Infusion Of Mesenchymal Stem Cells Research Articles

Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus.

Diabetes mellitus (DM) is a disease syndrome characterized by chronic hyperglycaemia. A long-term high-glucose environment leads to reactive oxygen species (ROS) production and nuclear DNA damage. Human umbilical cord mesenchymal stem cell (HUcMSC) infusion induces significant antidiabetic effects in type 2 diabetes mellitus (T2DM) rats. Insulin-like growth factor 1 (IGF1) receptor (IGF1R) is important in promoting glucose metabolism in diabetes; however, the mechanism by which HUcMSC can treat diabetes through IGF1R and DNA damage repair remains unclear. In this study, a DM rat model was induced with high-fat diet feeding and streptozotocin (STZ) administration and rats were infused four times with HUcMSC. Blood glucose, interleukin-6 (IL-6), IL-10, glomerular basement membrane, and renal function were examined. Proteins that interacted with IGF1R were determined through coimmunoprecipitation assays. The expression of IGF1R, phosphorylated checkpoint kinase 2 (p-CHK2), and phosphorylated protein 53 (p-p53) was examined using immunohistochemistry (IHC) and western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of 8-hydroxydeoxyguanosine (8-OHdG). Flow cytometry experiments were used to detect the surface markers of HUcMSC. The identification of the morphology and phenotype of HUcMSC was performed by way of oil red "O" staining and Alizarin red staining. DM rats exhibited abnormal blood glucose and IL-6/10 levels and renal function changes in the glomerular basement membrane, increased the expression of IGF1 and IGF1R. IGF1R interacted with CHK2, and the expression of p-CHK2 was significantly decreased in IGF1R-knockdown cells. When cisplatin was used to induce DNA damage, the expression of p-CHK2 was higher than that in the IGF1R-knockdown group without cisplatin treatment. HUcMSC infusion ameliorated abnormalities and preserved kidney structure and function in DM rats. The expression of IGF1, IGF1R, p-CHK2, and p-p53, and the level of 8-OHdG in the DM group increased significantly compared with those in the control group, and decreased after HUcMSC treatment. Our results suggested that IGF1R could interact with CHK2 and mediate DNA damage. HUcMSC infusion protected against kidney injury in DM rats. The underlying mechanisms may include HUcMSC-mediated enhancement of diabetes treatment via the IGF1R-CHK2-p53 signalling pathway.

Apoptotic vesicles rescue impaired mesenchymal stem cells and their therapeutic capacity for osteoporosis by restoring miR-145a-5p deficiency.

Apoptotic vesicles (apoVs) play a vital role in various pathological conditions; however, we have yet to fully understand their precise biological effects in rescuing impaired mesenchymal stem cells (MSCs) and regulating tissue homeostasis. Here, we proved that systemic infusion of bone marrow MSCs derived from wild-type (WT) mice effectively improved the osteopenia phenotype and hyperimmune state in ovariectomized (OVX) mice. Importantly, the WT MSCs rescued the impairment of OVX MSCs both in vivo and in vitro, whereas OVX MSCs did not show the same efficacy. Interestingly, treatment with apoVs derived from WT MSCs (WT apoVs) restored the impaired biological function of OVX MSCs and their ability to improve osteoporosis. This effect was not observed with OVX MSCs-derived apoVs (OVX apoVs) treatment. Mechanistically, the reduced miR-145a-5p expression hindered the osteogenic differentiation and immunomodulatory capacity of OVX MSCs by affecting the TGF-β/Smad 2/3-Wnt/β-catenin signaling axis, resulting in the development of osteoporosis. WT apoVs directly transferred miR-145a-5p to OVX MSCs, which were then reused to restore their impaired biological functions. Conversely, treatment with OVX apoVs did not produce significant effects due to their limited expression of miR-145a-5p. Overall, our findings unveil the remarkable potential of apoVs in rescuing the biological function and therapeutic capability of MSCs derived from individuals with diseases. This discovery offers a new avenue for exploring apoVs-based MSC engineering and expands the application scope of stem cell therapy, contributing to the maintenance of bone homeostasis through a previously unrecognized mechanism.

