外源性骨髓间充质干细胞通过外泌体H19lncRNA 调控宿主细胞线粒体生物发生减轻脓毒症相关急性呼吸窘迫综合征

Acute respiratory distress syndrome (ARDS) is a serious complication. However current therapies for ARDS remain limited. Mesenchymal stem cells (MSCs) therapy arises as an effective treatment to mediate lung repair and regeneration, inhibit pulmonary fibrosis, and therefor alleviate ARDS, but the underlying mechanisms are incompletely understood. Mitochondrial biogenesis plays an important role in the pathophysiological process of cell proliferation and fibrosis. Moreover, NRF2 and TFAM mitochondrial biogenesis, which is mediated by NRF2 and TFAM, is also involved in the pathologic process of ARDS. Previous studies showed that H19LncRNA could regulate NRF2 and TFAM expression by sponging microRNA-200a, and possessed regulatory functions as competing endogenous RNA (ceRNAs). In our previous studies, MSCs could enhance H19lncRNA expression by paracrine fashion, and then promotes cell proliferation. Thus, we hypothesized that MSCs might mediate lung repair and regeneration, and inhibit pulmonary fibrosis through the release of exosomes containing H19 lncRNA. At present study, we focuses on the regulation of mitochondrial biogenesis by exosomes containing H19 lncRNA, which can provide theoretical foundation for formulating lung protective strategy for ARDS and can lay foundation for exploring stem cell therapy approach for ARDS.

急性呼吸窘迫综合征（ARDS）是致命性的危重综合征，尚无有效治疗手段。外源性间充质干细胞（MSC）可旁分泌外泌体促进肺泡上皮修复抑制肺纤维化，是ARDS的潜在治疗手段，但机制未明。我们前期发现外源性MSC可通过旁分泌提高宿主H19长链非编码RNA（H19 lncRNA）水平。 而H19lncRNA可作为microRNA-200a的竞争性内源RNA，调控线粒体生物发生。线粒体生物发生是调控细胞增殖与纤维化的重要机制，预实验也发现线粒体生物发生与ARDS密切相关。因此我们认为，外源性MSC可通过外泌体H19lncRNA调控肺泡上皮细胞和肺纤维母细胞线粒体生物发生，从而促进肺泡上皮修复重建抑制肺纤维化，减轻ARDS。本课题将重点明确MSC通过外泌体H19lncRNA调控线粒体生物发生减轻ARDS的机制，通过RNA干扰和基因敲除等手段在动物和细胞水平证明该假说，为MSC治疗ARDS提供理论依据。

急性呼吸窘迫综合征（ARDS）是一种常见的、致命性的危重综合征，但是发病机制不明，临床上尚无有效治疗手段。本课题围绕外泌体介导的细胞间交流机制研究ARDS发生发展的病理机制和治疗手段。首先我们发现，间充质干细胞可以通过外泌体调控肺泡Ⅱ型上皮细胞microRNA-200a的水平，进而调控肺泡Ⅱ型上皮细胞死亡和ARDS。我们还发现，间充质干细胞治疗减轻ARDS的另一机制，间充质干细胞通过外泌体转运去乙酰化酶SIRT1蛋白至肺泡巨噬细胞，进而抑制肺泡巨噬细胞HMGB1的出核，进一步减轻肺泡巨噬细胞焦亡和ARDS。此外我们发现，线粒体的功能调控参与肺泡Ⅱ型上皮细胞的死亡和ARDS发生发展。ARDS患者血浆来源的外泌体通过转运高迁移率族蛋白1（HMGB1）至肺泡Ⅱ型上皮细胞，进而促进肺泡Ⅱ型上皮细胞线粒体分裂，进一步通过mtDNA/cGAS/STING信号通路诱导肺泡Ⅱ型上皮细胞坏死。通过本课题研究，围绕外泌体介导的细胞间交流机制在ARDS发生发展中的作用，证明了间充质干细胞的治疗作用和机制，为临床上ARDS的治疗和诊断提供新的理论依据。