Mesenchymal Stem Cell Transplantation Research Articles

Cytoplasm or Supernatant: Where Is the Treasury of the Bioactive Antiaging Factor from Mesenchymal Stem Cells?

Cell-free compounds of mesenchymal stem cells (MSCs) could be a safer and cheaper substitution for MSC transplantation and have gained substantial research interest for antiaging skin treatments. However, whether those bioactive components should be obtained from the cytoplasm or supernatant is yet to be determined. In this study, we examined the ingredients of the MSC cytoplasm extract (MSC-ex) and MSC supernatant (MSC-s) and evaluated their effect in a photoaging model. Although MSC-ex has a richer protein composition than MSC-s, the latter has a proteome associated with wound healing and blood vessel development. Over 85% of the proteins in MSC-s were also found in MSC-ex, including extracellular matrix protein and various growth factors. The results of real-time PCR and western blot also demonstrate that both MSC-s and MSC-ex can upregulate collagen, transforming growth factor β (TGF-β), and vascular endothelial growth factor (VEGF) and downregulate IL-1β and matrix metalloproteinase-1 (MMP-1), which were considered critical for antiphotoaging. This supports our observations in the Hematoxylin and Eosin (HE) and Masson staining assay that they have a comparable effect as MSCs in terms of enhancing dermal thickness, and stimulating collagen regeneration. Although MSC-s and MSC-ex showed a weaker immunosuppression effect than MSCs, moisture measurement showed that they repair damage more rapidly than MSCs. Furthermore, the histological results showed that MSC-s maintains a super effect on immunosuppression, epidermal repair, and angiogenesis. That may be associated with the higher content of laminin, TGF-β, and VEGF in MSC-s, as well as its super cytokine transcriptional regulation ability. Thus, both MSC-s and MSC-ex can safely and effectively promote the repair of skin light injury, similar to MSCs. Our findings can broaden the range of active factors available in cell-free treatment, determine the difference between MSC-s and MSC-ex, and provide a reference for the development of similar products in regenerative medicine.

Mesenchymal stem cell transplantation alleviates Sjögren's syndrome symptoms by modulating Tim-3 expression

Mesenchymal stem cell (MSC) transplantation has been proven to be an effective treatment for Sjögren’s syndrome (SS) to improve salivary gland pathology and exocrine function, but the mechanism remains unclear. A recently reported inhibitory receptor, Tim-3, also appears to be closely related to autoimmune diseases. Here, we aimed to explore the roles of Tim-3 in the pathogenesis of SS and MSC treatment. The results showed that Tim-3 was downregulated in T cells of SS patients and nonobese diabetic (NOD) mice, which is correlated with SS pathogenesis. MSC transplantation ameliorated SS-like symptoms and pathological changes in the submandibular glands with modulated Tim-3 expression, resulting in attenuation of localized inflammation, fibrosis, and epithelial-mesenchymal transition. Furthermore, Tim-3 is crucial for the inhibitory effect of MSCs on PBMC proliferation in vitro. Therefore, our work has demonstrated that MSC transplantation effectively mitigates the pathological changes of SS by regulating Tim-3 expression, which provides a novel mechanism of MSC treatment and indicates a brand-new perspective of the combination of inhibitory-receptor-targeted treatment and MSC therapy in SS.

Mesenchymal Stem Cell Use in Acute Tendon Injury: In Vitro Tenogenic Potential vs. In Vivo Dose Response.

