Infusion Of Mesenchymal Stem Cells Research Articles

Utero Vesical Fistula Closure After 3 Weeks Treatment with Intravenous Mesenchymal Stem Cells Infusion Case Report

Utero Vesical Fistula Closure After 3 Weeks Treatment with Intravenous Mesenchymal Stem Cells Infusion Case Report

Stem Cells in Kidney Ischemia: From Inflammation and Fibrosis to Renal Tissue Regeneration

Ischemic nephropathy consists of progressive renal function loss due to renal hypoxia, inflammation, microvascular rarefaction, and fibrosis. We provide a literature review focused on kidney hypoperfusion-dependent inflammation and its influence on renal tissue's ability to self-regenerate. Moreover, an overview of the advances in regenerative therapy with mesenchymal stem cell (MSC) infusion is provided. Based on our search, we can point out the following conclusions: 1. endovascular reperfusion is the gold-standard therapy for RAS, but its success mostly depends on treatment timeliness and a preserved downstream vascular bed; 2. anti-RAAS drugs, SGLT2 inhibitors, and/or anti-endothelin agents are especially recommended for patients with renal ischemia who are not eligible for endovascular reperfusion for slowing renal damage progression; 3. TGF-β, MCP-1, VEGF, and NGAL assays, along with BOLD MRI, should be extended in clinical practice and applied to a pre- and post-revascularization protocols; 4. MSC infusion appears effective in renal regeneration and could represent a revolutionary treatment for patients with fibrotic evolution of renal ischemia.

Human Umbilical Cord-Derived Mesenchymal Stem Cells Alleviate Psoriasis Through TNF-α/NF-κB/MMP13 Pathway.

Psoriasis is a chronic, immune-mediated disease that affects 2-3% of the global population. Recently, mesenchymal stem cells (MSCs) have been used to alleviate psoriasis. However, the therapeutic mechanisms of MSCs remain unclear. Matrix metalloproteinase-13 (MMP13), a member of the MMPs family, is the key enzyme in the cleavage of type II collagen and plays a pivotal role in extracellular matrix (ECM) remodeling. Here, it was found that Mmp13 was upregulated in the skin lesions of an imiquimod-induced mouse model, which was downregulated after intravenous infusion of human umbilical cord MSCs (hUC-MSCs). Knockdown of MMP13 inhibited the proliferation of keratinocytes and arrested the cell cycle in G1 stage. In addition, hUC-MSCs were co-cultured with THP-1 or PMA-stimulated THP-1 directly in vitro to simulate the fate of systematically infused hUC-MSCs. The level of TNF-α was decreased in the supernatant of co-cultured hUC-MSCs and THP-1 or PMA-stimulated THP-1. Moreover, it was identified that TNF-α upregulated MMP13 through the NF-κB pathway in keratinocytes. In conclusion, we propose that systematically infused hUC-MSCs exert a therapeutic effect on psoriasis through the TNF-α/NF-κB/MMP13 pathway.

Targeting the pentraxin 3/CD44 axis: A potential treatment for pulmonary fibrosis

Targeting the pentraxin 3/CD44 axis: A potential treatment for pulmonary fibrosis

Distribution of Embryonic Stem Cell-Derived Mesenchymal Stem Cells after Intravenous Infusion in Hypoxic-Ischemic Encephalopathy.

Systemic administration of mesenchymal stem cells (MSCs) has been reported to improve neurological function in brain damage, including hypoxic-ischemic encephalopathy (HIE), though the action mechanisms have not been fully elucidated. In this study, the cells were tracked live using a Pearl Trilogy Small Animal fluorescence imaging system after human embryonic stem Cell-Derived MSCs (ES-MSCs) infusion for an HIE mouse model. ES-MSC-treated HIE mice showed neurobehavioral improvement. In vivo imaging showed similar sequential migration of ES-MSCs from lungs, liver, and spleen within 7 days in both HIE and normal mice with the exception of lungs, where there was higher entrapment in the HIE 1 h after infusion. In addition, ex vivo experiments confirmed time-dependent infiltration of ES-MSCs into the organs, with similar findings in vivo, although lungs and brain revealed small differences. ES-MSCs seemed to remain in the brain only in the case of HIE on day 14 after the cell infusion. The homing effect in the host brain was confirmed with immunofluorescence staining, which showed that grafted cells remained in the brain tissue at the lesion area with neurorestorative findings. Further research should be carried out to elucidate the role of each host organ's therapeutic effects when stem cells are systemically introduced.

