scholarly journals Therapeutic Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Recovering From Murine Pulmonary Emphysema Under Cigarette Smoke Exposure

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiao-Yue Chen ◽  
Yi-Ying Chen ◽  
Willie Lin ◽  
Chien-Han Chen ◽  
Yu-Chieh Wen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cigarette Smoke ◽  
Umbilical Cord ◽  
Inflammatory Responses ◽  
Lung Fibroblasts ◽  
Cigarette Smoke Exposure ◽  
High Dose ◽  
Human Umbilical Cord ◽  
Emphysema Severity

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were shown to have potential for immunoregulation and tissue repair. The objective of this study was to investigate the effects of hUC-MSCs on emphysema in chronic obstructive pulmonary disease (COPD). The C57BL/6JNarl mice were exposed to cigarette smoke (CS) for 4 months followed by administration of hUC-MSCs at 3 × 106 (low dose), 1 × 107 (medium dose), and 3 × 107 cells/kg body weight (high dose). The hUC-MSCs caused significant decreases in emphysema severity by measuring the mean linear intercept (MLI) and destructive index (DI). A decrease in neutrophils (%) and an increase in lymphocytes (%) in bronchoalveolar lavage fluid (BALF) were observed in emphysematous mice after hUC-MSC treatment. Lung levels of interleukin (IL)-1β, C-X-C motif chemokine ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and matrix metalloproteinase (MMP)-12 significantly decreased after hUC-MSC administration. Significant reductions in tumor necrosis factor (TNF)-α, IL-1β, and IL-17A in serum occurred after hUC-MSC administration. Notably, the cell viability of lung fibroblasts improved with hUC-MSCs after being treated with CS extract (CSE). Furthermore, the hUC-MSCs-conditioned medium (hUC-MSCs-CM) restored the contractile force, and increased messenger RNA expressions of elastin and fibronectin by lung fibroblasts. In conclusion, hUC-MSCs reduced inflammatory responses and emphysema severity in CS-induced emphysematous mice.

scholarly journals Chronic Toxicity Test in Cynomolgus Monkeys For 98 Days with Repeated Intravenous Infusion of Cynomolgus Umbilical Cord Mesenchymal Stem Cells

2017 ◽  
Vol 43 (3) ◽  
pp. 891-904 ◽  
Author(s):  
Jie He ◽  
Guang-ping Ruan ◽  
Xiang Yao ◽  
Ju-fen Liu ◽  
Xiang-qing Zhu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Umbilical Cord ◽  
Intravenous Infusion ◽  
Dose Group ◽  
High Dose ◽  
Human Umbilical Cord ◽  
Cynomolgus Monkeys ◽  
Cell Based Therapy

Background/Aims: Stem cell-based therapy is attractive in many clinical studies, but current data on the safety of stem cell applications remains inadequate. This study observed the safety, immunological effect of cynomolgus monkey umbilical cord mesenchymal stem cells (mUC-MSCs) injected into cynomolgus monkeys, in order to evaluate the safety of human umbilical cord mesenchymal stem cells (hUC-MSCs) prepared for human clinical application. Methods: Eighteen cynomolgus monkeys were divided into three groups. Group 1 is control group, Group 2 is low-dose group, Group 3 is high-dose group. After repeated administrations of mUC-MSCs, cynomolgus monkeys were observed for possible toxic reactions. Results: During the experiment, no animal died. There were no toxicological abnormalities in body weight, body temperature, electrocardiogram, coagulation and pathology. In the groups 2 and 3, AST and CK transiently increased, and serum inorganic P slightly decreased. All animals were able to recover at 28 days after the infusion was stopped. In the groups 2 and 3, CD3+ and IL-6 levels significantly increased, and recovery was after 28 days of infusion. There were no obvious pathological changes associated with the infusion of cells in the general and microscopic examinations. Conclusions: The safe dosage of repeated intravenous infusion of mUC-MSCs in cynomolgus monkeys is 1.0 × 107/kg, which is 10 times of that in clinical human use.

Human Umbilical Cord Mesenchymal Stem Cells to Treat Neuromyelitis Optica Spectrum Disorder (hUC-MSC-NMOSD): A Study Protocol for a Prospective, Multicenter, Randomized, Placebo-Controlled Clinical Trial

2020 ◽  
Author(s):  
Xiaoying Yao ◽  
Li Xie ◽  
Yu Cai ◽  
Ying Zhang ◽  
Ye Deng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Dose Group ◽  
Optimal Dose ◽  
Controlled Clinical Trial ◽  
High Dose ◽  
Human Umbilical Cord ◽  
Neuromyelitis Optica Spectrum Disorder

