapy, optimization of islet preparation process, islet engineering and Mesenchymal stem cells cotransplantation. We also expounded the heterogeneity, plasticity and activation mechanism of macrophages in islet transplantation, providing a theoretical basis for further research.

A Prospective, Multi-Center, Randomized, Controlled Clinical Trial to Explore the Role of Mesenchymal Stem Cells in Preventing Graft Versus Host Disease

Background: There are few studies currently available on the prevention of GVHD by mesenchymal stem cells (MSCs) that use a systematic approach to prevent both aGVHD and cGVHD simultaneously. The clinical investigation of MSCs preventing either aGVHD or cGVHD independently is the main focus of the earlier studies. Aim:Using the strategy of co-transplantation of MSCs and HSCs and phased application of MSCs after transplantation (MSCs 100-day scheme), we seek to develop a secure and dependable system that can avoid both aGVHD and cGVHD based on our preliminary research. Method:Patients undergoing haploidentical adult hematopoietic stem cell transplantation will receive unaltered, fourth-generation UC-MSCs(Umbilical Cord). In addition to the usual GVHD preventive measures, UC-MSCs are given four hours before the transplantation of peripheral blood stem cells on day 0. UC-MSCs are administered once weekly for 1-4 weeks, once every 2-8 weeks, and once every 4-12 weeks after transplantation. The dose needed for each transfusion is 1 10 6/kg. Our research will look at how well UC-MSCs prevent GVHD following haplo-HSCT, as well as recurrence rates after transplantation, transplant-related issues, and the state of immunological reconstruction. the frequency, severity, 1- and 2-year survival rates, cumulative death rates, and the occurrence of aGVHD and cGVHD.Real-time tracking will be performed to monitor the occurrence of aGVHD and cGVHD, as well as their severity, frequency, 1-year and 2-year survival rates, and cumulative mortality rates. The analysis of the differences between the control group and the experiment will take into account the pre-transplant ferritin levels, CMV serological status of the donor-recipient, blood type matching situation, HLA locus matching situation, disease remission status, residual disease conditions, recipient age, donor-recipient gender matching situation, stem cell quantities (nucleated cells and CD34+ cell counts), and stem cell numbers (nucleated cells and CD34+ cell counts). Results: 96 patients from the MSCs group and 96 patients from the control group are now accessible for statistical purposes. Demographic factors for age and gender distribution do not differ considerably. Acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome-EB2, and acute mixed cell leukemia,which were all classified as having the same level of risk. The cumulative incidence of aGVHD grades II to IV is 19.8% in the MSCs group, while grades III to IV is 0%. Comparable indications for the control group are 43.8% and 9.3%, respectively. The overall incidence of aGVHD differs between the two groups in a statistically significant way (P=0.0047). The rates of moderate and severe cGVHD in the control group were 10.4% and 9.4%, respectively, whereas they were 13.5% and 4.2% in the MSCs group. Over the course of 1 year, the cumulative incidence of cGVHD for the MSCs group was 36.5%, compared to 39.6% for the control group. Regarding the overall two-year OS, there is no discernible difference between the MSCs group and the control group (P=0.43).While the MSCs group outperformed the control group in terms of GRFS (GVHD free and relapse free survival). Conclusion: The strategy of MSCs 100-day scheme infusion can successfully lower the incidence of acute and chronic GVHD and is beneficial for enhancing patient GRFS.

Integrin beta1 mediates the effect of telocytes on mesenchymal stem cell proliferation and migration in the treatment of acute lung injury.