A phase I study assessing the safety and tolerability of allogeneic mesenchymal stem cell infusion in adults with cystic fibrosis

BackgroundMesenchymal stem cells are of particular interest in cystic fibrosis (CF) as a potential therapeutic. Data from pre-clinical studies suggest that allogeneic bone marrow-derived human mesenchymal stem cells (hMSCs) may provide a new therapeutic treatment for CF lung disease by attenuating pulmonary inflammation while decreasing bacterial growth and enhancing antibiotic efficacy. MethodsFifteen adults with CF were enrolled in a phase 1 dose-escalation trial of a single intravenous infusion of hMSCs derived from bone marrow aspirates obtained from a single pre-clinically validated healthy volunteer donor. The study employed a 3+3 dose escalation design with subjects receiving a single, intravenous dose of either 1×106, 3×106, or 5×106 hMSCs/kg. Subjects were monitored inpatient for 24 hours and by outpatient visits and telephone calls for 12 months after the infusion. Safety and tolerability were evaluated by monitoring symptoms, patient reported outcome questionnaires, adverse events (AEs), physical exam findings, spirometry, and analyses of safety laboratories. Preliminary evidence for potential efficacy using inflammatory markers in the blood and sputum were also evaluated. ResultsNo dose-limiting toxicities, deaths or life-threatening adverse events were observed. Most AEs and serious adverse events (SAEs) were consistent with underlying CF. Vital signs, physical exam findings, spirometry and safety laboratory results showed no significant change from baseline. No trends over time were seen in serum or sputum inflammatory markers nor with clinical spirometry. ConclusionAllogeneic hMSC intravenous infusions were safe and well-tolerated in this phase 1 study and warrant additional clinical testing as a potential therapeutic for CF lung disease.

Impact of repeated intravenous infusions of umbilical cord-derived versus bone marrow-derived mesenchymal stem cells on angiogenesis in a pregnant experimentally induced deep venous thrombosis rat model.

Deep venous thrombosis (DVT) therapy during pregnancy warrants special consideration for the woman and the fetus. This study aimed to evaluate the impact of umbilical cord-derived mesenchymal stem cells (UC-MSCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs) in terms of pro-angiogenic capacity and amelioration of pregnancy outcomes. The pregnant DVT rat model was successfully established by the "stenosis" method. Three consecutive injections of both UC-MSCs and BM-MSCs improved angiogenesis and ameliorated the embryo absorption rate in pregnant SD rats with DVT, in which UC-MSCs promoted angiogenesis more significantly. Furthermore, the levels of serum vascular endothelial growth factor-A (VEGF-A) and epidermal growth factor (EGF) were significantly higher in the UC-MSC group compared to those of the BM-MSC group. Thereafter, differentially expressed genes (DEGs) in thrombosed inferior vena cava tissues in the UC-MSC and BM-MSC groups were identified using transcriptome sequencing and further assessed by RT-qPCR and western blotting. The bioinformatics analysis indicated that the enriched DEG terms occurred in the cytokine activity, and the DEG pathways were significantly enriched in the cytokine-cytokine receptor interaction. In addition, both the mRNA and protein levels of angiogenic genes and their receptors, including VEGF-A, VEGF receptor-1, EGF, and EGF receptor, were significantly higher in the UC-MSC group. In conclusion, the BM-MSCs and UC-MSCs both significantly stimulate angiogenesis and ameliorate the embryo absorption rate in pregnant SD rats with DVT, but the difference in cytokine secretion causes UC-MSCs to have more potent angiogenic effects than BM-MSCs.

