Mesenchymal Stem Cells Treatment Group Research Articles

Effects of xenogeneic transplantation of umbilical cord-derived mesenchymal stem cells combined with irbesartan on renal podocyte damage in diabetic rats

BackgroundThe leading cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN). Podocyte damage is an early event in the development of DN. Currently, there is no effective treatment strategy that can slow the progression of DN or reverse its onset. The role of mesenchymal stem cells (MSCs) transplantation in diabetes and its complications has been extensively studied, and diabetic nephropathy has been a major focus. Irbesartan exerts reno-protective effects independent of lowering blood pressure, can reduce the incidence of proteinuria in rats, and is widely used clinically. However, it remains undetermined whether the combined utilization of the angiotensin II receptor antagonist irbesartan and MSCs could enhance efficacy in addressing DN.MethodsA commonly used method for modeling type 2 diabetic nephropathy (T2DN) was established using a high-fat diet and a single low-dose injection of STZ (35 mg/kg). The animals were divided into the following 5 groups: (1) the control group (CON), (2) the diabetic nephropathy group (DN), (3) the mesenchymal stem cells treatment group (MSCs), (4) the irbesartan treatment group (Irb), and (5) the combined administration group (MSC + Irb). MSCs (2 × 106 cells/rat) were injected every 10 days through the tail vein for a total of three injections; irbesartan (30 mg/kg/d) was administered by gavage. Additionally, the safety and homing of mesenchymal stem cells were verified using positron emission tomography (PET) imaging.ResultsThe combination treatment significantly reduced the UACR, kidney index, IGPTT, HOMA-IR, BUN, serum creatine, and related inflammatory factor levels and significantly improved renal function parameters and the expression of proteins related to glomerular podocyte injury in rats. Moreover, MSCs can homing target to damaged kidneys.ConclusionsCompared to the administration of MSCs or irbesartan alone, the combination of MSCs and irbesartan exerted better protective effects on glomerular podocyte injury, providing new ideas for the clinical application of mesenchymal stem cells.

Human umbilical cord mesenchymal stem cell transplantation for the treatment of acute-on-chronic liver failure: protocol for a multicentre random double-blind placebo-controlled trial

IntroductionAcute-on-chronic liver failure (ACLF) is a prevalent and life-threatening liver disease with high short-term mortality. Although recent clinical trials on the use of mesenchymal stem cells (MSCs) for ACLF treatment...

Delivery of Mesenchymal Stem Cells during Hypothermic Machine Perfusion in a Translational Kidney Perfusion Study.

In transplantation, hypothermic machine perfusion (HMP) has been shown to be superior to static cold storage (SCS) in terms of functional outcomes. Ex vivo machine perfusion offers the possibility to deliver drugs or other active substances, such as Mesenchymal Stem Cells (MSCs), directly into an organ without affecting the recipient. MSCs are multipotent, self-renewing cells with tissue-repair capacities, and their application to ameliorate ischemia- reperfusion injury (IRI) is being investigated in several preclinical and clinical studies. The aim of this study was to introduce MSCs into a translational model of hypothermic machine perfusion and to test the efficiency and feasibility of this method. Methods: three rodent kidneys, six porcine kidneys and three human kidneys underwent HMP with 1-5 × 106 labelled MSCs within respective perfusates. Only porcine kidneys were compared to a control group of 6 kidneys undergoing HMP without MSCs, followed by mimicked reperfusion with whole blood at 37 °C for 2 h for all 12 kidneys. Reperfusion perfusate samples were analyzed for levels of NGAL and IL-β by ELISA. Functional parameters, including urinary output, oxygen consumption and creatinine clearance, were compared and found to be similar between the MSC treatment group and the control group in the porcine model. IL-1β levels were higher in perfusate and urine samples in the MSC group, with a median of 285.3 ng/mL (IQR 224.3-407.8 ng/mL) vs. 209.2 ng/mL (IQR 174.9-220.1), p = 0.51 and 105.3 ng/mL (IQR 71.03-164.7 ng/mL) vs. 307.7 ng/mL (IQR 190.9-349.6 ng/mL), p = 0.16, respectively. MSCs could be traced within the kidneys in all models using widefield microscopy after HMP. The application of Mesenchymal Stem Cells in an ex vivo hypothermic machine perfusion setting is feasible, and MSCs can be delivered into the kidney grafts during HMP. Functional parameters during mimicked reperfusion were not altered in treated kidney grafts. Changes in levels of IL-1β suggest that MSCs might have an effect on the kidney grafts, and whether this leads to a positive or a negative outcome on IRI in transplantation needs to be determined in further experiments.

