YAP 调控的人脐带间充质干细胞诱导的 II 型肺泡上皮细胞分化在急性呼吸窘迫综合征中的作用。

YAP-regulated type II alveolar epithelial cell differentiation mediated by human umbilical cord-derived mesenchymal stem cells in acute respiratory distress syndrome.

机构信息

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; National Heart and Lung Institute, Imperial College London, London, UK.

Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.

出版信息

Biomed Pharmacother. 2023 Mar;159:114302. doi: 10.1016/j.biopha.2023.114302. Epub 2023 Jan 25.

DOI:10.1016/j.biopha.2023.114302

PMID:36701989

Abstract

Acute respiratory distress syndrome (ARDS) contributes to higher mortality worldwide. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have immunomodulatory and regenerative potential. However, the effects of hUC-MSCs as an ARDS treatment remain unclear. We investigated the role of hUC-MSCs in the differentiation of type II alveolar epithelial cells (AECII) by regulating Yes-associated protein (YAP) in ARDS. Male C57BL/6JNarl mice were intratracheally (i.t.) administered lipopolysaccharide (LPS) to induce an ARDS model, followed by a single intravenous (i.v.) dose of hUC-MSCs. hUC-MSCs improved pulmonary function, decreased inflammation on day 3, and mitigated lung injury by reducing the lung injury score and increasing lung aeration (%) in mice on day 7 (p < 0.05). hUC-MSCs inactivated YAP on AECII and facilitated cell differentiation by decreasing Pro-surfactant protein C (Pro-SPC) and galectin 3 (LGALS3) while increasing podoplanin (T1α) in lungs of mice (p < 0.05). In AECII MLE-12 cells, both coculture with hUC-MSCs after LPS exposure and the YAP inhibitor, verteporfin, reduced Pro-SPC and LGALS3, whereas the YAP inhibitor increased T1α expression (p < 0.05). In conclusion, hUC-MSCs ameliorated lung injury of ARDS and regulated YAP to facilitate AECII differentiation.

摘要

急性呼吸窘迫综合征（ARDS）在全球范围内导致较高的死亡率。人脐带间充质干细胞（hUC-MSCs）具有免疫调节和再生潜能。然而，hUC-MSCs 作为 ARDS 治疗方法的效果尚不清楚。我们通过调节 YAP 研究了 hUC-MSCs 在 ARDS 中对 II 型肺泡上皮细胞（AECII）分化的作用。雄性 C57BL/6JNarl 小鼠经气管内（i.t.）给予脂多糖（LPS）诱导 ARDS 模型，随后给予单次静脉（i.v.）hUC-MSCs 剂量。hUC-MSCs 改善了肺功能，第 3 天减少了炎症，第 7 天通过降低肺损伤评分和增加肺充气（%）减轻了肺损伤（p<0.05）。hUC-MSCs 在 AECII 上使 YAP 失活，并通过降低 Pro-表面活性剂蛋白 C（Pro-SPC）和半乳糖凝集素 3（LGALS3）同时增加肺部的 podoplanin（T1α）促进细胞分化（p<0.05）。在 AECII MLE-12 细胞中，LPS 暴露后与 hUC-MSCs 共培养以及 YAP 抑制剂 verteporfin 均可降低 Pro-SPC 和 LGALS3，而 YAP 抑制剂增加 T1α 表达（p<0.05）。总之，hUC-MSCs 改善了 ARDS 的肺损伤，并通过调节 YAP 促进了 AECII 的分化。