Stem cell therapy for the treatment of tendon injury is an emerging clinical practice in the fields of human and veterinary sports medicine; however, the therapeutic benefit of intralesional transplantation of mesenchymal stem cells in tendonitis cases is not well designed. Questions persist regarding the overall tenogenic potential and efficacy of this treatment alone. In this study, we aimed to isolate a rat mesenchymal stem cell lineage for in vitro and in vivo use, to assess the effects of growth factor exposure in vitro on cell morphology, behavior, and tendon-associated glycoprotein production, and to assess the therapeutic potential of intralesional stem cells, as a function of dose, in vivo. First, rat adipose-derived (rAdMSC) and bone marrow-derived (rBMSC) stem cell lineages were isolated, characterized with flow cytometric analysis, and compared in terms of proliferation (MTS assay) and cellular viability (calcein AM staining). Rat AdMSCs displayed superior proliferation and more homogenous CD 73, CD 44H, and CD 90 expression as compared to rBMSC. Next, the tenogenic differentiation potential of the rAdMSC lineage was tested in vitro through isolated and combined stimulation with reported tenogenic growth factors, transforming growth factor (TGF)-β3 and connective tissue growth factor (CTGF). We found that the most effective tenogenic factor in terms of cellular morphologic change, cell alignment/orientation, sustained cellular viability, and tendon-associated glycoprotein upregulation was TGFβ3, and we confirmed that rAdMSC could be induced toward a tenogenic lineage in vitro. Finally, the therapeutic potential of rAdMSCs as a function of dose was assessed using a rat acute Achilles tendon injury model. Amounts of 5 × 105 (low dose) and 4 × 106 (high dose) were used. Subjectively, on the gross morphology, the rAdMSC-treated tendons exhibited fewer adhesions and less scar tissue than the control tendons; however, regardless of the rAdMSC dose, no significant differences in histological grade or tissue collagen I deposition were noted between the rAdMSC-treated and control tendons. Collectively, rAdMSCs exhibited appropriate stem cell markers and tenogenic potential in vitro, but the clinical efficacy of intralesional implantation of undifferentiated cells in acute tendonitis cases could not be proven. Further investigation into complementary therapeutics or specialized culture conditions prior to implantation are warranted.

Update on the Pharmacological Treatment of Primary Biliary Cholangitis.

Ursodeoxycholic acid (UDCA) is the first-line therapy used for the treatment of PBC. In recent years, new pharmacological agents have been proposed for PBC therapy to cure UDCA-non-responders. Obeticholic acid (OCA) is registered in many countries for PBC, and fibrates also seem to be effective in ameliorating biochemistry alteration and symptoms typical of PBC. Moreover, a variety of new agents, acting with different mechanisms of action, are under clinical evaluation for PBC treatment, including PPAR agonists, anti-NOX agents, immunomodulators, and mesenchymal stem cell transplantation. Since an insufficient amount of data is currently available about the effect of these novel approaches on robust clinical endpoints, such as transplant-free survival, their clinical approval needs to be supported by the consistent improvement of these parameters. The intensive research in this field will hopefully lead to a novel treatment landscape for PBC in the near future, with innovative therapies based on the combination of multiple agents acting on different pathogenetic mechanisms.

Mesenchymal stem cells protect against TBI-induced pyroptosis in vivo and in vitro through TSG-6

BackgroundPyroptosis, especially microglial pyroptosis, may play an important role in central nervous system pathologies, including traumatic brain injury (TBI). Transplantation of mesenchymal stem cells (MSCs), such as human umbilical cord MSCs (hUMSCs), has been a focus of brain injury treatment. Recently, MSCs have been found to play a role in many diseases by regulating the pyroptosis pathway. However, the effect of MSC transplantation on pyroptosis following TBI remains unknown. Tumor necrosis factor α stimulated gene 6/protein (TSG-6), a potent anti-inflammatory factor expressed in many cell types including MSCs, plays an anti-inflammatory role in many diseases; however, the effect of TSG-6 secreted by MSCs on pyroptosis remains unclear.MethodsMice were subjected to controlled cortical impact injury in vivo. To assess the time course of pyroptosis after TBI, brains of TBI mice were collected at different time points. To study the effect of TSG-6 secreted by hUMSCs in regulating pyroptosis, normal hUMSCs, sh-TSG-6 hUMSCs, or different concentrations of rmTSG-6 were injected intracerebroventricularly into mice 4 h after TBI. Neurological deficits, double immunofluorescence staining, presence of inflammatory factors, cell apoptosis, and pyroptosis were assessed. In vitro, we investigated the anti-pyroptosis effects of hUMSCs and TSG-6 in a lipopolysaccharide/ATP-induced BV2 microglial pyroptosis model.ResultsIn TBI mice, the co-localization of Iba-1 (marking microglia/macrophages) with NLRP3/Caspase-1 p20/GSDMD was distinctly observed at 48 h. In vivo, hUMSC transplantation or treatment with rmTSG-6 in TBI mice significantly improved neurological deficits, reduced inflammatory cytokine expression, and inhibited both NLRP3/Caspase-1 p20/GSDMD expression and microglial pyroptosis in the cerebral cortices of TBI mice. However, the therapeutic effect of hUMSCs on TBI mice was reduced by the inhibition of TSG-6 expression in hUMSCs. In vitro, lipopolysaccharide/ATP-induced BV2 microglial pyroptosis was inhibited by co-culture with hUMSCs or with rmTSG-6. However, the inhibitory effect of hUMSCs on BV2 microglial pyroptosis was significantly reduced by TSG-6-shRNA transfection.ConclusionIn TBI mice, microglial pyroptosis was observed. Both in vivo and in vitro, hUMSCs inhibited pyroptosis, particularly microglial pyroptosis, by regulating the NLRP3/Caspase-1/GSDMD signaling pathway via TSG-6.1Hpvw1WsEdBy8VCZXh5Sc1Video

Cobalt protoporphyrin-induced nano-self-assembly for CT imaging, magnetic-guidance, and antioxidative protection of stem cells in pulmonary fibrosis treatment.