Mesenchymal stem cells from human umbilical cord decrease inflammation and increase vascularization of induced apical periodontitis model in diabetes mellitus rats.

to evaluate inflammation and vascularization in a model of apical periodontitis in diabetic Wistar rats through histopathological examination of blood vessels and immunohistochemical examination of interleukin 1b (IL-1b) and tumor necrosis factor-a (TNF-a). Diabetes was induced in 20 Wistar rats using multiple low-dose injections of streptozotocin (STZ) until blood glucose levels stabilized above 300 mg/dL, confirmed by glucometer. Under anesthesia, apical periodontitis was induced in the right mandibular first molars. After preparing the access cavity and extirpating pulp and canal, the teeth were left open. Apical periodontitis was projected seven days afterwards and the Wistar rats were assigned in random into four groups, each group consisting of five rats. The first group (C14) was euthanized 14 days post-induction, while the second group (C28) was euthanized 28 days later, serving as controls. The third group (T14) received mesenchymal stem cells from human umbilical cords and was euthanized after 14 days, while the fourth group (T28) received mesenchymal stem cells from human umbilical cord and was euthanized after 28 days. The number of blood vessels and the expressions of IL-1b and TNF-a were analyzed. Data were evaluated with ANOVA and by Tukey's HSD test, with significance at p<0.05. Both control and treatment groups showed a significant increase in vascularization in the apical periodontal area of apical periodontitis in the control and treatment groups at 14 and 28 days (p<0.05). A significant reduction of IL-1b and TNF-a levels was found in the mesenchymal stem cells treatment groups when compared to control groups (p<0.05). Our findings support the use of mesenchymal stem cells from human umbilical cords to decrease inflammation and increase vascularization in an induced apical periodontitis model in diabetes mellitus Wistar rats.

Regulatory effects of umbilical cord mesenchymal stem cells and their conditioned medium on gut microbiota of septic mice

To investigate and compare the regulatory effects of umbilical cord mesenchymal stem cells (MSC) and their conditioned medium (MSC-CM) on gut microbiota of septic mice. Twenty-eight six-to-eight-week-old female C57BL/6J mice were randomly divided into sham operation group (Sham group), sepsis model group (CLP group), sepsis+MSC treatment group (CLP+MSC group) and sepsis+MSC-CM treatment group (CLP+MSC-CM group), with seven mice in each group. The septic mouse model was established by cecal ligation and puncture (CLP). In Sham group, CLP were not performed, and other operations were the same as CLP group. Mice in the CLP+MSC group and CLP+MSC-CM group received 0.2 mL 1×106 MSC or 0.2 mL concentrated MSC-CM via intraperitoneal injection 6 hours after CLP, respectively. Sham group and CLP group were given 0.2 mL sterile phosphate buffer saline (PBS) via intraperitoneal injection. Histopathological changes were evaluated by hematoxylin-eosin (HE) staining and colon length. Levels of inflammatory factors in serum were detected by enzyme-linked immunosorbent assay (ELISA). Phenotype of peritoneal macrophages was analyzed by flow cytometry, and the gut microbiota was analyzed via 16S rRNA sequencing. Compared with Sham group, significant inflammatory injury in lung and colon was observed, and shorter colon was detected in CLP group (cm: 6.00±0.26 vs. 7.11±0.09), the level of inflammatory cytokine interleukin-1β (IL-1β) in serum was significantly increased (ng/L: 432.70±17.68 vs. 353.70±17.01), the proportion of F4/80+ peritoneal macrophages was increased [(68.25±3.41)% vs. (50.84±4.98)%], while the ratio of F4/80+CD206+ anti-inflammatory peritoneal macrophages was decreased [(45.25±6.75)% vs. (66.66±3.36)%]. The α diversity sobs index of gut microbiota was downregulated significantly (118.50±23.25 vs. 255.70±6.87), the structure of species composition was altered, and the relative abundance of functional gut microbiota related to transcription, secondary metabolites biosynthesis, transport and catabolism, carbohydrate transport and metabolism, and signal transduction were decreased significantly in CLP group (all P < 0.05). Compared with CLP group, upon MSC or MSC-CM treatment, the pathological injury in lung and colon was alleviated to varying extent, the length of colon was increased (cm: 6.53±0.27, 6.87±0.18 vs. 6.00±0.26), the level of IL-1β in serum was downregulated (ng/L: 382.10±16.93, 343.20±23.61 vs. 432.70±17.68), the ratio of F4/80+ peritoneal macrophages was decreased [(47.65±3.93)%, (48.68±2.51)% vs. (68.25±3.41)%], the ratio of F4/80+CD206+ anti-inflammatory peritoneal macrophages was increased [(52.73±5.02)%, (66.38±4.73)% vs. (45.25±6.75)%], and the α diversity sobs index of gut microbiota was increased (182.50±16.35, 214.00±31.18 vs. 118.50±23.25), and the effects of MSC-CM were more significant (all P < 0.05). At the same time, species composition of gut microbiota was rebuilt, and a tendency of increase in relative abundance of functional gut microbiota was observed upon MSC and MSC-CM treatment. Both MSC and MSC-CM could alleviate inflammatory injury in tissues, and showed regulatory effects on gut microbiota in septic mouse model, moreover, MSC-CM exhibited superior advantages over MSC.