Evaluation of type 1 diabetes’ partial clinical remission after three years of heterologous adipose tissue derived stromal/stem cells transplantation associated with vitamin D supplementation

BackgroundMesenchymal stem cell infusion and vitamin D supplementation may have immunomodulatory actions that could prolong the preservation of residual insulin secretion in patients with type 1 diabetes (T1D). Intervention with these agents after onset of T1D could favor the development of a remission phase, with potential clinical impact. We aimed to compare the presence of clinical remission (CR), glycemic control and daily insulin requirement at 6, 12, 18, 24 and 36 months after the diagnosis of T1D using IDAA1c in patients who received therapy with adipose tissue-derived mesenchymal stem cell (ASC) infusion and vitamin D supplementation and a control group. Methods: This retrospective cohort study analyzed data from the medical records of patients with T1D diagnosed between 15 and 40 years. Partial CR was defined as an IDAA1c index < 9. Patients in the intervention group received an infusion of adipose tissued-derived mesenchymal stem cells (ASCs) within 3 months after diagnosis and supplementation with 2000 IU of cholecalciferol for 1 year, started on the day following the infusion. Partial CR was also determined using the ISPAD criteria, to assess its agreement with IDAA1c. Results: A total of 28 patients were evaluated: 7 in the intervention group (group 1) and 21 in the control group (group 2). All patients in group 1 evolved with partial CR while only 46.7% of patients in group 2 had this outcome. Group 1 had a higher frequency of CR when evaluated with IDAA1c and ISPAD criteria. The mean duration of CR varied between the two criteria. Although HbA1c was similar between groups during follow-up, group 1 had a lower total daily insulin requirement (p < 0.005) at all time points. At 36 months, group 1 used 49% of the total daily insulin dose used by group 2 with similar glycemic control. Conclusion: The intervention with infusion of ASC + vitamin D supplementation was associated with partial CR at 6 months. Although there were no differences in CR established by the IDAA1c and ISPAD criteria after three years of follow-up, patients who underwent intervention had nearly the half insulin requirement of controls with conventional treatment, with similar glycemic control.Trial Registration37001514.0.0000.5257.

Mesenchymal Stem Cells Infusion and Renal Revascularization in Atherosclerotic Renal Artery Stenosis - New Modalities in Therapeutic Approach

Mesenchymal Stem Cells Infusion and Renal Revascularization in Atherosclerotic Renal Artery Stenosis - New Modalities in Therapeutic Approach

Mesenchymal Stem Cells Infusion and Renal Revascularization in Atherosclerotic Renal Artery Stenosis - New Modalities in Therapeutic Approach

Mesenchymal Stem Cells Infusion and Renal Revascularization in Atherosclerotic Renal Artery Stenosis - New Modalities in Therapeutic Approach

Human umbilical cord mesenchymal stem cell therapy for renal dysfunction in Alport syndrome: protocol for an open-label, single-arm trial in China

IntroductionAlport syndrome (AS) is one of the most common fatal hereditary renal diseases in human, with a high risk of progressing to end-stage renal disease without effective treatments. Mesenchymal stem...

The therapeutic effect of mesenchymal stem cells in diabetic kidney disease

Diabetes mellitus (DM) often causes chronic kidney damage despite best medical practices. Diabetic kidney disease (DKD) arises from a complex interaction of factors within the kidney and the whole body. Targeting specific disease-causing agents using drugs has not been effective in treating DKD. However, stem cell therapies offer a promising alternative by addressing multiple disease pathways and promoting kidney regeneration. Mesenchymal stem cells (MSCs) offer great promise due to their superior accessibility ratio from adult tissues and remarkable modes of action, such as the production of paracrine anti-inflammatory and cytoprotective substances. This review critically evaluates the development of MSC treatment for DKD as it moves closer to clinical application. Results from animal models suggest that systemic MSC infusion may positively impact DKD progression. However, few registered and completed clinical trials exist, and whether the treatments are effective in humans is still being determined. Significant knowledge gaps and research opportunities exist, including establishing the ideal source, dose, and timing of MSC delivery, better understanding of in vivo mechanisms, and developing quantitative indicators to obtain a more significant therapeutic response. This paper reviews recent literature on using MSCs in preclinical and clinical trials in DKD. Potent biomarkers related to DKD are also highlighted, which may help better understand MSCs’ action in this disease progression.Key messagesMesenchymal stem cells have anti-inflammatory and paracrine effects in diabetic kidney disease.Mesenchymal stem cells alleviate in animal models having diabetic kidney disease.Mesenchymal stem cells possess promise for the treatment of diabetic kidney disease.