Mesenchymal stem cells (MSCs) transplantation is a promising approach for pulmonary fibrosis (PF), however it is impeded by several persistent challenges, including the lack of long-term tracking, low retention, and poor survival of MSCs, as well as the low labeling efficiency of nanoprobes. Herein, a cobalt protoporphyrin IX (CoPP) aggregation-induced strategy is applied to develop a multifunctional nano-self-assembly (ASCP) by combining gold nanoparticle (AuNPs), superparamagnetic iron oxide nanoparticles (SPIONs), and CoPP through a facile solvent evaporation-driven approach. Since no additional carrier materials are employed during the synthesis, high loading efficiency of active ingredients and excellent biocompatibility are achieved. Additionally, facile modification of the ASCPs with bicyclo[6.1.0]nonyne (BCN) groups (named as ASCP-BCN) enables them to effectively label MSCs through bioorthogonal chemistry. The obtained ASCP-BCN could not only help to track MSCs with AuNP-based computed tomography (CT) imaging, but also achieve an SPIONs-assisted magnetic field based improvement in the MSCs retention in lungs as well as promoted the survival of MSCs via the sustained release of CoPP. The in vivo results demonstrated that the labeled MSCs improved the lung functions and alleviated the fibrosis symptoms in a bleomycin–induced PF mouse model. Collectively, a novel ASCP-BCN multifunctional nanoagent was developed to bioorthogonally-label MSCs with a high efficiency, presenting a promising potential in the high-efficient MSC therapy for PF.

Bone marrow mesenchymal stem cells combined with estrogen synergistically promote endometrial regeneration and reverse EMT via Wnt/β-catenin signaling pathway

BackgroundIntrauterine adhesion (IUA) is a clinical disease characterized by the uterine cavity occlusion caused by the damage of the endometrial basal layer. Bone marrow mesenchymal stem cells (BMSCs) transplantation have the potential to promote endometrial regeneration mainly through paracrine ability. Estrogen is an indispensable and important factor in the repair of endometrial damage, which has been reported as a promising and adjunctive therapeutic application for stem cell transplantation therapy. This study aims to investigate the synergistic effect of BMSCs and estrogen on improving the endometrial regeneration and restoring the endometrium morphology in a dual damage model of IUA in rabbits and the underlying molecular mechanisms.MethodsBMSCs were isolated and identified by adipogenic and osteogenic differentiation and flow cytometry assays. The rabbit IUA animal model was established by a dual damage method of mechanical curettage and lipopolysaccharide infection. Additionally, we investigated the therapeutic impact of both BMSCs and estrogen either separately or in combination in a rabbit model. The retention of PKH26-labeled BMSCs was observed by vivo fluorescence imaging.The number of endometrial glands and the degree of fibrosis were observed by H&E and Masson staining respectively. Western blotting, Immunohistochemistry and immunofluorescence staining were performed to detect biomarkers related to endometrial epithelium, endometrial fibrosis and EMT. Finally, the protein expression of core molecules of Wnt/β-catenin pathway was detected by Western blotting.ResultsPKH26-labeled fluorescence results revealed that BMSCs appeared and located in the endometrial glands and extracellular matrix area when orthotopic transplanted into the uterine cavity. Histological assays showed that remarkably increasing the number of endometrial glands and decreasing the area of endometrial fibrosis in the BMSCs combined with estrogen treatment group. Moreover, downregulated expression of fibrosis markers (fibronectin, CollagenI, a-SMA) and interstitial markers (ZEB1, Vimentin, N-cadherin), as well as upregulated E-cadherin expression were found in the combined group. Further study of in vivo staining revealed that fluorescence intensity of CK7 was stronger in the combined group than that of direct BMSCs intrauterine transplantation, while vimentin showed the opposite results. Moreover, the protein levels of β-catenin, Axin2, C-myc, CycinE of Wnt/β-catenin signaling pathway increased in the BMSCs combined with estrogen group than in the other treatment groups.ConclusionBMSCs combined with estrogen can promote the differentiation of stem cells into endometrial epithelial cells to facilitate the regeneration of damaged endometrium. The potential mechanism of the synergistic effect may inhibit the occurrence of EMT by activating the Wnt/β-catenin signaling pathway.