The role of mesenchymal stem cells in allergic rhinitis and its relationship with IL-10, plasma cells and regulatory T cells.

Aim Allergic rhinitis (AR) is an IgE-mediated inflammation of the nose. Regulatory T cells (Tregs), plasma cells and inflammatory cytokines have shown to play a critical role in allergic airway inflammation. The aim of the study was to investigate the role of mesenchymal stem cells (MSCs) in generating Treg cells and plasma cells associated with regulating interlukin-10 (IL-10) in AR model. Methods Fifteen male Wistar rats (6 to 8 weeks old) were randomly divided into three groups (control group, sham group, and MSCs treatment group). Ovalbumin (OVA) nasal challenge was conducted daily from day 15 to 21, and MSCs (1x106) were administrated intraperitoneally to OVA-sensitized rats on day 21. Sneezing was observed from day 24 to 27. The rats were sacrificed on day 24 and day 27. The expression of Treg and plasma cells was analysed by flow cytometry assay. The level of IL-10 was analysed under ELISA assay. Results This study showed that the percentage of sneezing and rubbing times significantly decreased in MSCs treatment associated with the regulation of IL-10 level and plasma cell. This finding was aligned with the significant increase of Treg level. Conclusion MSCs administration regulates IL-10 and plasma cell-mediated immune and inflammatory responses while increasing Treg cell production. MSCs may be a promising therapeutic target for treating Treg-mediated allergic diseases.

Effect of Recombinant Netrin-1 Protein Combined with Peripheral Blood Mesenchymal Stem Cells on Angiogenesis in Rats with Arteriosclerosis Obliterans.

This work was aimed to explore the effect of recombinant netrin-1 protein and peripheral blood mesenchymal stem cells (MSCs) on the angiogenesis ability of atherosclerosis. 28 Sprague Dawley (SD) rats were taken as research models. The arterial occlusion models were created by surgery and then divided into the saline control group (n =7), netrin-1 treatment group (n =7), MSCs treatment group (n =7), and netrin-1 + MSCs combined treatment group (n =7). The peripheral blood MSCs were extracted from the peritoneal cavity of diseased SD rats and cultured alone or in combination with netrin-1. The individually cultured MSCs and netrin-1 were locally injected into the ischemic tissues of SD rats. The Tarlov scoring was performed at the first, second, and third week of treatment, respectively. The expression of vascular endothelial growth factor (VEGF) was also measured by quantitative real-time polymerase chain reaction (qRT-PCR), and the capillary density was measured by immunofluorescence staining. The mean maximum contractility of the gastrocnemius muscle in each group was determined in the third week after treatment. The Tarlov score of the netrin-1 + MSCs group was significantly higher than that of the control group (P < 0.05) at the second week. To the 4th week of treatment, the Tarlov score of the netrin-1 + MSCs group was highly increased compared to the netrin-1 group and the MSCs group (P < 0.05). The expression of VEGF in the treatment groups was greatly increased each week compared to the control group (P < 0.05). Compared with the netrin-1 and the MSCs groups, the VEGF was also notably increased in the netrin-1 + MSCs group (P <0.05). The capillary densities of the treatment groups were observably greater than that of the control group in the second and third weeks (P <0.05), while the capillary density in the netrin-1 + MSCs group was also significantly increased than those in the netrin-1 group and the MSCs group (P < 0.05). The mean maximum contractility of the netrin-1 + MSCs group was remarkably higher than that of the other groups (P < 0.05). The netrin-1 + MSCs group achieved the higher Tarlov score, higher VEGF expression, higher capillary density, and better muscle recovery than netrin-1 and MSCs treatments.

Treatment of Abdominal Aortic Aneurysm Utilizing Adipose-Derived Mesenchymal Stem Cells in a Porcine Model