(228) Cell-Based Therapy Can Restore Erectile Function in Men with Type 2 Diabetes and Metabolic Syndrome by Promoting Angiogenesis and Endothelial Repair

Abstract Introduction Although there has been a growing interest in restorative therapies for erectile dysfunction (ED) in recent years, there is still limited mechanistic evidence to support their effectiveness in the clinical setting. Objective The goal of this research was to investigate the mechanistic impact of cell-based therapy in men with ED secondary to Type 2 Diabetes Mellitus (DM2) and Metabolic Syndrome (MetS) through analysis of plasma biomarkers. Methods International Index of Erectile Function (IIEF) was completed by all men in the ACESO (NCT02886884) and CERES (NCT03059355) clinical trials. ACESO and CERES were both randomized, blinded, pilot phase clinical trials in which all participants received cellular therapy at varying doses and sources to treat endothelial dysfunction secondary to either DM2 or MetS, respectively. The intervention in both trials was peripheral intravenous infusion of allogeneic Mesenchymal Stem Cells (MSCs) of either 20 or 100 million cells derived from either bone marrow (BM) or umbilical cord tissue (UC). Follow-up was for 1 year. Endothelial function was measured via Brachial Artery Flow Mediated Vasodilation (FMD) and Endothelial Progenitor Cell-Colony Forming Units (EPC-CFU) assay. Plasma aliquots were isolated from blood samples and subjected to multiplex ELISA assay for analysis of angiogenic biomarkers. Results Data was pooled from all 20 men in the ACESO and CERES clinical trials. Overall, 7 received 20 million BM-MSCs, 9 received 100 million BM-MSCs, 2 received 20 million UC-MSCs, and 2 received 100 million UC-MSCs. There were no treatment emergent serious adverse effects (TE-SAEs) within 30 days following infusion in any of the participants. Among men with ED (IIEF-EF&amp;lt;25), 31.25% achieved MCID in erectile function. Participants with mild or moderate ED at baseline showed greater improvements in erectile function and endothelial function compared to those with severe ED. Participants who achieved MCID following cell therapy also experienced statistically significant improvements in FMD (P=0.05), whereas those who did not achieve MCID or had normal erectile function at baseline did not experience an improvement in FMD. Furthermore, men with Metabolic Syndrome who met MCID criteria were found to have increased Angiopoietin 1 and decreased Angiopoietin 2 following cell therapy. Conclusions The findings of this study demonstrate the potential of cell-based therapies in improving erectile function, angiogenic, and endothelial function. Future studies should aim to identify the causative mechanisms underlying these restorative effects in humans, paving the way for enhanced understanding and optimization of such therapies. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Longeveron LLC.

Segurança e eficácia das células-tronco mesenquimais alogênicas da medula óssea para o tratamento da leucopenia canina induzida pela infecção por parvovírus canino

ABSTRACT: This study aims to establish a therapy strategy for canine leukopenia induced by canine parvovirus (CPV) infection through intravenous infusion of allogeneic bone marrow mesenchymal stem cells (BMMSCs) and to evaluate the therapeutic effect of BMMSCs on canine parvovirus. Forty healthy 2-month-old dogs were randomly divided into four groups including the BMMSC treatment group (A), conventional treatment group (B), CPV infection group (C), and a normal control group (D). Then the A, B, and C groups were orally infected with CPV (103.25 TCID50/mL) at 1mL/kg, and the D group received the same dose of saline. After the onset of infection, Group A received mesenchymal stem cells (MSCs) and rehydration as the treatment; Group B was treated with anti-inflammatory therapeutics and rehydration; and Group C and D were injected with the same dose of physiological saline. The level of leukocytes rebounded significantly after the treatment with BMMSCs and returned to reference numbers on Day 3 after treatment, which was significantly higher than that in the conventional treatment group. The concentrations of IL-2 and IFN-α were gradually increased during the treatment, and the BMMSC treatment group exhibited significantly higher IL-2 and IFN-α concentrations than the conventional treatment group on Days 3 and 4. The expression of the virus in the blood gradually decreased during the treatment, and the BMMSC treatment group displayed a faster decrease than the conventional treatment group. These results showed the advantages of BMMSC treatment over conventional treatment. This study provides a new BMMSC treatment strategy for canine leukopenia induced by CPV infection and reveals the mechanism by which BMMSC increases leukocytes after CPV infection.