Insufficient S-adenosylhomocysteine hydrolase compromises the beneficial effect of diabetic BMSCs on diabetic cardiomyopathy

BackgroundAutologous stem cell therapy is a promising strategy for cardiovascular diseases including diabetic cardiomyopathy (DCM), but conclusions from clinical trials were compromised. We assumed that diabetes might induce the dysfunction of stem cells and thus limit its therapeutic effect. This study aimed to compare the effect of diabetes and nondiabetes-derived bone marrow mesenchymal stem cells (BMSCs) transplantation on DCM and explored the potential mechanism.MethodsRats with diabetes were induced using high-fat diets and streptozotocin (STZ) injection. BMSCs harvested from diabetic and nondiabetic rats were infused into DCM rats, and the effects on the heart were identified by echocardiography and histopathology. The inhibition or overexpression of SAHH in nondiabetic and diabetic BMSCs was used to confirm its key role in stem cell activity and cardiac therapy.ResultsCompared with normal BMSCs, the therapeutic effects of diabetic rat-derived stem cells on improving cardiac function and adverse remodeling were significantly attenuated. In vitro, diabetic BMSCs had lower cell viability and paracrine function than nondiabetic BMSCs. It was further found that diabetic BMSCs had obvious mitochondrial oxidative stress damage and S-adenosylhomocysteine (SAH) accumulation due to S-adenosylhomocysteine hydrolase (SAHH) deficiency. SAHH inhibition by adenosine dialdehyde (ADA) or shSAHH plasmid in normal BMSCs significantly reduced the favorable effects on endothelial cell proliferation and tube-forming capacity. In contrast, SAHH overexpression in diabetic BMSCs significantly improved cellular activity and paracrine function. Transplantation of BMSCs with SAHH overexpression improved cardiac adverse remodeling and angiogenesis. Activation of the Nrf2 signaling pathway may be one of the key mechanisms of SAHH-mediated improvement of stem cell viability and cardiac repair.ConclusionsDiabetes leads to compromised bioactivity and repair capacity of BMSCs. Our study suggests that SAHH activation may improve the cardioprotective effect of autologous transplantation of diabetes-derived BMSCs on patients with DCM.Graphical abstractDiabetes induced the inhibition of S-adenosylhomocysteine (SAH) expression and aging phenotype in BMSCs and thus decreased the cell viability and paracrine function. Compared with normal BMSCs, the therapeutic effects of diabetic rat-derived BMSCs on improving cardiac function and adverse remodeling were significantly attenuated. SAHH overexpression in diabetic BMSCs significantly rescued cellular function partly via activating Nrf2/HO-1 signal. Transplantation of diabetic BMSCs with SAHH overexpression improved angiogenesis and cardiac adverse remodeling in rats.

Clumps of mesenchymal stem cells/extracellular matrix complexes directly reconstruct the functional periodontal tissue in a rat periodontal defect model.

Periodontitis is an inflammatory disease characterized by tooth-supporting periodontal tissue destruction, including the cementum, periodontal ligament, and alveolar bone. To regenerate the damaged periodontal tissue, mesenchymal stem cells (MSCs) have attracted much scientific and medical attention. Recently, we generated clumps of MSCs/extracellular matrix (ECM) complexes (C-MSCs), which consist of cells and self-produced ECM. C-MSCs can be transplanted into lesion areas without artificial scaffold to induce tissue regeneration. To develop reliable scaffold-free periodontal tissue regenerative cell therapy by C-MSCs, this study investigated the periodontal tissue regenerative capacity of C-MSCs and the behavior of the transplanted cells. Rat bone marrow-derived MSCs were isolated from rat femur. Confluent cells were scratched using a micropipette tip and then torn off. The sheet was rolled to make a three-dimensional round clump of cells, C-MSCs. Then, ten C-MSCs were grafted into a rat periodontal fenestration defect model. To trace the grafted cells in the defect, PKH26-labeled cells were also employed. Micro-CT and histological analyses demonstrated that transplantation of C-MSCs induced successful periodontal tissue regeneration in the rat periodontal defect model. Interestingly, the majority of the cells in the reconstructed tissue, including cementum, periodontal ligaments, and alveolar bone, were PKH26 positive donor cells, suggesting the direct tissue formation by MSCs. This study demonstrates a promising scaffold-free MSCs transplantation strategy for periodontal disease using C-MSCs and offers the significance of multipotency of MSCs to induce successful periodontal tissue regeneration.