Co-transplantation of mesenchymal stem cells (MSCs) with telocytes (TCs) was found to have therapeutic effects, although the mechanism of intercellular communication is still unknown. Our current studies aim at exploring the potential molecular mechanisms of TCs interaction and communication with MSCs with a focus on integrin beta1 (ITGB1) in TCs. We found that the co-culture of MSCs with ITGB1-deleted TCs (TCITGB1-ko ) changed the proliferation, differentiation and growth dynamics ability of MSC in responses to LPS or PI3K inhibitor. Changes of MSC proliferation and apoptosis were accompanied with the dysregulation of cytokine mRNA expression in MSCs co-cultured with TCITGB1-ko during the exposure of PI3Kα/δ/β inhibitor, of which IL-1β, IL-6 and TNF-α increased, while IFN-γ, IL-4 and IL-10 decreased. The responses of PI3K p85, PI3K p110 and pAKT of MSCs co-cultured with TCITGB1-ko to LPS or PI3K inhibitor were opposite to those with ITGB1-presented TCs. The intraperitoneal injection of TCITGB1-ko , TCvector or MSCs alone, as well as the combination of MSCs with TCITGB1-ko or TCvector exhibited therapeutic effects on LPS-induced acute lung injury. Thus, our data indicate that telocyte ITGB1 contributes to the interaction and intercellular communication between MSCs and TCs, responsible for influencing other cell phenomes and functions.

Benefit of Adjuvant Mesenchymal Stem Cell Transplantation to Critical-Sized Peripheral Nerve Defect Repair: A Systematic Review and Meta-Analysis of Preclinical Studies.

Critically sized nerve defects cause devastating life-long disabilities and require interposition for reconstruction. Additional local application of mesenchymal stem cells (MSCs) is considered promising to enhance peripheral nerve regeneration. To better understand the role of MSCs in peripheral nerve reconstruction, we performed a systematic review and meta-analysis of the effects of MSCs on critically sized segment nerve defects in preclinical studies. 5146 articles were screened following PRISMA guidelines using PubMed and Web of Science. A total of 27 preclinical studies (n = 722 rats) were included in the meta-analysis. The mean difference or the standardized mean difference with 95% confidence intervals for motor function, conduction velocity, and histomorphological parameters of nerve regeneration, as well as the degree of muscle atrophy, was compared in rats with critically sized defects and autologous nerve reconstruction treated with or without MSCs. The co-transplantation of MSCs increased the sciatic functional index (3.93, 95% CI 2.62 to 5.24, p < 0.00001) and nerve conduction velocity recovery (1.49, 95% CI 1.13 to 1.84, p = 0.009), decreased the atrophy of targeted muscles (gastrocnemius: 0.63, 95% CI 0.29 to 0.97 p = 0.004; triceps surae: 0.08, 95% CI 0.06 to 0.10 p = 0.71), and promoted the regeneration of injured axons (axon number: 1.10, 95% CI 0.78 to 1.42, p < 0.00001; myelin sheath thickness: 0.15, 95% CI 0.12 to 0.17, p = 0.28). Reconstruction of critically sized peripheral nerve defects is often hindered by impaired postoperative regeneration, especially in defects that require an autologous nerve graft. This meta-analysis indicates that additional application of MSC can enhance postoperative peripheral nerve regeneration in rats. Based on the promising results in vivo experiments, further studies are needed to demonstrate potential clinical benefits.

Combinational Treatment Involving Decellularized Extracellular Matrix Hydrogels With Mesenchymal Stem Cells Increased the Efficacy of Cell Therapy in Pancreatitis.

Cell transplantation using mesenchymal stem cells (MSCs) has emerged as a promising approach to repairing and regenerating injured or impaired organs. However, the survival and retention of MSCs following transplantation remain a challenge. Therefore, we investigated the efficacy of co-transplantation of MSCs and decellularized extracellular matrix (dECM) hydrogels, which have high cytocompatibility and biocompatibility. The dECM solution was prepared by enzymatic digestion of an acellular porcine liver scaffold. It could be gelled and formed into porous fibrillar microstructures at physiological temperatures. MSCs expanded three-dimensionally in the hydrogel without cell death. Compared to the 2-dimensional cell culture, MSCs cultured in the hydrogel showed increased secretion of hepatocyte growth factor (HGF) and tumor necrosis factor-inducible gene 6 protein (TSG-6), both of which are major anti-inflammatory and anti-fibrotic paracrine factors of MSCs, under TNFα stimulation. In vivo experiments showed that the co-transplantation of MSCs with dECM hydrogel improved the survival rate of engrafted cells compared to those administered without the hydrogel. MSCs also demonstrated therapeutic effects in improving inflammation and fibrosis of pancreatic tissue in a dibutyltin dichloride (DBTC)-induced rat pancreatitis model. Combinational use of dECM hydrogel with MSCs is a new strategy to overcome the challenges of cell therapy using MSCs and can be used for treating chronic inflammatory diseases in clinical settings.