Peripheral Injection of hUC‐MSCs in the Treatment of Acute Liver Failure: A Pre‐Clinical Cohort Study in Rhesus Monkeys

Background. Using a toxin‐induced lethal acute liver failure (ALF) monkey model, we have recently shown that early peripheral infusion of human umbilical cord mesenchymal stem cells (hUC‐MSCs) can alleviate liver damage and improve animal survival by suppressing the activation of circulating monocytes and the subsequent cytokine storm. Here, we explored whether the administration of hUC‐MSCs could still improve ALF when the cytokine storm is fully developed. Method. We treated ALF monkeys with peripheral delivery of hUC‐MSCs at 48 hr after toxin challenge. Liver indices, histology, imaging, and animal survival were recorded and analyzed. Results. In our cohort study, we conducted and demonstrated that the infusion of hUC‐MSCs significantly improved liver histology, effectively controlled inflammatory cytokine storms, and increased survival rates. Additionally, the administration of a higher dose of hUC‐MSCs (2 × 107/monkey) yielded superior outcomes compared to a lower dose (1 × 107/monkey). Conclusion. Treatment of hUC‐MSCs can significantly improve the pathological and survival outcomes of ALF even when the cytokine storm has been fully developed, indicating a promising clinical solution for ALF.

Mesenchymal Stem Cells for Prophylaxis of Chronic Graft-vs-Host Disease After Haploidentical Hematopoietic Stem Cell Transplant

ImportanceChronic graft-vs-host disease (GVHD) limits the long-term benefit of haploidentical hematopoietic stem cell transplant (HSCT). This clinical trial evaluated repeated infusions of umbilical cord mesenchymal stem cells (MSCs) during the early stage (45 days and 100 days) after haplo-HSCT to prevent chronic GVHD.ObjectiveTo determine whether repeated infusions of MSCs during the early stage after haplo-HSCT decreases the incidence of severe chronic GVHD.Design, Setting, and ParticipantsThis open-label, multicenter, parallel randomized clinical trial was conducted from April 2016 to January 2022. Eligibility criteria included a diagnosis of acute leukemia and having a haploidentical, suitable related donor for HSCT. The median (range) follow-up time was 39.0 (1.5-67.0) months.InterventionsThe enrolled patients with a haploidentical relative for HSCT received the modified busulfan/cyclophosphamide + antithymocyte globulin modified regimen and standard GVHD prophylaxis. Patients were randomly chosen to receive MSCs (the MSC group) (1 × 106 cells/kg, every 2 weeks, starting from 45 days after transplant, 4 times total) or regular prophylaxis (control group).Main Outcome and MeasureThe cumulative incidence of severe chronic GVHD.ResultsOf 158 patients, 58 (36.7%) were female individuals; the median (range) age for the MSC and control groups was 28 (18-60) years and 28 (18-56) years, respectively. A total of 158 patients were screened, and 148 patients were randomly assigned to the MSC group (n = 74) or control group (n = 74) 1 day before MSCs infusion. The estimated 2-year cumulative incidence of severe chronic GVHD was 5.4% (95% CI, 1.8%-14.0%) in the MSC group and 17.4% (95% CI, 10.1%-28.5%) in the control group (hazard ratio [HR], 0.29; 95% CI, 0.10-0.88; P = .03). There was no difference between the MSC and control groups in the cumulative incidence of leukemia relapse (HR, 1.17; 95% CI, 0.55-2.47; P = .68). The cumulative incidence of stage II to IV acute GVHD in the MSC group was significantly lower than that in the control group (HR, 0.25; 95% CI, 0.09-0.67; P = .01). The MSC group had better GVHD-free and relapse-free survival rates than the control group (HR, 0.62; 95% CI, 0.39-0.98; P = .04).Conclusions and RelevanceThe results of this randomized clinical trial show that early repeated infusions of MSCs decreased the incidence and severity of chronic GVHD, and the incidence and severity of acute GVHD manifested as a better GVHD-free and relapse-free survival rate for patients after haplo-HSCT.Trial RegistrationChinese Clinical Trial Registry: ChiCTR-IIR-16007806

