间充质干细胞近年来取得了显著进展。许多研究报道人脐带间充质干细胞(hUC-MSCs)没有毒性,但用hUC-MSCs治疗的患者出现血栓栓塞.因此,人们仍然担心临床应用的安全性。该研究旨在确定安全性,hUC-MSCs的潜在毒性机制和生物分布。根据良好实验室规范标准,通过单次施用给予F344RG大鼠5或5千万个细胞/kg的hUC-MSC。进行标准毒性。然后进行RNA测序以探索潜在的毒性机制。并行,检查hUC-MSCs的生物分布。5百万细胞/kg剂量的hUC-MSCs对症状无明显毒性,体重,食物摄入量,血液学,血清生物化学,尿液生化,细胞因子,和组织病理学。然而,尿道口的血液分泌和20%的死亡率发生在50万个细胞/kg。弥散性血管内凝血病(DIC)是导致死亡的主要原因。hUC-MSCs显著上调补体和凝血级联通路基因表达,导致DIC。此外,hUC-MSCs上调纤溶系统抑制基因A2m,Serping1和Serpinf2。hUC-MSCs在大鼠中存活少于28天,在肺外组织中未检测到hUC-MSC.F344RG大鼠在500万细胞/kg时没有毒性,但是在50万个细胞/kg时检测到一些毒性。hUC-MSCs显著上调补体和凝血级联通路,上调纤溶系统抑制基因A2m的表达,Serping1和Serpinf2,抑制纤溶系统,引起了DIC,这为hUC-MSCs的毒性机制提供了新的见解。
Mesenchymal stem cells have made remarkable progress in recent years. Many studies have reported that human umbilical cord mesenchymal stem cells (hUC-MSCs) have no toxicity, but thromboembolism appeared in patients treated with hUC-MSCs. Therefore, people are still worried about the safety of clinical application. The study aims to determine the safety, potential toxic mechanism and
biodistribution of hUC-MSCs. F344RG rats were given 5 or 50 million cells/kg of hUC-MSCs by single administration in compliance with Good Laboratory Practice standards. Standard toxicity was performed. RNA sequencing was then performed to explore the potential toxic mechanisms. In parallel, the
biodistribution of hUC-MSCs was examined. The dose of 5 million cells/kg hUC-MSCs had no obvious toxicity on symptom, weight, food intake, hematology, serum biochemistry, urine biochemistry, cytokines, and histopathology. However, blood-tinged secretions in the urethral orifice and 20% mortality occurred at 50 million cells/kg. Disseminated intravascular coagulopathy (DIC) is the leading cause of death. hUC-MSCs significantly upregulated complement and coagulation cascade pathways gene expression, resulting in DIC. Besides, hUC-MSCs upregulated fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2. hUC-MSCs survived in rats for less than 28 days, no hUC-MSC was detected in tissues outside the lungs. There was no toxicity in F344RG rats at 5 million cells/kg, but some toxicities were detected at 50 million cells/kg. hUC-MSCs significantly upregulated complement and coagulation cascade pathways, upregulated the expression of fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2, to inhibit fibrinolytic system, caused DIC, which provided a new insight into the toxic mechanism of hUC-MSCs.