MSCs-ILC2s-Tecs Axis Promotes the Recovery of Thymic Function in aGVHD

Background: Previous studies found that mesenchymal stem cells (MSCs) administrated at the acute graft versus host disease (aGVHD) phase effectively decreased the incidence and severity of chronic GVHD (cGVHD) by boosting thymic regeneration. However, the mechanism for MSCs repairing the damaged thymus caused by aGVHD is unclear. It has been reported that innate lymphoid cells (ILCs) are also important for the structural remodeling of the thymus in recipients after allogeneic bone marrow transplantation (allo-BMT). Here, we explored the mechanisms on how MSCs promote thymus recovery post allo-BMT through ILCs. Methods: We carried out studies in a aGVHD mice model of fully MHC-mismatched myeloablative bone marrow transplantation (C57BL/6 to BALB/c). MSCs or ILC2s were generated and administrated intravenously at day 7 post-BMT to the treated groups to compare therapeutic effects of GVHD with the untreated group. Clinical scores and survival were recorded once every days. Flow cytometery was employed for analyzing the number and proportion of ILCs and their subtypes (ILCs Lin-CD45+iCD3-CD127+, type 1 ILCs (ILC1s) Tbet+, type 2 ILCs (ILC2s) GATA3+, type 3 ILCs (ILC3s) RORγt+) in the thymus to assess the effect of MSCs on ILCs in the thymus at day 14 post-BMT. We analyzed the thymic T cells subsets and thymic epithelial cells (TECs) substes among these two groups to evaluate the repair effect of ILC2s for thymus. Thymic ILC2s were cultured alone or co-cultured with murine MSCs in vitro to investigate the effect and underlying mechanism of MSCs on ILC2s. Results: We found that ILC2s in the thymus are sensitive to conditioning therapy and and further impaired by aGVHD. But infusion of MSCs was effective in reducing the lethality of aGVHD and promote expansion of thymic ILC2s in aGVHD mice compared with the control group. The absolute number of ILC2s in the thymus had a significant negative correlation with GVHD scores in aGVHD mice. Then we found that ILC2s infusion significant increases in thymus size and weight, as well as the number of total thymocytes and the more organized cortical medullary structure compared to the untreated groups. The number of TECs and its proportion of thymus stroma were significantly improved, including cortical TEC and medullary TECs. As for thymocyte, ILC2s infusion significantly increased the number and proportion of CD4+CD8+T cells. In vitro study showed co-cultured ILC2s had a increased proliferation compared to ILC2s cultured alone, and anti-IL33 antibody inhibited the pro-proliferative effect of MSCs on ILC2. Then we perform in vivo validation by injecting IL33 knocked down MSCs and found that the effect of MSC in repairing the damaged thymus was reduced. And the number and proportion of thymic ILC2s were also significantly decreased in the thymus. Furthermore, treatment with rIL33 on day 7-11 also ameliorated aGVHD and promoted the proliferation of thymic ILC2s in aGVHD mice as well as MSCs infusion. Conclusion: These findings suggest that MSCs participate in thymus regeneration from aGVHD damage through ILC2s-mediated tissue recovery. The study outlined here provide a new insight into the mechanism of MSC therapy for aGVHD.

Autologous Extracellular Vesicles Attenuate Cardiac Injury in Experimental Atherosclerotic Renovascular Disease More Effectively Than Their Parent Mesenchymal Stem/Stromal Cells.

Atherosclerotic renovascular disease (RVD) leads to hypertension, chronic kidney disease (CKD), and heart disease. Intrarenal delivery of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) attenuate renal injury and suppress release of inflammatory cytokines in porcine RVD. We hypothesized that this strategy would also be useful for cardioprotection. Pigs with renovascular hypertension and metabolic syndrome were studied 4 weeks after treatment with a single intrarenal infusion of autologous MSCs, EVs, or vehicle. Cardiac structure and function were assessed in vivo, and myocardial remodeling and expression of the pro-fibrotic factor growth factor receptor-bound protein-2 (Grb2) were measured ex-vivo. Inflammatory cytokine levels were measured in the systemic circulation and myocardial tissue. Blood pressure was elevated in all RVD groups, but serum creatinine increased in RVD and decreased in both RVD + MSCs and RVD + EVs. RVD-induced diastolic dysfunction (lower E/A ratio) was normalized in both MSCs- and EVs- treated pigs. Intrarenal delivery of MSCs and EVs also attenuated RVD-induced myocardial fibrosis, collagen deposition, and Grb2 expression, yet EVs restored capillary density and inflammation more effectively than MSCs. These observations suggest that autologous EVs attenuate cardiac injury in experimental RVD more effectively than their parent MSCs.