IntroductionThe current treatment paradigm of abdominal aortic aneurysms (AAA) focuses on observing patients until their disease reaches certain thresholds for intervention, with no preceding treatment available. There is an opportunity to develop novel therapies to prevent further aneurysmal growth and decrease the risk of a highly morbid rupture. We used a porcine model of aortic dilation to assess the ability of human adipose-derived mesenchymal stem cells (MSCs) to attenuate aortic dilation. Materials and methodsTwelve Yorkshire pigs received periadventitial injections (collagenase and elastase) into a 4-cm segment of infrarenal aorta. Animals were treated with either 1 × 106 MSCs placed onto Gelfoam or treated with media as a control. Aortic diameters were measured at the time of surgery and monitored at postoperative day (POD) 7 and 14 with ultrasound. Animals were sacrificed on POD 21. Aortic tissue was harvested for histopathological analyses and immunohistochemistry. Groups were compared with paired t-tests or Mann–Whitney U-tests. ResultsAll animals survived until POD 21. The mean aortic diameter was reduced in the aortic dilation + MSC treatment group compared to aortic dilation control animals (1.10 ± 0.126 versus 1.48 cm ± 0.151, P < 0.001). Aortic media thickness was reduced in the aortic dilation group compared to the aortic dilation + MSC group (609.14 IQR 445.21-692.93 μm versus 643.55 IQR 560.91-733.88 μm, P = 0.0048). There was a significant decrease in the content of collagen and alpha-smooth muscle actin and elastin perturbation in the aortic dilation group as compared to the aortic dilation + MSC group. Immunohistochemistry demonstrated an increased level of vascular endothelial growth factor, tissue inhibitor of matrix metalloproteinase 1, and tissue inhibitor of matrix metalloproteinase 3 expression in the aorta of aortic dilation + MSC animals. ConclusionsStem cell therapy suppressed the aortic dilation in a porcine model. Animals from the aortic dilation group showed more diseased gross features, histologic changes, and biochemical properties of the aorta compared to that of the aortic dilation + MSC treated animals. This novel finding should prompt further investigation into translatable drug and cell therapies for aneurysmal disease.

Mesenchymal stem cells regulate activation of microglia cells to improve hippocampal injury of heat stroke rats.

Heat stroke is a severe systemic inflammatory response disease caused by high fever, mainly with nervous system damage. Mesenchymal stem cells (MSCs) are currently believed to have anti-inflammation and immunomodulatory effects. Therefore, we aimed to explore the protective effect and mechanism of MSCs on heat stroke-induced excessive inflammation and neurological dysfunction. We established a heat stroke model in rats under conditions of continuous high temperature and high humidity. After modeling, rats were randomly divided into heat stroke model group, MSCs treatment group and normal temperature control group without any treatment. We performed survival analysis, neurological deficit score, histological staining of hippocampus and cerebellum, immunofluorescence staining of microglia, detection of inflammatory and chemokine levels in the hippocampus and cerebellum in each group. We found that MSCs treatment not only significantly reduced early (day 3) and late (day 28) mortality, but also prominently reduced nerve injury in heat stroke rats, and improved pathology and neuronal cell damage in the hippocampus and cerebellum. In addition, MSCs treatment can significantly inhibit the over-activation of hippocampal microglia in heat stroke rats and the levels of pro-inflammatory factors and chemokines in the hippocampus. Early treatment of MSCs can greatly promote the activation of cerebellar microglia in heat stroke rats. Meanwhile, MSCs treatment has an inhibitory effect on the level of chemokine in the cerebellum of rats in the early stage of heat stroke. In conclusion, the application of MSCs in the treatment of heat stroke in rats can significantly reduce mortality and neurological deficits and improve hippocampal damage, possibly by inhibiting the excessive activation of hippocampal microglia in heat stroke rats.

Clinical efficacy on glycemic control and safety of mesenchymal stem cells in patients with diabetes mellitus: Systematic review and meta-analysis of RCT data.

BackgroundDiabetes mellitus as a chronic metabolic disease is threatening human health seriously. Although numerous clinical trials have been registered for the treatment of diabetes with stem cells, no articles have been published to summarize the efficacy and safety of mesenchymal stem cells (MSCs) in randomized controlled trials (RCTs).Methods and findingsThe aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to provide a reliable numerical summary and the most comprehensive assessment of therapeutic efficacy and safety with MSCs in diabetes. PubMed, Web of Science, Ovid, the Cochrane Library and CNKI were searched. The retrieval time was from establishment of these databases to January 4, 2020. Seven RCTs were eligible for analysis, including 413 participants. Meta-analysis results showed that there were no significant differences in the reduction of fasting plasma glucose (FPG) compared to the baseline [mean difference (MD) = -1.05, 95% confidence interval (CI) (-2.26,0.16), P<0.01, I2 = 94%] and the control group [MD = -0.62, 95%CI (-1.46,0.23), P<0.01, I2 = 87%]. The MSCs treatment group showed a significant decrease in hemoglobin (Hb) A1c [random-effects, MD = -1.32, 95%CI (-2.06, -0.57), P<0.01, I2 = 90%] after treatment. Additionally, HbA1c reduced more significantly in MSC treatment group than in control group [random-effects, MD = -0.87, 95%CI (-1.53, -0.22), P<0.01, I2 = 82%] at the end of follow-up. However, as for fasting C-peptide levels, the estimated pooled MD showed that there was no significant increase [MD = -0.07, 95%CI (-0.30, 0.16), P<0.01, I2 = 94%] in MSCs treatment group compared with that in control group. Notably, there was no significant difference in the incidence of adverse events between MSCs treatment group and control group [relative risk (RR) = 0.98, 95%CI (0.72, 1.32), P = 0.02, I2 = 70%]. The most commonly observed adverse reaction in the MSC treatment group was hypoglycemia (29.95%).ConclusionsThis meta-analysis revealed MSCs therapy may be an effective and safe intervention in subjects with diabetes. However, due to the limited studies, a number of high-quality as well as large-scale RCTs should be performed to confirm these conclusions.