Combination effects of mesenchymal stem cells transplantation and anodal transcranial direct current stimulation on a cuprizone-induced mouse model of multiple sclerosis.

Multiple sclerosis (MS) has no absolute treatment, and researchers are still exploring to introduce promising therapy for MS. Transcranial direct current stimulation (tDCS), is a safe, non-invasive procedure for brain stimulating which can enhance working memory, cognitive neurohabitation and motor recovery. Here, we evaluated the effects of tDCS treatment and Mesenchymal stem cells (MSCs) transplantation on remyelination ability of a Cuprizone (CPZ)-induced demyelination mouse model. tDCS significantly increased the motor coordination and balance abilities in CPZ + tDCS and CPZ + tDCS + MSCs mice in comparison to the CPZ mice. Luxol fast blue (LFB) staining showed that tDCS and MSCs transplantation could increase remyelination capacity in CPZ + tDCS and CPZ + MSCs mice compared to the CPZ mice. But, the effect of tDCS with MSCs transplantation on remyelination process was larger than each of treatment alone. Immunofluorescence technique indicated that the numbers of Olig2+ cells were increased by tDCS and MSCs transplantation in CPZ + tDCS and CPZ + MSCs mice compared to the CPZ mice. Interestingly, the combination effect of tDCS and MSCs was larger than each of treatment alone on Oligodendrocytes population. MSCs transplantation significantly decreased the TUNEL+ cells in CPZ + MSCs and CPZ + tDCS + MSCs mice in comparison to the CPZ mice. Also, the combination effects of tDCS and MSCs transplantation was much larger than each of treatment alone on increasing the mRNA expression of BDNF and Sox2, while decreasing P53 as compared to CPZ mice. It can be concluded that the combination usage of tDCS and MSCs transplantation enhance remyelination process in CPZ-treated mice by increasing transplanted stem cell homing, oligodendrocyte generation and decreasing apoptosis.

Aloe vera gel as a stimulant for mesenchymal stem cells differentiation and a natural therapy for radiation induced liver damage

Aloe vera is a medical plant that has been used, traditionally, in treatment of several dermal disorders. In addition to its role as an anti-cancer, anti-oxidant, anti-diabetic, and anti-hyperlipidemic agent. Aloe vera gel extract contains several compounds like minerals, enzymes, hormones and carbohydrates. Therefore, Aloe vera as well as its bioactive constituents have been studied to determine its intriguing potential roles in medicinal science. Mesenchymal stem cells (MSCs) are biologically active precursor cells that can self-renew and develop into a variety of cell types. Plant extracts have been used, in vitro, to enhance the proliferation and differentiation of MSCs. Therefore, the present study aimed to evaluate the therapeutic effect of lyophilized Aloe vera gel together with bone marrow (BM)-MSCs transplantation against radiation induced liver damage (RILD) in X-ray irradiated Sprague dawley male rats. By determining the oxidative stress, antioxidant enzymes, and pro-inflammatory cytokines in liver tissue homogenate, the antioxidant and anti-inflammatory properties of lyophilized Aloe vera gel were investigated. The degree of liver damage and NF-κB expression were determined using histological and immunohistochemical staining techniques. The results showed that treatment of irradiated rats with lyophilized Aloe vera gel and MSCs transplantation has led to an improvement in liver function and a decrease in fibrotic markers, oxidative stress, and pro-inflammatory cytokines; as well as, a reduction in the pathological alterations in the rats' liver and a reduced NF-κB activation. Lyophilized Aloe vera gel provided two important functions; where it stimulated the differentiation of transplanted MSCs and alleviated the radiation induced damages in liver. Aloe vera's antioxidant and anti-inflammatory properties have enhanced liver function, as well as, creating a favorable environment for MSCs development in the liver. MSCs, in combination with lyophilized Aloe vera gel, hold promise for regenerative medicine; where, it has a considerable impact on MSCs differentiation.

First-in-human pilot trial of combined intracoronary and intravenous mesenchymal stem cell therapy in acute myocardial infarction.

