源自人类胚胎干细胞的免疫和基质调节细胞可安全有效地治疗小鼠肺损伤和纤维化,bioRxiv - Cell Biology

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源自人类胚胎干细胞的免疫和基质调节细胞可安全有效地治疗小鼠肺损伤和纤维化
bioRxiv - Cell Biology Pub Date : 2020-06-06 , DOI: 10.1101/2020.04.15.042119
Jun Wu , Dingyun Song , Zhongwen Li , Baojie Guo , Yani Xiao , Wenjing Liu , Lingmin Liang , Chunjing Feng , Tingting Gao , Yanxia Chen , Ying Li , Zai Wang , Jianyan Wen , Shengnan Yang , Peipei Liu , Lei Wang , Yukai Wang , Liang Peng , Glyn Nigel Stacey , Zheng Hu , Guihai Feng , Wei Li , Yan Huo , Ronghua Jin , Ng Shyh-Chang , Qi Zhou , Liu Wang , Baoyang Hu , Huaping Dai , Jie Hao

肺损伤和纤维化代表严重和急性肺部疾病（包括COVID-19）的最显着结果。但是，仍然没有有效的药物来治疗肺损伤和纤维化。在这项研究中，我们报告了在良好生产规范（GMP）要求下生产的临床级人类胚胎干细胞（hESCs）衍生的免疫和基质调节细胞（IMRC）的产生，它们可以在体内治疗肺损伤和纤维化。我们通过用无血清试剂依次区分hESC来生成IMRC。IMRC具有不同于脐带间充质干细胞（UCMSC）的独特基因表达谱，例如较高水平的增殖，免疫调节和抗纤维化基因。此外，在小鼠肺部损伤模型中，IMRC的静脉内给药可抑制肺部炎症和纤维化，并可能通过旁分泌调节机制以剂量依赖性方式显着提高受体小鼠的存活率。IMRC优于主要的UCMSC和FDA批准的吡非尼酮，在小鼠和猴子中具有出色的功效和安全性。鉴于涉及肺炎，急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的公共卫生危机，我们的研究结果表明IMRCs已准备就绪，可用于肺部疾病的临床试验。

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Immunity-and-Matrix-Regulatory Cells Derived from Human Embryonic Stem Cells Safely and Effectively Treat Mouse Lung Injury and Fibrosis

Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice (GMP) requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from umbilical cord mesenchymal stem cells (UCMSCs), such as higher levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and FDA-approved pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), our findings suggest that IMRCs are ready for clinical trials on lung disorders.

更新日期：2020-06-06

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