How mesenchymal stem cell cotransplantation with hematopoietic stem cells can improve engraftment in animal models.

BACKGROUNDBone marrow transplantation (BMT) can be applied to both hematopoietic and nonhematopoietic diseases; nonetheless, it still comes with a number of challenges and limitations that contribute to treatment failure. Bearing this in mind, a possible way to increase the success rate of BMT would be cotransplantation of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) to improve the bone marrow niche and secrete molecules that enhance the hematopoietic engraftment. AIMTo analyze HSC and MSC characteristics and their interactions through cotransplantation in murine models.METHODSWe searched for original articles indexed in PubMed and Scopus during the last decade that used HSC and MSC cotransplantation and in vivo BMT in animal models while evaluating cell engraftment. We excluded in vitro studies or studies that involved graft versus host disease or other hematological diseases and publications in languages other than English. In PubMed, we initially identified 555 articles and after selection, only 12 were chosen. In Scopus, 2010 were identified, and six were left after the screening and eligibility process.RESULTSOf the 2565 articles found in the databases, only 18 original studies met the eligibility criteria. HSC distribution by source showed similar ratios, with human umbilical cord blood or animal bone marrow being administered mainly with a dose of 1 × 107 cells by intravenous or intrabone routes. However, MSCs had a high prevalence of human donors with a variety of sources (umbilical cord blood, bone marrow, tonsil, adipose tissue or fetal lung), using a lower dose, mainly 106 cells and ranging 104 to 1.5 × 107 cells, utilizing the same routes. MSCs were characterized prior to administration in almost every experiment. The recipient used was mostly immunodeficient mice submitted to low-dose irradiation or chemotherapy. The main technique of engraftment for HSC and MSC cotransplantation evaluation was chimerism, followed by hematopoietic reconstitution and survival analysis. Besides the engraftment, homing and cellularity were also evaluated in some studies. CONCLUSIONThe preclinical findings validate the potential of MSCs to enable HSC engraftment in vivo in both xenogeneic and allogeneic hematopoietic cell transplantation animal models, in the absence of toxicity.

Infusion of haploidentical HSCs combined with allogenic MSCs for the treatment of ALL patients.

Although haploidentical stem cell transplantation (haplo-HSCT) offers almost all acute lymphoblastic leukaemia (ALL) patients an opportunity for immediate transplantation, it exhibits a higher incidence of graft failure and graft versus host disease (GVHD). Mesenchymal stem cells (MSCs) are characterised by their haematopoiesis-promoting and immunomodulatory capacity. Thus, we designed a combination of haplo-HSCT and MSCs for ALL patients. ALL patients (n = 110) were given haploidentical HSCs combined with allogenic MSCs, and ALL patients without MSC infusion (n = 56) were included as controls. The 100-day cumulative incidences of grade ≥2 acute GVHD (aGVHD) and grade ≥3 aGVHD were 40.00% and 9.09% compared to 42.32% (P = 0.79) and 22.79% (P = 0.03) in patients without MSC infusion, respectively. The 3-year cumulative incidences of chronic GVHD (cGVHD) and extensive cGVHD were 22.27% and 10.27% compared to 32.14% (P = 0.19) and 22.21% (P = 0.04) in patients without MSC infusion, respectively. No significant differences in the 3-year relapse incidence, nonrelapse mortality, leukaemia-free survival or overall survival in groups with and without MSC cotransplantation were observed. Multivariate analysis showed that MSC infusion contributed to a lower risk of developing extensive cGVHD. Our data suggested that haplo-HSCT combined with MSCs may provide an effective and safe treatment for ALL patients.