Safety of multiple intravenous infusions of adipose-derived mesenchymal stem cells for hospitalized cases of COVID-19: a randomized controlled trial.

The purpose of the study was to assess the safety of allogeneic, Hope Biosciences Adipose Derived Mesenchymal Stem Cells (HB-adMSCs) for the treatment of hospitalized subjects with COVID-19. N = 48 patients were randomly assigned to HB-adMSC (100 MM) or placebo group. Four intravenous infusions of HB-adMSCs or saline were administered at days 0, 3, 7, 10. The primary safety endpoint was incidence of adverse and serious adverse events (AE/SAEs); secondary endpoints were incidence of specific AEs and alterations in hematology, biochemistry, and coagulation parameters. Majority of AEs were mild in severity. HB-adMSC group showed a higher incidence of cardiopulmonary failure, anemia, anxiety, and diarrhea, while placebo group showed a higher incidence of headaches, fatigue, and chest discomfort (posterior probabilities ≥80%). Deaths were attributed to severe complications due to COVID-19 and were unrelated to study drug. No AEs were attributed to the treatment. Hematology and coagulation panel alterations were not associated with HB-adMSCs. Analyses of inflammatory markers showed increased levels of interleukin-6 and C-reactive protein over time in HB-adMSC group (posterior probabilities ≥78%). Multiple infusions of 100MM allogeneic HB-adMSCs were considered safe for the study population. More research is needed to determine the safety of MSC therapy. (www.ClinicalTrials.gov) identifier NCT04362189.

Rehabilitation facilitates functional improvement following intravenous infusion of mesenchymal stem cells in the chronic phase of cerebral ischemia in rats

The primary objective of this study was to investigate the potential facilitating effects of daily rehabilitation for chronic cerebral ischemia following the intravenous infusion of mesenchymal stem cells (MSC) in rats. The middle cerebral artery (MCA) was occluded by intraluminal occlusion using a microfilament (MCAO). Eight weeks after MCAO induction, the rats were used as a chronic cerebral ischemia model. Four experimental groups were studied: Vehicle group (medium only, no cells); Rehab group (vehicle + rehabilitation), MSC group (MSC only); and Combined group (MSC + rehabilitation). Rat MSCs were intravenously infused eight weeks after MCAO induction, and the rats received daily rehabilitation through treadmill exercise for 20 min. Behavioral testing, lesion volume assessment using magnetic resonance imaging (MRI), and histological analysis were performed during the observation period until 16 weeks after MCAO induction. All treated animals showed functional improvement compared with the Vehicle group; however, the therapeutic efficacy was greatest in the Combined group. The combination therapy is associated with enhanced neural plasticity shown with histological analysis and MRI diffusion tensor imaging. These findings provide behavioral evidence for enhanced recovery by combined therapy with rehabilitation and intravenous infusion of MSCs, and may form the basis for the development of clinical protocols in the future.

Allogeneic Hematopoietic Stem Cell Transplantation for Adult Metachromatic Leukodystrophy (MLD): A Case Series