Efficacy and Safety of Mesenchymal Stem Cell Therapy in Patients with Acute Myocardial Infarction: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

The adjuvant treatment of stem cell therapy for acute myocardial infarction (AMI) has been studied in multiple clinical trials, but many questions remain to be addressed, such as efficacy, safety, identification of the optimal cell type, tractable route of delivery, transplant dosage, and transplant timing. The current meta-analysis aimed to explore the issues of mesenchymal stem cells (MSCs) transplantation in patients with AMI based on published randomized controlled trials (RCTs) and guide the design of subsequent clinical trials of MSCs therapy for AMI. The Cochrane Library, PubMed, EMBASE databases were searched for relevant clinical trials from January 1, 2000, to January 23, 2021. Results from RCTs involving MSCs transplantation for the treatment of AMI were identified. According to the Cochrane systematic review method, the literature quality, including studies, was evaluated and valid data was extracted. Rev- Man 5.3 and Stata 15.1 software were used for Meta-analysis. After literature search and detailed evaluation, 9 randomized controlled trials enrolling 460 patients were included in the quantitative analysis. Pooled analyses indicated that MSCs therapy was associated with a significantly greater improvement in overall left ventricular ejection fraction (LVEF), and the effect was maintained for up to 24 months. No significant difference in favor of MSCs treatment in left ventricular (LV) volume and in the risk of rehospitalization as a result of heart failure (HF) was noted, compared with the controls. For transplantation dose, the LVEF of patients accepting a MSCs dose of 107-108 cells was significantly increased by 2.62% (95% CI 1.54 to 3.70; P < 0.00001; I2 =0%), but this increase was insignificant in the subgroup that accepted a MSCs dose of < 107 cells (1.65% in LVEF, 95% CI, 0.03 to 3.27; P =0.05; I2 =75%) or >108 cells (4.65% in LVEF, 95% CI, -4.55 to 13.48; P =0.32; I2 =95%), compared with the controls. For transplantation timing, a significant improvement of LVEF of 3.18% was achieved in the group of patients accepting a MSCs infusion within 2 to 14 days after percutaneous coronary intervention (PCI) (95% CI, 2.89 to 3.47; P <0.00001; I2 = 0). There was no association between MSCs therapy and major adverse events. Results from our systematic review suggest that MSCs therapy for patients with AMI appears to be safe and might induce a significant increase in LVEF with a limited impact on LV volume and rehospitalization caused by HF. The effect was maintained for up to 24 months. MSCs dose of 107-108 cells was more likely to achieve better clinical endpoints than <107 or >108 cells. The optimal time window for cell transplantation might be within 2-14 days after PCI. This meta-analysis was registered with PROSPERO, number CRD 42021241104.

Endovascular Stem Cell Therapy Promotes Neuronal Remodeling to Enhance Post Stroke Recovery by Alleviating Endoplasmic Reticulum Stress Modulated by BDNF Signaling.