Recent Progress of Research Regarding the Applications of Stem Cells for Treating Diabetes Mellitus

At present, the number of diabetes patients has exceeded 537 million worldwide and this number continues to increase. Stem cell therapy represents a new direction for the treatment of diabetes; the use of stem cells overcomes some shortcomings associated with traditional therapies. Functional β cells play an important role in the pathogenesis of diabetes. As therapeutic targets, functional β cells are restored by a variety of stem cells, including pluripotent stem cells, mesenchymal cells, and urine-derived stem cells. Although all types of stem cells have their own characteristics, they mainly promote the repair and regeneration of β cells through directional differentiation, immunomodulation, and paracrine signaling after homing to the injured site. However, stem cell therapy still faces many obstacles, such as low long-term cell survival rate after transplantation, low maintenance time of blood glucose homeostasis, immune rejection, and tumorigenesis. Recently, genetically edited pluripotent stem cells and the cotransplantation of mesenchymal stem cells and islet cells have made significant progress in improving the efficacy of stem cell transplantation processes, also providing powerful tools for the study of the mechanisms underlying diabetes and disease modeling. In this review, we first focused on: (1) stem cells as a pool for the differentiation of insulin-producing cells; (2) stem cells as a source for regenerative repair of damaged islets and as a potential cotransplanted population with islets; (3) the potential of combining gene editing with stem cell therapy; and (4) selection of the stem cell transplantation approach. Based on these topics, we discuss the challenges within the field of adapting stem cell-supported and stem cell-derived transplantations and the promising routes for overcoming these problems.

Promotion of Platelet Production by Co-Transplantation of Mesenchymal Stem Cells in Bone Marrow Transplantation.

Therapeutic strategies that can promote platelet production are in demand to enhance clinical outcomes of bone marrow transplantation (BMT). Our research group has studied human tonsil-derived mesenchymal stem cells (T-MSCs) and their effectiveness in promoting bone marrow (BM) engraftment. Here, we analyzed the effects of T-MSCs on platelet production and hemostasis. Donor BM cells (BMCs) were isolated from C57BL/6 mice and transplanted with or without T-MSCs to BALB/c recipient mice. Mice were sacrificed and blood cells were counted using an Auto Hematology Analyzer. Femur sections were stained with CD41 antibody to analyze megakaryocytes in the BM. Growth factor secretion from MSCs was analyzed using the Quantibody Array. Effects of T-MSC conditioned medium (CM) on megakaryopoiesis were investigated using the MegaCult assay. In a mouse model of BMT, T-MSC CM was injected with or without anti-placental growth factor (α-PlGF) blocking antibody, and blood cell numbers and coagulation were analyzed. T-MSC co-transplantation increased percent survival of BMT mice. Platelet numbers were significantly lower in the BMC-only group, whereas T-MSC co-transplantation restored circulating platelets to levels similar to those of the control group. Significantly reduced numbers of CD41 + megakaryocytes in Bu-Cy and BMC groups were increased by T-MSC co-transplantation. PlGF secretion from T-MSCs were detected and enhanced megakaryopoiesis, platelet production, and coagulation by T-MCS CM were disrupted in the presence of the α-PlGF blocking antibody. We demonstrated the effectiveness of T-MSC co-transplantation in promoting platelet production and coagulation after BMT. These findings highlight the potential therapeutic relevance of T-MSCs for preventing thrombocytopenia after BMT.