BackgroundAcute ST-elevation myocardial infarction (STEMI) elicits a robust cardiomyocyte death and inflammatory responses despite timely revascularization.ObjectivesThis phase 1, open-label, single-arm, first-in-human study aimed to assess the safety and efficacy of combined intracoronary (IC) and intravenous (IV) transplantation of umbilical cord-derived mesenchymal stem cells (UMSC01) for heart repair in STEMI patients with impaired left ventricular ejection fraction (LVEF 30-49%) following successful reperfusion by percutaneous coronary intervention.MethodsConsenting patients received the first dose of UMSC01 through IC injection 4-5 days after STEMI followed by the second dose of UMSC01 via IV infusion 2 days later. The primary endpoint was occurrence of any treatment-related adverse events and the secondary endpoint was changes of serum biomarkers and heart function by cardiac magnetic resonance imaging during a 12-month follow-up period.ResultsEight patients gave informed consents, of whom six completed the study. None of the subjects experienced treatment-related serious adverse events or major adverse cardiovascular events during IC or IV infusion of UMSC01 and during the follow-up period. The NT-proBNP level decreased (1362 ± 1801 vs. 109 ± 115 pg/mL, p = 0.0313), the LVEF increased (52.67 ± 12.75% vs. 62.47 ± 17.35%, p = 0.0246), and the wall motion score decreased (26.33 ± 5.57 vs. 22.33 ± 5.85, p = 0.0180) at the 12-month follow-up compared to the baseline values. The serial changes of LVEF were 0.67 ± 3.98, 8.09 ± 6.18, 9.04 ± 10.91, and 9.80 ± 7.56 at 1, 3, 6, and 12 months, respectively as compared to the baseline.ConclusionThis pilot study shows that combined IC and IV transplantation of UMSC01 in STEMI patients with impaired LVEF appears to be safe, feasible, and potentially beneficial in improving heart function. Further phase 2 studies are required to explore the effectiveness of dual-route transplantation of UMSC01 in STEMI patients.

The role of microenvironment in stem cell-based regeneration of intervertebral disc.

Regenerative medicine for intervertebral disc (IVD) disease, by utilizing chondrocytes, IVD cells, and stem cells, has progressed to clinical trials in the treatment of back pain, and has been studied in various animal models of disc degeneration in the past decade. Stem cells exist in their natural microenvironment, which provides vital dynamic physical and chemical signals for their survival, proliferation and function. Long-term survival, function and fate of mesenchymal stem cells (MSCs) depend on the microenvironment in which they are transplanted. However, the transplanted MSCs and the endogenous disc cells were influenced by the complicated microenvironment in the degenerating disc with the changes of biochemical and biophysical components. It is important to understand how the MSCs and endogenous disc cells survive and thrive in the harsh microenvironment of the degenerative disc. Furthermore, materials containing stem cells and their natural microenvironment have good clinical effects. However, the implantation of tissue engineering IVD (TE-IVD) cannot provide a complete and dynamic microenvironment for MSCs. IVD graft substitutes may need further improvement to provide the best engineered MSC microenvironment. Additionally, the IVD progenitor cells inside the stem cell niches have been regarded as popular graft cells for IVD regeneration. However, it is still unclear whether actual IVD progenitor cells exist in degenerative spinal conditions. Therefore, the purpose of this review is fourfold: to discuss the presence of endogenous stem cells; to review and summarize the effects of the microenvironment in biological characteristics of MSC, especially those from IVD; to explore the feasibility and prospects of IVD graft substitutes and to elaborate state of the art in the use of MSC transplantation for IVD degeneration in vivo as well as their clinical application.

Comparison of therapeutic effects of mesenchymal stem cells from umbilical cord and bone marrow in the treatment of type 1 diabetes

BackgroundThe therapeutic potential of mesenchymal stem cells (MSCs) in type 1 diabetes (T1D) has been demonstrated in both preclinical and clinical studies. MSCs that have been used in research on T1D are derived from various tissue sources, with bone marrow (BM) and umbilical cord (UC) tissues being the most commonly used. However, the influence of tissue origin on the functional properties and therapeutic effects of MSCs in T1D remains unclear. This study aimed to compare the therapeutic efficacy of UC-MSCs and BM-MSCs in a mouse model of T1D as well as in patients with T1D.MethodsIn non-obese diabetic (NOD) mice, the development of diabetes was accelerated by streptozotocin injections. Thereafter, diabetic mice were randomized and treated intravenously with UC-MSCs, BM-MSCs or phosphate-buffered saline as a control. Blood glucose and serum insulin were measured longitudinally after transplantation. At 14 days post-transplantation, pancreatic tissues were collected to assess insulitis and the β-cell mass. Flow cytometry was performed to evaluate the composition of T lymphocytes in the spleen and pancreatic lymph nodes of the NOD mice. In our retrospective study of patients with T1D, 28 recipients who received insulin therapy alone or a single transplantation of UC-MSCs or BM-MSCs were enrolled. The glycaemic control and β-cell function of the patients during the first year of follow-up were compared.ResultsIn NOD mice, UC-MSC and BM-MSC transplantation showed similar effects on decreasing blood glucose levels and preserving β cells. The regulation of islet autoimmunity was examined, and no significant difference between UC-MSCs and BM-MSCs was observed in the attenuation of insulitis, the decrease in T helper 17 cells or the increase in regulatory T cells. In patients with T1D, MSC transplantation markedly lowered haemoglobin A1c (HbA1c) levels and reduced insulin doses compared to conventional insulin therapy. However, the therapeutic effects were comparable between UC-MSCs and BM-MSCs, and they also exerted similar effects on the endogenous β-cell function in the patients.ConclusionIn conclusion, both UC-MSCs and BM-MSCs exhibited comparable therapeutic effects on improving glycaemic control and preserving β-cell function in T1D. Considering their abundance and higher cell yields, UC-MSCs appear to be more promising than BM-MSCs in clinical applications.Trial registration NCT02763423. Registered on May 5, 2016—Retrospectively registered, https://www.clinicaltrials.gov/.