The impact of increased BDNF expression in brain by endovascular delivered mesenchymal stem cells (MSCs) post stroke towards modulating endoplasmic reticulum (ER) stress mediated neuronal remodeling has not been directly studied. Therefore, the present study investigates ER stress mediated neuronal remodeling following IA MSCs infusion in rodent model of ischemic stroke. Ovariectomized Sprague Dawley rats were subjected to MCAO followed by 1 × 105 IA MSCs administration at 6h. Infarct and functional outcomes at different time points post-stroke were evaluated. Further, various genes and protein expression studies were performed to determine the underlying mechanisms of the effect of IA MSCs towards ER stress mediated neuronal remodeling. Post-strokeIA MSCs administration significantly increased BDNF expression anddecreased ER stress markersexpression at day 1 post-stroke. A gradual rise in the expression of growth associate protein-43 (GAP 43) and spinophilin were observed at 7, 14- and 28-days post-stroke indicating an increase in neuronal remodeling towards functional restoration. The results suggest that IA MSCs post-stroke can modulate neuronal remodeling by BDNF-mediated reduction in ER stress that contribute towards functional recovery.

Intravenous infusion of bone marrow-derived mesenchymal stem cells improves tissue perfusion in a rat hindlimb ischemia model

Intravenous infusion of stem cells is a minimally invasive cellular delivery method, though a few have been reported in a critical limb-threatening ischemia (CLTI) animal model or patients. In the present study, we hypothesized that intravenous infusion of bone-marrow derived mesenchymal stem cells (MSCs) improves tissue perfusion in a rat hindlimb ischemia model. Hindlimb ischemia was generated in Sprague–Dawley rats by femoral artery removal, then seven days after ischemic induction intravenous infusion of 1 × 106 MSCs (cell group) or vehicle (control group) was performed. As compared with the control, tissue perfusion was significantly increased in the cell group. Histological findings showed that capillary density was significantly increased in the cell group, with infused green fluorescent protein (GFP)-MSCs distributed in the ischemic limb. Furthermore, gene expression of vascular endothelial growth factor (VEGF) was significantly increased in ischemic hindlimb muscle tissues of rats treated with MSC infusion. In conclusion, intravenous infusion of bone-marrow derived MSCs improved tissue perfusion in ischemic hindlimbs through angiogenesis, suggesting that intravenous infusion of MSCs was a promising cell delivery method for treatment of CLTI.

Mesenchymal stem cell therapy on top of triple therapy with remdesivir, dexamethasone, and tocilizumab improves PaO2/FiO2 in severe COVID-19 pneumonia.

BackgroundDespite patients with severe coronavirus disease (COVID-19) receiving standard triple therapy, including steroids, antiviral agents, and anticytokine therapy, health condition of certain patients continue to deteriorate. In Taiwan, the COVID-19 mortality has been high since the emergence of previous variants of this disease (such as alpha, beta, or delta). We aimed to evaluate whether adjunctive infusion of human umbilical cord mesenchymal stem cells (MSCs) (hUC-MSCs) on top of dexamethasone, remdesivir, and tocilizumab improves pulmonary oxygenation and suppresses inflammatory cytokines in patients with severe COVID-19.MethodsHospitalized patients with severe or critical COVID-19 pneumonia under standard triple therapy were separated into adjuvant hUC-MSC and non-hUC-MSC groups to compare the changes in the arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio and biological variables.ResultsFour out of eight patients with severe or critical COVID-19 received either one (n = 2) or two (n = 2) doses of intravenous infusions of hUC-MSCs using a uniform cell dose of 1.0 × 108. Both high-sensitivity C-reactive protein (hs-CRP) level and monocyte distribution width (MDW) were significantly reduced, with a reduction in the levels of interleukin (IL)-6, IL-13, IL-12p70 and vascular endothelial growth factor following hUC-MSC transplantation. The PaO2/FiO2 ratio increased from 83.68 (64.34–126.75) to 227.50 (185.25–237.50) and then 349.56 (293.03–367.92) within 7 days after hUC-MSC infusion (P < 0.001), while the change of PaO2/FiO2 ratio was insignificant in non-hUC-MSC patients (admission day: 165.00 [102.50–237.61]; day 3: 100.00 [72.00–232.68]; day 7: 250.00 [71.00–251.43], P = 0.923).ConclusionTransplantation of hUC-MSCs as adjunctive therapy improves pulmonary oxygenation in patients with severe or critical COVID-19. The beneficial effects of hUC-MSCs were presumably mediated by the mitigation of inflammatory cytokines, characterized by the reduction in both hs-CRP and MDW.