Efficacy and safety of mesenchymal stem cells co-infusion in allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is life-saving for severe hematological conditions. However, its outcomes need further improvement, and co-infusion of mesenchymal stem cells (MSCs) may show promise. A growing body of research on this subject exists, while the results of different trials are conflicting. A systematic review and meta-analysis is needed to appraise the real efficacy and safety of MSC co-transplantation in allo-HSCT.MethodsStudies comparing MSC co-transplantation in allo-HSCT with allo-HSCT alone were searched in six medical databases from inception to June 10, 2020. The primary outcomes were engraftment and graft-versus-host disease (aGVHD and cGVHD, respectively). Other outcomes included overall survival (OS), relapse rate (RR), non-relapse mortality (NRM), and immune reconstitution. Information was independently extracted by two investigators. Methodological quality was assessed using the Cochrane Collaboration tool. Meta-analysis was performed using RevMan 5.4.ResultsSix randomized controlled trials (RCTs) and 13 non-randomized controlled trials (nRCTs) were included. MSC co-infusion resulted in shorter times to neutrophil engraftment (RCTs: standardized mean difference (SMD) − 1.20, p = 0.04; nRCTs: SMD − 0.54, p = 0.04) and platelet engraftment (RCTs: SMD − 0.60, p = 0.04; nRCTs: SMD − 0.70, p = 0.01), a lower risk of cGVHD (RCTs: risk ratio (RR) 0.53, p = 0.01; nRCTs: RR 0.50, p < 0.01), and a slightly positive trend towards reducing the risk of aGVHD and NRM, without affecting RR and OS. Subgroup analyses revealed that when MSCs were co-transplanted, children and adolescents, and patients receiving human leukocyte antigen (HLA)-nonidentical HSCT showed improvements in engraftment and incidence of GVHD and NRM; adults and patients who received HLA-identical HSCT had lower cGVHD; patients with malignancies exhibited improvements in GVHD and NRM incidence; and patients with non-malignancies experienced accelerated engraftment. Notably, a reduced OS was observed in patients with hematological malignancies undergoing HLA-identical HSCT.ConclusionMSC co-infusion generally improved engraftment and reduced cGVHD, without increasing mortality or relapse. Regarding aGVHD and NRM, the effects of MSCs were not quite significant. Specifically, our data support the utilization of MSC co-transplantation in children and young individuals with HLA-nonidentical HSCT, but not in adult patients with hematological malignancies undergoing HLA-identical HSCT.

The effect of bone marrow-derived mesenchymal stem cell co-transplantation with hematopoietic stem cells on liver fibrosis alleviation and survival in patients with class III \u03b2-thalassemia major

BackgroundHepatic fibrosis is a common complication in transfusion-dependent thalassemia patients. Data on the co-transplantation of mesenchymal stem cells (MSCs) with hematopoietic stem cells (HSCs) in beta-thalassemia major patients are scarce. Therefore, we aimed to evaluate the effect of co-transplantation of bone marrow-derived MSC with HSCs on the liver fibrosis alleviation and transplant outcomes in class III beta-thalassemia major.MethodsBetween April 1998 and January 2017, a total of 224 consecutive patients with class III beta-thalassemia major underwent allogeneic HSCT in the Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran. To assess liver fibrotic changes after transplantation, 47 patients participated in the MSC plus HSC group and 30 patients in the HSC only group at the end of the follow-up period. All patients underwent laboratory tests, especially serum ferritin and liver function testing, hepatic T2* MRI, liver biopsy, and FibroScan before and 2 years after transplantation. Kaplan-Meier curves were derived to determine survival and were compared using the log-rank test. Repeated-measure, mixed-effect linear regression models were used to examine the changes in liver fibrosis over time.ResultsThe 10-year OS rate was 71.84% in the mesenchymal group and 61.89% in the non-mesenchymal group (P value = 0.294), while the 10-year TFS rate was 63.64% in the mesenchymal group and 52.78% in the non-mesenchymal group (P value = 0.285). No significant difference was observed in the 10-year NRM, rejection rate, ANC engraftment, platelet engraftment, acute GvHD, and chronic GvHD between the two groups. In addition, the results of repeated-measure, mixed-effect linear regression models showed that none of the variables determining hepatic fibrosis had a significant difference between patients receiving MSCs and patients who did not receive MSCs.ConclusionsBased on the results of this study, a single infusion of MSCs at the time of HSCT to patients with class III beta-thalassemia major could not significantly improve the liver fibrosis alleviation and transplantation outcomes, including OS, TFS, TRM, rejection rate, ANC engraftment, platelet engraftment, acute GvHD, and chronic GvHD.

Preliminary studies of constructing a tissue-engineered lamellar corneal graft by culturing mesenchymal stem cells onto decellularized corneal matrix.

