Intravenous transplantation of bone marrow-derived mesenchymal stromal cells in patients with multiple sclerosis, a phase I/IIa, double blind, randomized controlled study.

Multiple sclerosis (MS) is a progressive, demyelinating neurodegenerative disease of the central nervous system. MS is immune-mediated and leads to disability especially in young adults. Even though 18 MS therapy drugs were approved, they slightly inhibit disease progression and do not induce regeneration and repair in the nervous system. Mesenchymal stromal cells (MSCs) have emerged as a new therapeutic modality in regenerative medicine and tissue engineering due to their immunomodulation and bio regenerative properties. We have designed a randomized, controlled clinical trial to assess safety and possible efficacy of MSC application in MS patients. Twenty-one MS patients were enrolled. Patients were allocated in two distinct groups: treatment group, which received systemic transplantation of autologous bone marrow-derived MSCs, and control group, which received placebo at the first injections. Patients in control group received MSCs at the second injection while the treatment group received placebo. All the patients were followed for 18 months. Follow-ups included regular visits, laboratory evaluation, and imaging analysis. Control patients received MSCs six month after treatment group. No severe immediate or late adverse events were observed in both groups after interventions. We did not find any significant differences in the rate of relapses, Expanded Disability Status Scale (EDSS) score, cognitive condition, Magnetic Resonance Imaging (MRI) findings, or any biomarkers of cerebrospinal fluid between the two groups and in each group before and after cell infusion. Transplantation of autologous bone marrow-derived mesenchymal stromal cells is safe and feasible. The efficacy of transplantation of these cells should be evaluated through designing randomized clinical trials with larger sample sizes, different administration routes, other cell types (allogeneic adipose derived MSCs, allogeneic Wharton's jelly derived MSCs …), repeated injections, and longer follow-up periods.

Allogenic mesenchymal stromal cells and their extracellular vesicles in COVID-19 induced ARDS: a randomized controlled trial.

BACKGROUND AND AIMS: The main causes of death in patients with severe Coronavirus disease-2019 (COVID-19) are acute respiratory distress syndrome (ARDS) and multiorgan failure caused by a severe inflammatory cascade. Novel treatment strategies, such as stem-cell-based therapy and their derivatives can be used to relieve inflammation in these cases. In this study, we aimed to evaluate the safety and efficacy of therapy using mesenchymal stromal cells (MSCs) and their derived extracellular vesicles in COVID-19 patients. MATERIALS AND METHODS: COVID-19 patients with ARDS were included in this study and allocated into two study and control groups using block randomization. While all patients received recommended treatment based on guidelines from the national advisory committee for COVID-19 pandemic, the two intervention groups received two consecutive injections of MSCs (100 × 106 cells) or one dose of MSCs (100 × 106 cells) followed by one dose of MSC-derived extracellular vesicles (EVs). Patients were assessed for safety and efficacy by evaluating clinical symptoms, laboratory parameters, and inflammatory markers at baseline and 48 h after the second intervention. RESULTS: A total number of 43 patients (the MSC alone group = 11, MSC plus EV group = 8, and control group = 24) were included in the final analysis. Mortality was reported in three patients in the MSC alone group (RR: 0.49; 95% CI 0.14-1.11; P = 0.08); zero patient in the MSC plus EV group (RR: 0.08; 95% CI 0.005-1.26; P = 0.07) and eight patients in the control group. MSC infusion was associated with a decrease in inflammatory cytokines such as IL-6 (P = 0.015), TNF-α (P = 0.034), IFN-γ (P = 0.024), and CRP (P = 0.041). CONCLUSION: MSCs and their extracellular vesicles can significantly reduce the serum levels of inflammatory markers in COVID-19 patients, with no serious adverse events. Trial registration IRCT, IRCT registration number: IRCT20200217046526N2. Registered 13th April 2020, http://www.irct.ir/trial/47073 .

The association between impaired autophagy and the development of congenital ureteropelvic junction obstruction.

OBJECTIVE: To investigate the association between impaired autophagy in smooth muscle cells and the development of congenital ureteropelvic junction (UPJ) obstruction (UPJO). MATERIALS AND METHODS: Tissue specimens were obtained from 40 patients with unilateral UPJO and were divided into 3 sections as renal pelvis, site of obstruction, and the ureter distal to obstruction. Control specimens were obtained from the UPJ of 40 age-matched cadavers. Autophagy was evaluated by image analysis techniques for the expression of light chain 3 (LC3) after immunohistochemical staining of LC3 rabbit polyclonal antibody and Western blot analysis; additionally, myocyte apoptosis was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, 4',6-diamidino-2-phenylindole staining, and p53 immunohistochemical staining. To assess the possible role of cell senescence, P21 and P16 immunohistochemistry staining was applied. Cellular proliferation was assessed by image analysis of proliferating cell nuclear antigen-stained specimens. RESULTS: LC3 expression was significantly increased at the renal pelvis (P <.05). Apoptotic indices of smooth muscle cells and Bcl-2 were significantly greater at the site of UPJO (5.15 ± 0.91) compared with the UPJs of the control group (P <.001). A significant negative correlation was found between TUNEL and LC3 in all sections of the obstructed UPJ complex (P <.05). Proliferating cell nuclear antigen and LC3 were positively correlated in the renal pelvis and UPJ (P <.05); however, no specimen was stained for p16, p21, and p53. CONCLUSION: In conclusion, impaired autophagy is associated with the development of congenital UPJO. Nonetheless, further studies are mandated to establish its etiologic role.