Introduction Adult Metachromatic Leukodystrophy (MLD) is a rare neurological disorder leading to devastating and progressive cognitive impairment and motor impairment with ataxia, spasticity and neuropathy as well as incontinence resulting in complete disability and reduced life expectancy. MLD is caused by autosomal recessive mutations of the ARSA gene, resulting in reduced arylsulfatase A enzyme (ARSA) activity and consecutive accumulation of galactosylceramide-3-0-sulfate in the central nervous system (CNS). Potential therapies in infantile and juvenile MLD include allogeneic hematopoietic stem cell transplantation (allo-HCT), ex-vivo gene therapy (Atidarsagen autotemcel), and (intrathecal) enzyme replacement as tested in ongoing trials. Allo-HCT may slow down or stop MLD progression. However, the outcome in adult patients treated with allo-HCT has been only reported in a few case reports. In this case series, we report our experience of allogeneic transplantation in four patients with adult MLD. Methods Four patients (2 male and 2 female) with a genetically confirmed diagnosis of adult MLD, with enzyme deficiency detectable in peripheral blood (ARSA activity range 0.00-0.06 E514nm/10 -6), evidence of white matter lesions on MRI and demyelinating polyneuropathy in EMG were treated with allo-HCT. One patient was still clinically asymptomatic at the treatment timepoint. Allo-HCT was performed at an age between 18 and 37 years (mean 25.75 years) and within one year after diagnosis. Bone marrow (n=2) or mobilized peripheral blood stem cells (n=2) from 10/10 matched related (n=1) or unrelated (n=3) donors were infused at a dose of 2.2-7.82x10 6 CD34+/kg after a reduced intensity conditioning regime with Fludarabine (150 mg/m²) and Treosulfane (10 or 14 g/m²). Three patients received further infusions with allogeneic mesenchymal stem cells (MSCs) manufactured in the hospital´s own GMP laboratory around day 30 after transplantation. One patient received a second MSC infusion at day 182. MSCs are able to secrete ARSA and were used to consolidate enzyme levels. In case of transplant failure donor lymphocytes (DLI) were given. For posttransplant immunosuppression Tacrolimus, Methotrexate, Mycophenolate mofetil or Anti-thymocyte globulin (ATG, Grafalon®, Neovii 10 mg/kg) were used. Results All patients engrafted 16-21 days after HCT. Platelets regenerated within 14 to 21 days (mean 16 days), neutrophils recovered within 16 to 21 days (mean 18.5 days). In two patients hepatitis and exanthema associated with ATG administration were observed as transient adverse events. Other therapy-associated adverse events were innappetence, hyperkalemia and diarrhea. A mild Graft-versus-host disease of the skin occurred only in one patient with full resolution on a course of steroids and Tacrolimus. After allo-HCT, an increase in ARSA levels reaching normal range values within the first 12 months after treatment was already documented in 3 out of 4 patients; measurements are pending in the 4 th more recently transplanted patient. Three out of four patients developed consistent full donor chimerism within 11 (1-11 ) months after HCT. In the fourth 18-year-old patient autologous chimerism increased to 60-80%, while ARSA activity decreased from 1.05 to 0.61 E514nm/10 -6. Consequently, the patient received DLIs. However, an improvement in chimerism has not be achieved so far. Longer follow-up data will be reported at the meeting. Discussion and Conclusion Allo-HCT in patients with MLD can be used to restore normal range ARSA activity. Donor-derived macrophages with an adequate secretion of ARSA migrate to the central nervous system and release ARSA. To our knowledge, there have been only a few individual case reports on allo-HCT in adult MLD so far. Our case series indicates that allo-HCT can be performed with tolerable risks and evident efficacy in adult patients with MLD. Based on this experience and previously reported cohorts in juvenile and infantile MLD allo-HCT should be thus also considered as a therapeutic option for adult patients with MLD. Longer clinical follow-up, higher patient numbers and ultimately a prospective randomised trial containing an untreated group would be needed to evaluate allo-HCT as a treatment option for adult MLD.

Intravenous infusion of auto-serum-expanded autologous mesenchymal stem cells into chronic severe brain injury patients