To construct a competent corneal lamellar substitute in order to alleviate the shortage of human corneal donor. Rabbit mesenchymal stem cells (MSCs) were isolated from bone marrow and identified by flow cytometric, osteogenic and adipogenic induction. Xenogenic decellularized corneal matrix (XDCM) was generated from dog corneas. MSCs were seeded and cultured on XDCM to construct the tissue-engineered cornea. Post-transplantation biocompatibility of engineered corneal graft were tested by animal experiment. Rabbits were divided into two groups then underwent lamellar keratoplasty (LK) with different corneal grafts: 1) XDCM group (n=5): XDCM; 2) XDCM-MSCs groups (n=4): tissue-engineered cornea made up with XDCM and MSCs. The ocular surface recovery procedure was observed while corneal transparency, neovascularization and epithelium defection were measured and compared. In vivo on focal exam was performed 3mo postoperatively. Rabbit MSCs were isolated and identified. Flow cytometry demonstrated isolated cells were CD90 positive and CD34, CD45 negative. Osteogenic and adipogenic induction verified their multipotent abilities. MSC-XDCM grafts were constructed and observed. In vivo transplantation showed the neovascularization in XDCM-MSC group was much less than that in XDCM group postoperatively. Post-transplant 3-month confocal test showed less nerve regeneration and bigger cell-absent area in XDCM-MSC group. This study present a novel corneal tissue-engineered graft that could reduce post-operatively neovascularization and remain transparency, meanwhile shows that co-transplantation of MSCs may help increase corneal transplantation successful rate and enlarge the source range of corneal substitute to overcome cornea donor shortage.

Cotransplantation of mesenchymal stem cells and endothelial progenitor cells for treating steroid-induced osteonecrosis of the femoral head.

Steroid‐induced osteonecrosis of the femoral head (ONFH) is characterized by decreased osteogenesis, angiogenesis, and increased adipogenesis. While bone tissue engineering has been widely investigated to treat ONFH, its therapeutic effects remain unsatisfactory. Therefore, further studies are required to determine optimal osteogenesis, angiogenesis and adipogenesis in the necrotic area of the femoral head. In our study, we developed a carboxymethyl chitosan/alginate/bone marrow mesenchymal stem cell/endothelial progenitor cell (CMC/ALG/BMSC/EPC) composite implant, and evaluated its ability to repair steroid‐induced ONFH. Our in vitro studies showed that BMSC and EPC coculture displayed enhanced osteogenic and angiogenic differentiation. When compared with single BMSC cultures, adipogenic differentiation in coculture systems was reduced. We also fabricated a three‐dimensional (3D) CMC/ALG scaffold for loading cells, using a lyophilization approach, and confirmed its good cell compatibility characteristics, that is, high porosity, low cytotoxicity and favorable cell adhesion. 3D coculture of BMSCs and EPCs also promoted secretion of osteogenic and angiogenic factors. Then, we established an rabbit model of steroid‐induced ONFH. The CMC/ALG/BMSC/EPC composite implant was transplanted into the bone tunnel of the rabbit femoral head after core decompression (CD) surgery. Twelve weeks later, radiographical and histological analyses revealed CMC/ALG/BMSC/EPC composite implants had facilitated the repair of steroid‐induced ONFH, by promoting osteogenesis and angiogenesis, and reducing adipogenesis when compared with CD, CMC/ALG, CMC/ALG/BMSC and CMC/ALG/EPC groups. Thus, our data show that cotransplantation of BMSCs and EPCs in 3D scaffolds is beneficial in treating steroid‐induced ONFH.

Combined Transplantation With Human Mesenchymal Stem Cells Improves Retinal Rescue Effect of Human Fetal RPE Cells in Retinal Degeneration Mouse Model.