Longitudinal electrophysiological changes after mesenchymal stem cell transplantation in a spinal cord injury rat model.

Transcranial electrically stimulated motor-evoked potentials (tcMEPs) are widely used to evaluate motor function in humans and animals. However, the relationship between tcMEPs and the recovery of paralysis remains unclear. We previously reported that transplantation of mesenchymal stem cells to a spinal cord injury (SCI) rat model resulted in various degrees of recovery from paraplegia. As a continuation of this work, in the present study, we aimed to establish the longitudinal electrophysiological changes in this SCI rat model after mesenchymal stem cell transplantation. SCI rats were established using the weight-drop method. The model rats were transvenously transplanted with two types of mesenchymal stem cells (MSCs), one derived from rat cranial bones and the other from the bone marrow of the femur and tibia bone, 24 h after SCI. A phosphate-buffered saline (PBS) group that received only PBS was also created for comparison. The degree of paralysis was evaluated over 28 days using the Basso-Beattie-Bresnahan (BBB) scale and inclined plane task score. Extended tcMEPs were recorded using a previously reported bone-thinning technique, and the longitudinal electrophysiological changes in tcMEPs were investigated. In addition, the relationship between the time course of recovery from paralysis and reappearance of tcMEPs was revealed. The appearance of the tcMEP waveform was earlier in MSC-transplanted rats than in PBS-administered rats (earliest date was 7 days after SCI). The MEP waveforms also appeared at approximately the same level on the BBB scale (average score, 11 points). Ultimately, this study can help enhance our understanding of the relationship between neural regeneration and tcMEP recording. Further application of tcMEP in regenerative medicine research is expected.

Transplantation of mesenchymal stem cells for prevention of acute myocardial infarction induced heart failure: study protocol of a phase III randomized clinical trial (Prevent-TAHA8)

BackgroundResults from recent clinical trials on bone marrow mononuclear cell (BM-MNC) transplantation show that this intervention can help reduce the incidence of heart failure (HF) after acute myocardial infarction (AMI). However, no study has evaluated the effect of the transplantation of mesenchymal stem cells (MSCs) on a clinical endpoint such as HF.MethodsThis single-blinded, randomized, multicenter trial aims to establish whether the intracoronary infusion of umbilical cord-derived Wharton’s jelly MSCs (WJ-MSCs) helps prevent HF development after AMI. The study will enroll 390 patients 3 to 7 days following AMI. Only patients aged below 65 years with impaired LV function (LVEF < 40%) will be included. They will be randomized (2:1 ratio) to either receive standard care or a single intracoronary infusion of 107 WJ-MSCs. The primary outcome of this study is the assessment of HF development during long-term follow-up (3 years).DiscussionData will be collected until Nov 2024. Thereafter, the analysis will be conducted. Results are expected to be ready by Dec 2024. We will prepare and submit the related manuscript following the CONSORT guidelines. This study will help determine whether or not the infusion of intracoronary WJ-MSCs in patients with AMI will reduce the incidence of AMI-induced HF.Trial registrationClinicalTrials.gov NCT05043610, Registered on 14 September 2021 - retrospectively registered.

Combination of Dexamethasone and Tofacitinib Reduces Xenogeneic MSC-Induced Immune Responses in a Mouse Model of Alzheimer's Disease.