The CD4+CD25+FoxP3+ Regulatory T Cells Regulated by MSCs Suppress Plasma Cells in a Mouse Model of Allergic Rhinitis.

Background:Allergic Rhinitis (AR) is the most common immunological disease that has been associated with inflammatory responses and is characterized by sneezing. Previous studies found that AR's allergen exposure significantly induces plasma cells and reduces regulatory T (Treg) cells, a population that contributes to control AR. Therefore, upregulating Treg expression can regulate plasma cells leading to inhibit sneezing in AR. Mesenchymal stem cells (MSCs) are multipotent stem cells that have the immunoregulatory and antiinflammation ability by secreting various cytokines including IL-10 and TGF-β which potent as a promising therapeutic modality for allergic airway diseases, including AR.Objective:To investigate the role of MSCs in generating CD4+, CD25+, and Foxp3+ Regulatory T cells associated with suppressing plasma cell in AR model.Methods:In this study, fifteen male Wistar rats (6 to 8 weeks old) were randomly divided into three groups (control group, sham group, and MSCs treatment group). OVA nasal challenge was conducted daily from day 15 to 21, and MSCs (1x106) were administrated intraperitoneally to OVA-sensitized rats on day 21. Sneezing was observed from day 22 to 28. The rats were sacrificed on day 22 and day 28. The expression of CD4+ CD25+ Foxp3+ in Treg and plasma cells was analyzed by flow cytometry assay.Results:This study showed that the percentage of plasma cell and sneezing times significantly decreased in MSCs treatment. This finding was aligned with the significant increase of CD4+CD25+Foxp3+ Treg level.Conclusion:MSCs administration suppress plasma cells population and sneezing times by up regulating Treg to control AR.

Nephroprotective Effect of Mesenchymal Stem Cell-Based Therapy of Kidney Disease Induced by Toxicants.

Background Renal damage caused by drug toxicity is becoming increasingly common in the clinic. Preventing and treating kidney damage caused by drug toxicity are essential to maintain patient health and reduce the social and economic burden. In this study, we performed a meta-analysis to assess the nephroprotective effect of mesenchymal stem cells (MSCs) in the treatment of kidney disease induced by toxicants. Methods The Cochrane Library, Embase, ISI Web of Science, and PubMed databases were searched up to December 31, 2019, to identify studies and extract data to assess the efficacy of MSCs treatment of kidney disease induced by toxicants using Cochrane Review Manager Version 5.3. A total of 27 studies were eligible and selected for this meta-analysis. Results The results showed that a difference in serum creatinine levels between the MSC treatment group and control group was observed for 2, 4, 5, 6-8, 10-15, 28-30, and ≥42 days (2 days: WMD = −0.88, 95% CI: -1.34, -0.42, P = 0.0002; 4 days: WMD = −0.74, 95% CI: -0.95, -0.54, P < 0.00001; 5 days: WMD = −0.46, 95% CI: -0.67, -0.25, P < 0.0001; 6-8 days: WMD = −0.55, 95% CI: -0.84, -0.26, P = 0.0002; 10-15 days: WMD = −0.37, 95% CI: -0.53, -0.20, P < 0.0001; 28-30 days: WMD = −0.53, 95% CI: -1.04, -0.02, P = 0.04; ≥42 days: WMD = −0.22, 95% CI: -0.39, -0.06, P = 0.007). Furthermore, a difference in blood urea nitrogen levels between the MSC treatment group and control group was observed for 2-3, 4-5, 6-8, and ≥28 days. The results also indicate that MSC treatment alleviated inflammatory cells, necrotic tubules, regenerative tubules, and renal interstitial fibrosis in kidney disease induced by toxicants. Conclusion MSCs may be a promising therapeutic agent for kidney disease induced by toxicants.

MSC-released TGF-β regulate α-SMA expression of myofibroblast during wound healing.