PurposeWe verified whether fetal RPE (fRPE) cells and mesenchymal stem cells (MSCs) cotransplantation can combine the features of these two cell types and alleviate retinal degeneration in a retinal degenerative disease mouse model.MethodsTail vein injection of sodium iodate (NaIO3) was conducted to establish the retinal degenerative disease mouse model. MSCs and fRPE cells were transplanted either separately or combined in the subretinal space of retinal degenerative disease animals. ERG, optical coherence tomography, histologic, and immunofluorescence analyses were performed. Furthermore, the expression level of Crx, rhodopsin, Iba1, F4/80, Caspase 3, nerve growth factor, and brain-derived neurotrophic factor were assessed to investigate the mechanisms involved in cell transplantation effects.ResultsCotransplantation of fRPE and MSC cells promoted significant improvements in ERG results and in the survival rate of transplanted cells. In addition, MSC and fRPE cell cotransplantation resulted in an increase in the thickness of the total retina, as well as in the outer and inner nuclear layers. Combined transplantation also upregulated the expression level of Crx and rhodopsin and downregulated caspase 3 expression, highlighting its better photoreceptor rescue effect in relation to the single cell type transplantation. Finally, combined transplantation suppressed the expression of Iba1 and F4/80 factors while increasing the endogenous expression of nerve growth factor and brain-derived nerve growth factor neurotrophic factors. These data suggest that MSC and fRPE cell cotransplantation is able to suppress immunoreactions and promote neurotrophic factor excretion.ConclusionsCombined transplantation of MSCs and fRPE cells results in a better retinal rescue effect than single cell type transplantation in NaIO3-induced retinopathy.

Hepatocyte and mesenchymal stem cell co-transplantation in rats with acute liver failure.

BackgroundCell therapy is considered a potential alternative to liver transplantation in acute liver failure (ALF). We aimed to evaluate the add-on therapeutic benefit of hepatocyte and mesenchymal stem cell (MSC) cotransplantation over hepatocyte-only transplantations in a rat model of ALF.MethodsALF was induced by D-galactosamine in Sprague-Dawley rats. Freshly isolated donor hepatocytes were derived from Tg (UBC-emGFP) rats and MSCs were collected from the bone marrow cells of DsRed rats. Donor hepatocytes (1×107/mL) were intraportally transplanted 24 hours after treatment with D-galactosamine over a 70-second interval, and donor MSCs (0.5, 1, or 2×106/0.5 mL) were intraportally transplanted 1 hour after the hepatocyte transplantation was complete. Animals were sacrificed after 7 and 14 days and subjected to donor cell identification, liver histology, serologic testing, and immunohistopathological examination.ResultsMSCs were observed in the periportal area, 1 and 2 weeks after transplantation. Transplanted hepatocytes did not actively proliferate when compared to hepatocyte-only transplantation. Morphologically, transplanted MSCs did not appear to differentiate into hepatocytes even 2 weeks after transplantation. Cotransplantation of MSCs was associated with lower macrophage infiltration, and reduced type I collagen, hepatocyte growth factor, tumor necrosis factor-α, and interleukin 10 expression, with similar gene expression profiles for epidermal growth factor and interleukin 6, when compared to hepatocyte-only transplantation.ConclusionsHepatocyte and MSC cotransplantation is feasible and safe in rat models of ALF. MSCs were found to survive the process and could be located within the periportal niches 2 weeks after treatment, without enhancing transplanted hepatocyte proliferation or differentiating into hepatocytes, while ameliorating the inflammatory response.

Syngeneic Mesenchymal Stem Cells Reduce Immune Rejection After Induced Pluripotent Stem Cell-Derived Allogeneic Cardiomyocyte Transplantation

Avoiding immune rejection after allogeneic induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) transplantation is a concern. However, mesenchymal stem cells (MSCs) can suppress immune rejection. To determine whether MSC co-transplantation can reduce immune rejection after allogeneic iPSC-CM transplantation, the latter cell type, harbouring a luciferase transgene, was subcutaneously transplanted alone or together with syngeneic MSCs into BALB/c mice. Bioluminescence imaging revealed that MSC co-transplantation significantly improved graft survival (day 7: iPSC-CMs alone 34 ± 5%; iPSC-CMs with MSCs, 61 ± 7%; P = 0.008). MSC co-transplantation increased CD4 + CD25 + FOXP3 + regulatory T cell numbers, apoptotic CD8-positive T cells, and IL-10 and TGF-beta expression at the implantation site. Analysis using a regulatory T cell depletion model indicated that enhanced regulatory T cell populations in the iPSC-CM with MSC group partially contributed to the extended iPSC-CM survival. Further, MSCs affected activated lymphocytes directly through cell–cell contact, which reduced the CD8/CD4 ratio, the proportion of Th1-positive cells among CD4-positive cells, and the secretion of several inflammation-related cytokines. Syngeneic MSC co-transplantation might thus control allogeneic iPSC-CM rejection by mediating immune tolerance via regulatory T cells and cell–cell contact with activated lymphocytes; this approach has promise for cardiomyogenesis-based therapy using allogeneic iPSC-CMs for severe heart failure.