We have recently reported on how transplantation of human mesenchymal stem cells (MSCs) into the mouse parenchyma generated immune responses. To facilitate the clinical translation of MSC-based AD therapy, the safety and efficacy of human derived MSCs (hMSCs) must be confirmed in the pre-clinical stage. Thus, it is imperative to investigate measures to reduce immune responses exerted via xenotransplantation. In this study, immunosuppressants were co-administered to mice that had received injections of hMSCs into the parenchyma. Prior to performing experiments using transgenic AD mice (5xFAD), varying immunosuppressant regimens were tested in wild-type (WT) mice and the combination of dexamethasone and tofacitinib (DexaTofa) revealed to be effective in enhancing the persistence of hMSCs. According to transcriptome sequencing and immunohistochemical analyses, administration of DexaTofa reduced immune responses generated via transplantation of hMSCs in the parenchyma of 5xFAD mice. Significant mitigation of amyloid burden, however, was not noted following transplantation of hMSCs alone or hMSCs with DexaTofa. The efficacy of the immunosuppressant regimen should be tested in multiple AD mouse models to promote its successful application and use in AD stem cell therapy.

Paracrine Effects of Mesenchymal Stem Cells in Ischemic Stroke: Opportunities and Challenges.

It is well acknowledged that neuroprotective effects of transplanted mesenchymal stem cells (MSCs) in ischemic stroke are attributed to their paracrine-mediated actions or bystander effects rather than to cell replacement in infarcted areas. This therapeutic plasticity is due to MSCs' ability to secrete a broad range of bioactive molecules including growth factors, trophic factors, cytokines, chemokines, and extracellular vesicles, overall known as the secretome. The secretome derivatives, such as conditioned medium (CM) or purified extracellular vesicles (EVs), exert remarkable advantages over MSC transplantation in stroke treating. Here, in this review, we used published information to provide an overview on the secretome composition of MSCs, underlying mechanisms of therapeutic effects of MSCs, and preclinical studies on MSC-derived products application in stroke. Furthermore, we discussed current advantages and challenges for successful bench-to-bedside translation.

Dose-Dependent Effects of Intravenous Mesenchymal Stem Cell Transplantation in Rats with Acute Focal Cerebral Ischemia.

Intravenous transplantation of mesenchymal stem (stromal) cells (MSC) is a promising approach to the treatment of ischemic stroke. In the published reports of the already completed preclinical and clinical studies the dosages of transplanted MSC greatly vary. However, the optimal dosage has not been determined. The dose-dependent effect of intravenous MSC transplantation was studied, in rats with experimental cerebral infarction. To this end, 5×105 and 2×106 MSC were intravenously administered 24 h after modeling of acute focal ischemia followed by complex assessment of the therapeutic efficacy over 60 days. The rate and degree of the recovery of neurological functions in rats increased with increasing the dose of injected cells, which confirms the dose-dependent effect of intravenous MSC transplantation.

Effects of Adrenomedullin (ADM)-Modified Bone Marrow Mesenchymal Stem Cells (BMSCs) Transplantation on Cardiac Function and Matrix Metalloproteinase Levels in Rats with Heart Failure

After ADM gene treatment, bone marrow mesenchymal stem cells (BMSCs) were transplanted into rats with heart failure to study its effect on rat heart function and matrix metalloproteinases (MMPs) expression. The rats were assigned into control group, BMSCs group and ADM group. 4 weeks after transplantation, the rats’ cardiac function indexes were detected and the levels of MMP-2 and MMP-9 was measured by western blot. Echocardiography analysis showed significant differences between groups (except LVDd) (P &lt; 0.05). BMSCs and ADM groups had significantly lower LVEF and LVFS levels than control group (P &lt; 0.05) with a significantly higher level in ADM group than BMSCs group (P &lt; 0.05). However, BMSCs and ADM groups presented a significantly higher LVDs (P &lt; 0.05) without difference between them (P &gt; 0.05). Interestingly, no difference of LVDd was found among groups (P &gt; 0.05). MMP-2 and MMP-9 levels in BMSCs group were 0.389±0.021, 0.512±0.018, respectively, which were significantly elevated compared to control group (P &lt; 0.05); MMP-2 and MMP-9 protein level in the ADM group was 0.440±0.018 and 0.539±0.032 respectively, which was significantly higher than control group (P &lt; 0.05). Compared with BMSCs group, ADM group had significantly increased protein levels of MMP-2/9 (P &lt; 0.05). In conclusion, ADM-modified BMSCs transplantation can significantly inhibit MMP-2 and MMP-9 level, thereby improving the heart function of rats with heart failure.