Objective: Wound healing without fibrosis remains a clinical challenge and a new strategy to promote the optimal wound healing is needed. Mesenchymal stem cells (MSCs) can completely regenerate tissue injury due to the robust MSCs ability in controlling inflammation niche leading to granulation tissue formation, particularly through a release of various growth factors including transforming growth factor-β (TGF-β). In response to TGF-β stimulation, fibroblasts differentiate into myofibroblast, marked by alpha-smooth muscle actin (α-SMA) that leads to wound healing acceleration. On the other hand, sustained activation of TGF-β in wound areas may contribute to fibrosis-associated scar formation. The aim of this study was to evaluate the α-SMA expression of myofibroblast induced by MSC-released TGF-β during wound healing process. Materials and Methods: Twenty-four full-thickness excisional rat wound models were randomly divided into four groups: sham (Sh), Control (C), and MSCs treatment groups; topically treated by the MSCs at doses 2x106 cells (T1) and 1x106 cells (T2), respectively. While the control group was treated with NaCl. TGF-β level was determined using ELISA assay, α-SMA expression of myofibroblast was analyzed by immunofluorescence staining, and wound size measurement was calculated using a standard caliper. Results: This study showed a significant increase in TGF-β levels in all treatment groups on days 3 and 6. This finding was consistent with a significant increase of α-SMA expression of myofibroblast at day 6 and wound closure percentage, indicating that MSCs might promote an increase of wound closure. Conclusion: MSCs regulated the release of TGF-β to induce α-SMA expression of myofibroblast for accelerating an optimal wound healing.

Mesenchymal stem cells negatively regulate CD4+ T cell activation in patients with primary Sj&ouml;gren syndrome through the miRNA‑125b and miRNA‑155 TCR pathway.

Treatment with mesenchymal stem cells (MSCs) has been revealed to suppress CD4+ T cells and autoimmunity in both mouse models and patients with primary Sjögren syndrome (pSS); however, the underlying mechanism remains unclear. MicroRNAs (miRNAs or miRs) mediate CD4+ T cell activation, but the mechanism is not understood, particularly for CD4+ T cells treated with MSCs. Characterization of miRNAs may reveal pSS pathogenesis, guide MSC treatment and provide more personalized management options. The present study aimed to perform an miRNome analysis of quiescent and T cell receptor (TCR)-activated CD4+ T cells treated with MSCs via miRNA profiles and bioinformatics. Following 72 h of co-culture, MSCs inhibited TCR-induced CD4+ T cell activation and decreased IFN-γ levels. The numbers of aberrant miRNAs in pSS naïve (vs. healthy naïve), pSS activation (vs. pSS naïve), MSC treatment and pre-IFN-γ MSC treatment (vs. pSS activation) groups were 42, 55, 27 and 32, respectively. Gene enrichment analysis revealed that 259 pathways were associated with CD4+ T cell stimulation, and 240 pathways were associated with MSC treatment. Increased miRNA-7150 and miRNA-5096 and decreased miRNA-125b-5p and miRNA-22-3p levels in activated CD4+ T cells from patients with pSS were reversed by MSC treatment. Notably, the proliferation of CD4+ T cells and CD4+ IFN-γ+ cells, expression levels of miRNA-125b-5p and miRNA-155 in CD4+ T cells and supernatant IFN-γ secretion were associated with disease activity. miRNA may play a vital role in MSC treatment for activated CD4+ T cells. The results indicated that the expression levels of miRNA-125b-5p and miRNA-155 in TCR-activated CD4+ T cells from patients with pSS may provide insight regarding autoimmune diseases and offer a novel target for prospective treatment. Therefore, these results may be crucial in providing MSC treatment for pSS.

A Systematic Review and Meta-Analysis: Safety and Efficacy of Mesenchymal Stem Cells Therapy for Heart Failure.

Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating Heart Failure (HF). However, the effects of stem cell therapy in patients with heart failure is an ongoing debate and the safety and efficacy of MSCs therapy are not well-known. We conducted a systematic review of clinical trials that evaluated the safety and efficacy of MSCs for HF. This study aimed to assess the safety and efficacy of MSCs therapy compared to the placebo in heart failure patients. We searched PubMed, Embase, Cochrane library systematically, with no language restrictions. Randomized Controlled Trials (RCTs) assessing the influence of MSCs treatment function controlled with placebo in heart failure were included in this analysis. We included RCTs with data on safety and efficacy in patients with heart failure after mesenchymal stem cell transplantation. Two investigators independently searched the articles, extracted data, and assessed the quality of the included studies. Pooled data was performed using the fixed-effect model or random-effect model by the use of Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The primary outcome was safely assessed by death and rehospitalization and the secondary outcome was efficacy, which was assessed by six-minute walk distance and Left Ventricular Ejection Fraction (LVEF), Left Ventricular End-systolic Volume (LVESV), Left Ventricular End-diastolic Volume (LVEDV) and Brain Natriuretic Peptide (BNP). A total of twelve studies were included, involving 823 patients who underwent MSCs or placebo treatment. The overall rate of death showed a trend of reduction of 27% (RR [CI]=0.73 [0.49, 1.09], p=0.12) in the MSCs treatment group. The incidence of rehospitalization was reduced by 47% (RR [CI]=0.53[0.38, 0.75], p=0.0004). The patients in the MSCs treatment group realised an average of 117.01m (MD [95% CI]=117.01m [94.87, 139.14], p<0.00001) improvement in 6MWT. MSCs transplantation significantly improved Left Ventricular Ejection Fraction (LVEF) by 5.66 % (MD [95% CI]=5.66 [4.39, 6.92], p<0.00001), decreased Left Ventricular End-Systolic Volume (LVESV) by 14.75 ml (MD [95% CI]=-14.75 [-16.18, - 12.83], p<0.00001) and Left Ventricular End-Diastolic Volume (LVEDV) by 5.78 ml (MD [95% CI]=- 5.78[-12.00, 0.43], p=0.07), in the MSCs group, BNP was decreased by 133.51 pg/ml MD [95% CI]= - 133.51 [-228.17,-38.85], p=0.54, I2= 0.0%) than did in the placebo group. Our results suggested that mesenchymal stem cells as a regenerative therapeutic approach for heart failure are safe and effective by virtue of their self-renewal potential, vast differentiation capacity and immune modulating properties. Allogenic MSCs have superior therapeutic effects and intracoronary injection is the optimum delivery approach. In the tissue origin, patients who received treatment with umbilical cord MSCs seem more effective than bone marrow MSCs. As to dosage injected, (1-10)*10^8 cells were of better effect.

IGF-1 and HGF Preconditioning of Bone Marrow Mesenchymal Stem Cells Reduced Proteinuria in Rat Focal Segmental Glomerulosclerosis Model

Background & Aim Focal Segmental Glomerulosclerosis (FSGS) is one of the leading causes of end-stage kidney disease requiring renal replacement therapy for survival. It is characterized by massive proteinuria that results in hypoalbuminemia, edema and hyperlipidemia. and is known as irreversible kidney disease that steroid-based drugs only slow down the progression. The use of Mesenchymal stem cells (MSCs) has been successful in the treatment of glomerular diseases. The biggest challenge of the MSC application is its engraftment into the site of injury and its loss due to the poor microenvironment. Preconditioning of MSCs by particular growth factors such as insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) increases their migration, immunomodulation and survival. IGF-1 and HGF have been proposed as promising therapeutic agents in recent years and are especially preferred in renal diseases with their renotrophic and nephroprotective effects. Therefore we aimed to test the effect of IGF-1 and HGF-preconditioned MSCs in a rat model of FSGS. Methods, Results & Conclusion Preconditioning of MSCs was performed by 10 ng/ml IGF-1 and 20 ng/ml HGF and designated as iMSCs. Rat (Sprague-Dawley) FSGS model was technically induced by a single-dose intraperitoneal administration of Puromycin Aminonucleoside (PAN) (150 mg/kg). There were PBS, MSC and iMSC treatment groups (n=6/gr77). The occurrence of FSGS was assessed by biochemistry (i.e. elevated urinary protein/creatinine (P/C) ratio), immunohistochemistry (i.e. decreased glomerular SYNPO protein level) and electron microscopy (i.e. presence of podocyte effacement). We applied 2 × 105 MSC or preconditioned MSC intravenously on the day of 4 following PAN administration. The effect of treatment was assessed by urinary P/C ratios in 24-hour urine which was collected on the treatment day of 9. iMSC treatment significantly decreased proteinuria (p As a result of our study, we demonstrated that iMSCs can partially reverse the glomerular damage and reduce proteinuria with regenerating glomerular filtering apparatus in the PAN model of FSGS and therefore may offer a new therapeutic strategy for human FSGS.

Efficacy of mesenchymal stem cells in animal models of lupus nephritis: a meta-analysis