Therapeutic role of intravenous mesenchymal stem cells infusion in a rat model of induced acute myocardial infarction

Therapeutic role of intravenous mesenchymal stem cells infusion in a rat model of induced acute myocardial infarction

P9.34: Application of Mesenchymal Stem Cells for the Treatment of Liver Graft Dysfunction Caused by Chronic Rejection. Case Report

Background: Development of immunosuppressive therapy (IST) complications after liver transplantation (LT) requires its minimization. Decrease of immunosuppression in the long-term period after transplantation in 8% of patients is accompanied with the development of chronic rejection (CR). Objective: The aim of this report was to demonstrate the successful treatment of liver transplant CR with mesenchymal stem cells (MSCs) in patient with acute kidney injury (AKI) and IST minimizing. Results: Patient with unresectable liver alveococcosis underwent LT. After surgery patient received a three-component IST, which after six months was de-escalated to tacrolimus monotherapy (Tac). A year after the operation graft dysfunction developed, which was accompanied by a maximum increase of AST up to 511 U/l and ALT up to 507 U/l, GGTP up to 1753 U/l and ALP up to 474 U/l. IST was escalated: pulse therapy with glucocorticosteroids was performed twice; mycophenolate mofetil, mTOR inhibitors, intravenous immunoglobulin were added. Thrice performed puncture liver biopsy demonstrated the chronicity of the alloimmune conflict. Developed AKI in the process of anti-rejection therapy required decreasing of Tac, which led to increase of cytolysis and cholestasis. Infusion of allogeneic MSCs with a total dose of 8 x 106 cells per kg led to normalization of laboratory blood tests. The Tac concentration was 0.8 ng/ml; kidney function recovered: urea level was 7.1 mmol/l, creatinine - 80 µmol/l, GFR - 25 ml/min. Application of MSCs formed immunotolerance: the suppressor subpopulation of T-regulatory CD3+CD4+CD25highCD127- lymphocytes increased and effector CD3+CD8+naïve T-lymphocytes, antigen-presenting myeloid dendritic cells, and antibodies-producing CD19+ naïve B-lymphocytes decreased. Conclusions: MSCs can be used in CR as an effective alternative IST that can replace the immunosuppressive effect of basic immunosuppressants.

Infusion of two-dose mesenchymal stem cells is more effective than a single dose in a dilated cardiomyopathy rat model by upregulating indoleamine 2,3-dioxygenase expression

Background and aimsThe therapeutic efficacy of single-dose mesenchymal stromal cell (MSC) therapy for heart failure (HF) remains inconsistent. This study aimed to investigate whether infusion with two-dose human umbilical cord MSC (hUCMSCs) could be therapeutically superior to single-dose therapy in a rat model of dilated cardiomyopathy (DCM) and explored the underlying mechanisms.MethodsMale Sprague–Dawley rats were intraperitoneally injected with doxorubicin (DOX) to establish a DCM model and randomized to intravenously receive single-dose or two-dose hUCMSCs at an interval of 14 days. Their left ventricular (LV) systolic and diastolic functions were analyzed by echocardiography. The percentages of Th1, Th2, Th17, and Treg cells in the heart, spleen, lymph nodes, and peripheral blood and the levels of serum cytokines in individual rats were analyzed by flow cytometry and cytometric bead assay, respectively. The degrees of cardiac fibrosis and cardiomyocyte apoptosis were examined by histology. The importance of indoleamine 2,3-dioxygenase (IDO), an activator of Treg differentiation, in the therapeutic effect of hUCMSCs on inflammation and heart function of rats was determined after induction of IDO over-expression (IDO-OE) using IFN-γ (1 ng/ml) and TNF-α (10 ng/ml) stimulation or silencing (IDO-KD) using small interfering RNA (siRNA) technology.ResultsCompared with the single dose, two-dose hUCMSCs were more effective in improving LV performance, attenuating cardiac dilation, reducing cardiomyocyte apoptosis and cardiac fibrosis. Two-dose hUCMSC therapy significantly increased Treg number in the heart and peripheral blood, accompanied by increased cardiac IDO expression. Compared with the control hUCMSCs, IDO-OE hUCMSCs significantly enhanced Treg and Th2 cell responses and decreased systemic Th17 cell responses and Th1 cell numbers in the mediastinal lymph nodes. Treatment with IDO-OE hUCMSCs significantly improved LV remodeling and dysfunction. However, treatment with IDO-KD hUCMSCs had opposite effects in rats.ConclusionsAdministration of two-dose hUCMSCs has better therapeutic effects than single-dose therapy for inhibiting myocardial inflammation to improve LV function in DCM rats. These effects are associated with upregulating IDO expression and its systemic anti-inflammatory activities.