Class I and II Histone Deacetylase Inhibitor LBH589 Promotes Endocrine Differentiation in Bone Marrow Derived Human Mesenchymal Stem Cells and Suppresses Uncontrolled Proliferation.

Mesenchymal stem cells are useful tools employed in clinical and preclinical medicine. Their beneficial potential in especially degenerative as well as autoimmune diseases is a constant focus of research. Regarding diabetes mellitus, transplantation of stem cells is seen as a possible therapeutic approach to overcome the loss of endocrine pancreatic cells. It was reported that co-transplantation of mesenchymal stem cells with pancreatic islet cells improves function and survival of the graft. However, these multipotent progenitors may be able to form tumors, especially under immunosuppressed conditions. Histone deacetylase inhibitors might offer the potential to overcome this issue. These small molecules can induce cell differentiation and control proliferation. Their potential to control lineage development of stem cells has been distinctly demonstrated in the treatment of cancer, mainly in hematopoietic neoplasias.In this study, we demonstrate that human bone marrow-derived mesenchymal stem cells exhibit low carcinogenic potential in an immunosuppressed condition in vivo. Further, the effect of histone deacetylase inhibitors LBH589, MS-275, and MGCD0103 was examined after normalizing histone deacetylase activities in culture. Interestingly, transcripts of insulin gene enhancer protein and paired-box-gene 6, two markers of pancreatic endocrine differentiation were constitutively expressed in the cell line. The broad spectrum inhibitor of class I and class II histone deacetylases LBH589 upregulated the expression of these transcription factors in a significant way, whereas addition of selective class I histone deacetylase inhibitors MS-275 and MGCD0103 did not result in significant changes in gene expression.In conclusion, we deliver evidence that a combined class I and II histone deacetylase inhibition is able to modulate the transcripts of differentiation markers of mesenchymal stem cells. The treatment holds the capability to facilitate endocrine differentiation in future approaches to replace endocrine cells by stem cell therapy.

Conditioned Medium from Human Tonsil-Derived Mesenchymal Stem Cells Enhances Bone Marrow Engraftment via Endothelial Cell Restoration by Pleiotrophin.

Cotransplantation of mesenchymal stem cells (MSCs) with hematopoietic stem cells (HSCs) has been widely reported to promote HSC engraftment and enhance marrow stromal regeneration. The present study aimed to define whether MSC conditioned medium could recapitulate the effects of MSC cotransplantation. Mouse bone marrow (BM) was partially ablated by the administration of a busulfan and cyclophosphamide (Bu–Cy)-conditioning regimen in BALB/c recipient mice. BM cells (BMCs) isolated from C57BL/6 mice were transplanted via tail vein with or without tonsil-derived MSC conditioned medium (T-MSC CM). Histological analysis of femurs showed increased BM cellularity when T-MSC CM or recombinant human pleiotrophin (rhPTN), a cytokine readily secreted from T-MSCs with a function in hematopoiesis, was injected with BMCs. Microstructural impairment in mesenteric and BM arteriole endothelial cells (ECs) were observed after treatment with Bu–Cy-conditioning regimen; however, T-MSC CM or rhPTN treatment restored the defects. These effects by T-MSC CM were disrupted in the presence of an anti-PTN antibody, indicating that PTN is a key mediator of EC restoration and enhanced BM engraftment. In conclusion, T-MSC CM administration enhances BM engraftment, in part by restoring vasculature via PTN production. These findings highlight the potential therapeutic relevance of T-MSC CM for increasing HSC transplantation efficacy.