Abstract Background：Neuromyelitis optica spectrum disorder (NMOSD) is a severe relapsing and disabling inflammatory autoimmune disease of the central nervous system. Despite the progress made in understanding the pathogenesis of the disease, the optimal first line treatment to reduce relapse rate and ameliorate neurological disability remains unclear. Mesenchymal stem cells (MSC) are known for having anti-inflammatory and regenerative properties and there are a number of studies on the use of human umbilical cord MSCs (hUC-MSCs) in NMOSD patients. Therefore, we will conduct a prospective, multicenter, randomized, placebo-controlled clinical trial to study the safety and effectiveness of hUC-MSCs in the treatment of NMOSD.Methods：The trial is planned to recruit 430 AQP4-IgG seropositive NMOSD patients. The multicenter study will be conducted in six clinical centers. The whole clinical trial consists of three consecutive stages. The first stage will be carried out in the leading center (Ren Ji Hospital) only and it will last 24 months. In the first stage the primary objective is to evaluate the safety of hUC-MSCs. Patients (n=30) will be treated with three different doses of hUC-MSC: the low dose group (n=10, 1×106 MSC / kg·weight), the medium dose group (n=10, 2×106 MSC / kg·weight) and the high dose group (n=10, 5×106 MSC / kg·weight). The second stage, which aims to find the optimal dosage, will last 24 months and will be carried out in six centers (one leading center and five branch centers). Patients (n=160) will be randomized into four groups by 1:1:1:1 allocation ratio: the low, medium, high dose groups and the controlled group (n=40). The third stage, which aims to evaluate the effectiveness, will lasts for 24 months and will be developed in six centers. Patients (n=320) will be 1:1 randomized into two groups: the optimal dose group (n=160) and the controlled group (n=160). HUC-MSC infusion will be given four times to the intervention groups and stem cell solution will be given four times to the control group every 3 months; besides the primary drugs will be provided to both groups. Primary endpoint is the first recurrent time and secondary endpoints are the recurrent times, EDSS scores, MRI lesion numbers, OSIS scores, Hauser walking index and SF-36 (quality of life short Form-36) scores. Exploratory endpoints will include: serum lymphocyte subsets, cytokines, complements, serum anti-AQP4 antibody titers etc. Endpoint events and side-effects will be evaluated at baseline and every 3 months for a total of 24 months follow-up.Discussion：Although hUC-MSC has shown promising treatment effect of NMOSD in preclinical study, there is still a lack of well-designed clinical trials to evaluate the safety and effectiveness of hUC-MSC among NMOSD patients. As far as we know, this trial will be the first one to systematically demonstrate the clinical safety and efficacy of hUC-MSC in treating NMOSD and might be able to determine the optimal dose of hUC-MSC for NMOSD patients.Trial registration：The study was registered with Chinese Clinical Trial Registry (CHICTR.org.cn) on Mar 2, 2016 (registration No. ChiCTR-INR-16008037), and the revised trial protocol (Protocol version 1.2.1) was released on March 16, 2020.

scholarly journals Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Seyed-Mohammad Reza Hashemian ◽  
Rasoul Aliannejad ◽  
Morteza Zarrabi ◽  
Masoud Soleimani ◽  
Massoud Vosough ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Respiratory Distress ◽  
Organ Failure ◽  
Critically Ill ◽  
Umbilical Cord ◽  
Case Series ◽  
High Dose ◽  
Human Umbilical Cord ◽  
Multi Organ Failure

Abstract Background Acute respiratory distress syndrome (ARDS) is a fatal complication of coronavirus disease 2019 (COVID-19). There are a few reports of allogeneic human mesenchymal stem cells (MSCs) as a potential treatment for ARDS. In this phase 1 clinical trial, we present the safety, feasibility, and tolerability of the multiple infusions of high dose MSCs, which originated from the placenta and umbilical cord, in critically ill COVID-19-induced ARDS patients. Methods A total of 11 patients diagnosed with COVID-19-induced ARDS who were admitted to the intensive care units (ICUs) of two hospitals enrolled in this study. The patients were critically ill with severe hypoxemia and required mechanical ventilation. The patients received three intravenous infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases). Findings There were eight men and three women who were 42 to 66 years of age. Of these, six (55%) patients had comorbidities of diabetes, hypertension, chronic lymphocytic leukemia (CLL), and cardiomyopathy (CMP). There were no serious adverse events reported 24–48 h after the cell infusions. We observed reduced dyspnea and increased SpO2 within 48–96 h after the first infusion in seven patients. Of these seven patients, five were discharged from the ICU within 2–7 days (average: 4 days), one patient who had signs of acute renal and hepatic failure was discharged from the ICU on day 18, and the last patient suddenly developed cardiac arrest on day 7 of the cell infusion. Significant reductions in serum levels of tumor necrosis factor-alpha (TNF-α; P < 0.01), IL-8 (P < 0.05), and C-reactive protein (CRP) (P < 0.01) were seen in all six survivors. IL-6 levels decreased in five (P = 0.06) patients and interferon gamma (IFN-γ) levels decreased in four (P = 0.14) patients. Four patients who had signs of multi-organ failure or sepsis died in 5–19 days (average: 10 days) after the first MSC infusion. A low percentage of lymphocytes (< 10%) and leukocytosis were associated with poor outcome (P = 0.02). All six survivors were well with no complaints of dyspnea on day 60 post-infusion. Radiological parameters of the lung computed tomography (CT) scans showed remarkable signs of recovery. Interpretation We suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.

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