BackgroundLupus nephritis is usually manifested by proteinuria, active urinary sediment, hypertension, and renal failure and is a serious complication with more than 50% occurrence in systemic lupus erythematosus patients. Mesenchymal stem cells (MSC) present remarkable immunomodulatory ability, and these cells are potential therapeutic agents for autoimmune disorders. In clinical trials, the effectiveness of MSC in the treatment of lupus nephritis is still controversial. A meta-analysis was performed to assess whether MSC can achieve good efficacy in the treatment of lupus nephritis in mice.MethodsA comprehensive literature search was performed in Cochrane Library, ISI Web of Science, PubMed, and EMBASE from inception to Oct 1, 2019. Two authors independently extracted the data, which were pooled and calculated using RevMan 5.3.ResultsA total of 28 studies met the inclusion criteria. MSC treatment resulted in lower levels of ds-DNA (OR = − 29.58, 95% CI − 29.58, − 17.99; P < 0.00001), ANA (OR = − 70.93, 95% CI − 104.55, − 37.32; P < 0.0001), Scr (OR = − 8.20, 95% CI − 12.71, − 3.69; P = 0.0004), BUN (OR = − 14.57, 95% CI − 20.50, − 8.64; P < 0.00001), proteinuria (OR = − 4.26, 95% CI − 5.15 to − 3.37; P < 0.00001), and renal sclerosis score (OR = − 1.92, 95% CI − 2.66 to − 1.18; P < 0.00001), and MSC treatment could get higher levels of albumin. To detect the potential, the cytokines were also assessed, and the MSC treatment group had lower levels of IL-2, IL-12, IL-17, and IFN-γ when compared with the control group. However, the difference was not notable for IL-4, IL-6, IL-10, TGF-β, MCP-1, TNF-α, Th1, Th17, Foxp3, or Tregs.ConclusionOur study confirmed that MSC treatment in an animal model for lupus nephritis in the studies included in the meta-analysis resulted in lower levels of ds-DNA, ANA, Scr, BUN, proteinuria, and renal sclerosis score, and MSC treatment could get higher levels of albumin.

Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia.

A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.

Adverse effects of xenogenic scaffolding in the context of a randomized double-blind placebo-controlled study for repairing full-thickness rotator cuff tears

PurposeThe purpose of the study was to compare the safety and efficacy of autologous mesenchymal stem cells (MSCs) embedded in a xenogenic scaffold for repairing the supraspinatus tendon.MethodsThis was a randomized, double-blind and placebo-controlled trial evaluating patients with full-thickness rotator cuff tears (Eudra-CT, 2007–007630-19). Effectiveness was evaluated using the Constant score and a visual analogue pain scale (VAS).Constant score has four domains including pain (15 possible points), activities of daily living (20 possible points), mobility (40 possible points), and strength (25 possible points). Scores range from 0 points (most disability) to 100 points (least disability).The structural integrity of the repaired tendon was assessed by magnetic resonance imaging (MRI) according to Patte and Thomazeau classification criteria.The primary study end point was an improvement in the Constant score by 20 points at one year compared to initial assessment.ResultsThe trial was stopped due to adverse effects observed in both groups. Only thirteen patients were included and analyzed. The Constant questionnaire showed a significant improvement in the MSC treatment group compared with the preoperative data (p = 0.0073). Secondary outcome measures were similar in both groups.ConclusionsOur study showed preliminary inconclusive clinical outcomes in the patients treated with MSCs. Adverse events revealed the need for further approaches using scaffolds of a different nature or perhaps no scaffolds, in the context of small joints.Trial registrationEudra-CT, 2007-007630-19. Registered on 30 January 2008.Level of evidenceA Level 1 of evidence treatment study.

Efficacy of mesenchymal stem cell therapy in systolic heart failure: a systematic review and meta-analysis

BackgroundHeart failure (HF) is the end stage of most heart disease. Mesenchymal stem cells (MSCs), with their specific biological effects, have been applied in several clinical trials to evaluate the efficacy in HF therapy. We performed this meta-analysis to review the clinical evidence of their therapeutic effect on HF.MethodsThree databases were searched. The outcomes of interest were death, readmission, the 6-min walk test (6MWT), New York Heart Association (NYHA) class and left ventricular ejection fraction (LVEF). The relative risk (RR) and weighted mean difference (WMD) were calculated to evaluate the effects of MSCs on HF compared to placebo.ResultsA total of nine studies were included, involving 612 patients who underwent MSCs or placebo treatment. The overall rate of death showed a trend of reduction of 36% (RR [CI] = 0.64 [0.35, 1.16], p = 0.143) in the MSC treatment group. The incidence of readmission was reduced by 34% (RR [CI] = 0.66 [0.51, 0.85], p = 0.001). The patients in the MSC treatment group realised an average of 40.44 m (WMD [95% CI] = 40.44 m [19.07, 61.82], p < 0.0001) improvement in 6MWT. The NYHA class was reduced obviously in the MSC group (WMD [95% CI] = − 0.42 [− 0.64, − 0.20], p < 0.0001). The changes of LVEF from baseline were significantly more than 5.25% (WMD [95% CI] = 5.25 [3.58, 6.92], p < 0.0001) in the MSCs group, unlike in the placebo group.ConclusionsOur results suggested that MSC treatment is an effective therapy for HF by improving the prognosis and exercise capacity. SCs derived from allosomes have superior therapeutic effects, and intracoronary injection is the optimum MSC delivery approach. Short-term cryopreservation is feasible in MSCs storage or transport.