ObjectiveThis study explores safety, feasibility, and potential improvement in functional status after intravenous infusion of mesenchymal stem cells (MSCs) in chronic severe brain injury (BI) patients. MethodsAn intravenous infusion of autologous MSCs in autoserum cultured under Good Manufacturing Practice was delivered to four chronic patients with BI. In addition to assessing feasibility and safety, neurological function was evaluated using the National Institutes of Health Stroke Scale, Fugl-Meyer Assessment, Barthel Index, and cognitive-related behavioral assessment. Imaging studies with 18F-FDG-PETCT and 11C-methionine-PETCT (METPET) were carried out to evaluate brain metabolic activity. ResultsNo serious adverse events were recorded. None of the patients developed CNS tumors, abnormal cell growth, or neurological deterioration. While this initial case series was not blinded, gradual functional improvement was observed after MSC infusion. Serial 11C-METPETs displayed a statistically significant increase in methionine uptake, primarily in the thalamus and pons. ConclusionWe emphasize that this study was unblinded and did not exclude placebo effects, the contribution of endogenous recovery, or observer bias; however, our observations support feasibility and safety. No adverse events were observed. The data suggests improved quality of life after infused MSCs; however, a blinded, larger-scale study will be necessary to fully address this possibility.

Metabolomics Analysis of Mesenchymal Stem Cell (MSC) Therapy in a Phase I Clinical Trial of Septic Shock: An Exploratory Study.

Sepsis is the result of an uncontrolled host inflammatory response to infection that may lead to septic shock with multiorgan failure and a high mortality rate. There is an urgent need to improve early diagnosis and to find markers identifying those who will develop septic shock and certainly a need to develop targeted treatments to prevent septic shock and its high mortality. Herein, we explore metabolic alterations due to mesenchymal stromal cell (MSC) treatment of septic shock. The clinical findings for this study were already reported; MSC therapy was well-tolerated and safe in patients in this phase I clinical trial. In this exploratory metabolomics study, 9 out of 30 patients received an escalating dose of MSC treatment, while 21 patients were without MSC treatment. Serum metabolomics profiling was performed to detect and characterize metabolite changes due to MSC treatment and to help determine the sample size needed for a phase II clinical trial and to define a metabolomic response to MSC treatment. Serum metabolites were measured using 1H-NMR and HILIC-MS at times 0, 24 and 72 h after MSC infusion. The results demonstrated the significant impact of MSC treatment on serum metabolic changes in a dose- and time-dependent manner compared to non-MSC-treated septic shock patients. This study suggests that plasma metabolomics can be used to assess the response to MSC therapy and that treatment-related metabolomics effects can be used to help determine the sample size needed in a phase II trial. As this study was not powered to detect outcome, how the treatment-induced metabolomic changes described in this study of MSC-treated septic shock patients are related to outcomes of septic shock in the short and long term will need to be explored in a larger adequately powered phase II clinical trial.

Clinical Application of Umbilical Cord Mesenchymal Stem Cells Preserves β-cells in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease associated with complications that reduce the quality of life of affected individuals and their families. The therapeutic options for T1D are limited to insulin therapy and islet transplantation; these options are not focused on preserving β-cell function and endogenous insulin. Despite the promising outcomes observed in current clinical trials involving allogeneic Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) infusion for the management of T1D, the precise underlying mechanism of action remains to be elucidated. In this correspondence, we propose prospective mechanisms of action of WJ-MSCs that may be mediating their observed capability to preserve β-cell function and prevent T1D progression and provide recommendations for further investigations in clinical settings. We also highlight the efficacy of WJ-MSCs for therapeutic applications in comparison to other adult MSCs. Finally, we recommend the participation of muti-centers governed by international organizations to implement guidelines for the safe practice of cell therapy and patients' welfare.

The administration of oral mucosal mesenchymal-derived stem cells improves hepatic inflammation, oxidative stress, and histopathology following traumatic brain injury