Repeated intravenous infusion of mesenchymal stem cells for enhanced functional recovery in a rat model of chronic cerebral ischemia.

Stroke is a major cause of long-term disability, and there are few effective treatments that improve function in patients during the chronic phase of stroke. Previous research has shown that single systemic infusion of mesenchymal stem cells (MSCs) improves motor function in acute and chronic cerebral ischemia models in rats. A possible mechanism that could explain such an event includes the enhanced neural connections between cerebral hemispheres that contribute to therapeutic effects. In the present study, repeated infusions (3 times at weekly intervals) of MSCs were administered in a rat model of chronic stroke to determine if multiple dosing facilitated plasticity in neural connections. The authors induced middle cerebral artery occlusion (MCAO) in rats and, 8 weeks thereafter, used them as a chronic stroke model. The rats with MCAO were randomized and intravenously infused with vehicle only (vehicle group); with MSCs at week 8 (single administration: MSC-1 group); or with MSCs at weeks 8, 9, and 10 (3 times, repeated administration: MSC-3 group) via femoral veins. Ischemic lesion volume and behavioral performance were examined. Fifteen weeks after induction of MCAO, the thickness of the corpus callosum (CC) was determined using Nissl staining. Immunohistochemical analysis of the CC was performed using anti-neurofilament antibody. Interhemispheric connections through the CC were assessed ex vivo by diffusion tensor imaging. Motor recovery was better in the MSC-3 group than in the MSC-1 group. In each group, there was no change in the ischemic volume before and after infusion. However, both thickness and optical density of neurofilament staining in the CC were greater in the MSC-3 group, followed by the MSC-1 group, and then the vehicle group. The increased thickness and optical density of neurofilament in the CC correlated with motor function at 15 weeks following induction of MCAO. Preserved neural tracts that ran through interhemispheric connections via the CC were also more extensive in the MSC-3 group, followed by the MSC-1 group and then the vehicle group, as observed ex vivo using diffusion tensor imaging. These results indicate that repeated systemic administration of MSCs over 3 weeks resulted in greater functional improvement as compared to single administration and/or vehicle infusion. In addition, administration of MSCs is associated with promotion of interhemispheric connectivity through the CC in the chronic phase of cerebral infarction.

Mesenchymal stem cells in fibrotic diseases-the two sides of the same coin.

Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.

Effect of Stem Cell Infusion Therapy on Sexual Function in Women with Type 2 Diabetes and Metabolic Syndrome: Post-Hoc Analysis of Randomized Controlled Trials