BackgroundThe inflammatory mediators produced after traumatic brain injury (TBI) are reaching peripheral organs causing organ and tissue damage, including the liver. Our study assessed the effect of intravenous (i.v.) infusion of oral mesenchymal stem cells (OMSCs) on TBI-induced liver damage by measuring liver inflammatory factors and liver oxidative stress. MethodsTwenty-eight adult male Wistar rats were divided into four groups: 1) sham control; 2) TBI alone (TBI); 3) TBI vehicle (Veh)-control; and 4) TBI with OMSC treatment (SC). OMSCs were obtained from oral mucosa biopsies. OMSCs were administered and administered i.v. at 1 and 24 h after TBI. Within 48 h after TBI, multiple parameters were analyzed, including inflammation, oxidative stress, and histopathological changes. ResultsIn comparison to sham controls, the TBI alone showed in liver significantly increased levels of interleukin-1β (IL-1β; P < 0.001), interleukin-6 (IL-6; P < 0.001), malondialdehyde (MDA; P < 0.001), and protein carbonyl (PC; P < 0.001). At the same time the TBI alone decreased the liver levels of superoxide dismutase (SOD; P < 0.001), total antioxidant capacity (TAC; P < 0.001), catalase (CAT; P < 0.001), and interleukin-10 (IL-10; P < 0.001). In comparison to the TBI alone group, the therapeutic group treated with i.v. infusion of OMSCs demonstrated significantly reduced changes of IL-1β (P < 0.001), IL-6 (P < 0.01), MDA (P < 0.01), PC (P < 0.05), SOD (P < 0.001), TAC (P < 0.01), CAT (P < 0.01), and IL-10 (P < 0.01). Histopathological evaluation showed in TBI alone group that the total score of liver tissue injury included extensive hydropic degeneration, lobular necrosis, inflammation as well as central vein congestion with subendothelial hemorrhage increased compared the sham group (P < 0.001). Administration of OMSC showed significantly smaller increase in the injury score compared to the TBI alone group (P < 0.001). ConclusionTherapy with i.v. OMSCs administration after TBI reduces liver injury, as measured by inflammation and oxidative stress. The use of OMSCs can be considered for treatment of liver injury caused by TBI.

Immunomodulatory effects of mesenchymal stem cells on B and T cells

Mesenchymal stem cells (MSCs) or adult multipotent progenitor cells with the ability to self-renew and differentiate, are extracted from a variety of tissues, including bone marrow, adipose tissue, umbilical cord blood, Wharton’s jelly, tooth pulp, menstrual blood, and others. Since they are multipotent, cultured MSCs can differentiate into the adipogenic, chondrogenic, and osteogenic lineages after being isolated. Due to their immunomodulatory, immunosuppressive, and regenerative potentials, multipotent mesenchymal stem cells (MSCs) have received extensive scrutiny as an efficient tool for cell-based therapy of inflammatory, immune-mediated, and degenerative illnesses. Mesenchymal stem cells (MSCs) have been the subject of numerous preclinical and clinical research that looked into their therapeutic potential. This potential is primarily supported by MSCs' immunosuppressive characteristics. Even while there is still much to learn about the therapeutic characteristics of MSC transplantation, mounting evidence suggests that T and B cells undergo changes after MSC infusion, most notably the induction of regulatory T (Tregs) and B (Bregs) cells. Tregs and Bregs have been shown to exhibit immunosuppressive properties, and these cells are being considered as potential novel targets for the therapy of inflammatory disorders.

Characterization of dynamical changes in vital signs during allogeneic human umbilical cord-derived mesenchymal stem cells infusion

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), a kind of adult stem cell, were studied for clinical applications in regenerative medicine. To date, the safety evaluations of intravenous infusion of allogeneic hUC-MSCs were focused on fever, infection, malignancy, and death. However, the characteristics of dynamical changes in vital signs during hUC-MSCs infusion are largely unknown. In this study, twenty participants with allogeneic hUC-MSCs transplanted (MSC group) and twenty sex- and age-matched individuals with cardiovascular disease who treated with the equal volume of 0.9% normal saline were recruited (NS group). Heart rate, respiratory rate, oxygen saturation, systolic and diastolic blood pressure, and temperature were monitored at intervals of 15 min during infusion. Adverse events were recorded during infusion and within seven days after infusion. No adverse events were observed during and after infusion in both groups. Compared with the baseline, the mean systolic blood pressure (SBP) levels were significantly decreased at 15 min, 30 min, 45 min and 60 min in the MSC group (all P < 0.05) during infusion. In addition, SBP changed significantly from baseline during hUC-MSCs infusion when compared with that of NS group (P < 0.05). Repeated measures analysis of variance confirmed difference over time on the SBP levels (P < 0.05). Our results showed that the process of allogeneic hUC-MSCs intravenous infusion was safe and the vital signs were stable, whereas a slight decrease in SBP was observed.