ABSTRACT Introduction There is a growing interest in restorative therapies for sexual function, yet there exists a paucity of human research into potential therapeutic applications of stem cell therapy (SCT). Mesenchymal Stem Cells (MSCs) and their effect on sexual function have not yet been explored in women with Type 2 Diabetes Mellitus (DM) and Metabolic Syndrome (MetS). Objective To determine the safety and efficacy of intravenous mesenchymal stem cell infusion therapy on sexual function in women with DM or MetS. Methods Female participants enrolled in the ACESO (NCT02886884) and CERES (NCT03059355) clinical trials completed the Sexual Quality of Life Questionnaire-Female (SQOL-F). SQOL-F is a validated 18-item self-assessment questionnaire rated on a six-point scale ranging from “completely agree” to “completely disagree” in which higher scores reflect better sexual quality of life. Participants were enrolled in the trials based on diagnosis of DM or MetS, respectively. Intervention in both trials was peripheral intravenous infusion of allogeneic MSCs. Follow-up was for 1 year. Questionnaires were collected at baseline and 1-, 3-, 6-, and 12-months post-infusion. Participants received 20 or 100 million MSCs from either bone marrow (n=5) or umbilical cord (n=2). Results Data was pooled from 7 women who participated in the two trials; 5 were from ACESO and 2 were from CERES. Three received high dose MSCs (100 million) and four received low dose (20 million) MSCs. The women in the ACESO trial received MSCs derived from healthy allogeneic donor bone marrow, and both women in the CERES trial received umbilical cord tissue derived MSCs. Median age was 73 [IQR=55-74] years. Six of the seven (86%) had past medical history of hypertension. Median SQOL score among all women at baseline was 30 [IQR=19-50], 25 [IQR=23-36] at 1 month, 34 [IQR=19-46] at 3 months, 29 [IQR=21-32] at 6 months, and 34 [IQR=26-49] at the end of 12 months. Improvements in SQOL from baseline through follow up did not meet level of statistical significance. Limitations of this study include the absence of a placebo-control group, the small sample size, and that sexual function was not a primary endpoint of the original trials. Conclusions SQOL did not appear to improve following peripheral infusion of MSCs in women with DM or MetS, but nevertheless appears to be safe with no decline in sexual function over the following 1 year. Larger clinical trials with placebo-controls are needed to further investigate the optimal dose, source, and route administration of SCT to enact a meaningful change in sexual function in women with DM or MetS. Disclosure Yes, this is sponsored by industry/sponsor: This work was supported by National Institutes of Health Grant R01 DK130991 and Clinician Scientist Development Grant from the American Cancer Society to RR. JMH is supported by National Institutes of Health grants 1R01 HL137355, 1R01 HL107110, 1R01 HL134558, 5R01 CA136387, and 5UM1 HL113460 and Soffer Family Foundation. Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: JMH discloses a relationship with Vestion Inc. that includes equity, board membership, and consulting. Neither Longeveron, Vestion, or any other companies participated in the funding of this work. All other authors indicated no potential conflicts of interest.

Feasibility and Safety of Low-Dose Mesenchymal Stem Cell Infusion in Lung Transplant Recipients.

BackgroundWe have previously shown bone marrow-derived mesenchymal stem cells (MSCs) may shift immune responses toward anti-inflammatory pathways and stabilize the course of obstructive chronic lung allograft syndrome (o-CLAD) after lung transplantation. In this study, we measured the response of lower dose infusions.MethodsWe infused low-dose MSCs intravenously in 13 patients who had developed moderate-to-severe o-CLAD. Three had previously received an infusion of MSCs from a different donor and were re-dosed at 1 × 106 MSC/kg, while 5 received a first dose at 1 × 106 MSC/kg and five received an even lower dose at 0.5 × 106 MSC/kg. We recorded pulmonary function tests before and after infusion, and patients were followed clinically for 12 months.ResultsInfusions were well tolerated, and no significant adverse events were recorded in the first 30 days. There was significant decline (mean ± SD) in forced vital capacity (FVC) (3.49 ± 1.03 vs 3.18 ± 0.94 L, P = .03) and forced expiratory volume in 1 second (FEV1) (2.28 ± 0.86 vs 1.77 ± 0.49 L, P = .04) over the year preceding infusion. FVC (3.18 ± 0.94 vs 3.46 ± 0.99 L, P = .53) and FEV1 was not significantly changed (1.77 ± 0.49 vs 1.88 ± 0.75, P = .72) when comparing values immediately prior to infusion to those obtained 1 year after infusion, indicating a possible stabilizing effect on lung function decline due to o-CLAD.ConclusionIntravenous infusions of bone marrow-derived MSCs are well tolerated in lung transplant recipients with moderate-to-severe CLAD. Low-dose MSCs appear to slow progression of CLAD in some patients.