Wnt5a/β-catenin 轴参与了 PAI-1 对 AT2 谱系的下调。
Wnt5a/β-catenin axis is involved in the downregulation of AT2 lineage by PAI-1.
机构信息
Department of Cellular and Molecular Biology, University of Texas at Tyler, Tyler, Texas.
Department of Computer Science and Engineering, University of North Texas, Denton, Texas.
出版信息
Am J Physiol Lung Cell Mol Physiol. 2022 Nov 1;323(5):L515-L524. doi: 10.1152/ajplung.00202.2022. Epub 2022 Sep 13.
Failure to regenerate injured alveoli functionally and promptly causes a high incidence of fatality in coronavirus disease 2019 (COVID-19). How elevated plasminogen activator inhibitor-1 (PAI-1) regulates the lineage of alveolar type 2 (AT2) cells for re-alveolarization has not been studied. This study aimed to examine the role of PAI-1-Wnt5a-β catenin cascades in AT2 fate. Dramatic reduction in AT2 yield was observed in mice. Elevated PAI-1 level suppressed organoid number, development efficiency, and total surface area in vitro. Anti-PAI-1 neutralizing antibody restored organoid number, proliferation and differentiation of AT2 cells, and β-catenin level in organoids. Both Wnt family member 5A (Wnt5a) and Wnt5a-derived N-butyloxycarbonyl hexapeptide (Box5) altered the lineage of AT2 cells. This study demonstrates that elevated PAI-1 regulates AT2 proliferation and differentiation via the Wnt5a/β catenin cascades. PAI-1 could serve as autocrine signaling for lung injury repair.
未能及时有效地再生受损的肺泡，是导致 2019 年冠状病毒病（COVID-19）高死亡率的主要原因。目前尚不清楚升高的纤溶酶原激活物抑制剂-1（PAI-1）如何调节肺泡Ⅱ型（AT2）细胞的谱系以实现肺泡再生成。本研究旨在探讨 PAI-1-Wnt5a-β连环蛋白级联反应在 AT2 命运中的作用。研究发现， 在 小鼠中，AT2 细胞数量明显减少。高水平的 PAI-1 抑制体外类器官数量、发育效率和总表面积。抗 PAI-1 中和抗体可恢复 AT2 细胞的类器官数量、增殖和分化，以及 β-连环蛋白水平。Wnt 家族成员 5A（Wnt5a）和 Wnt5a 衍生的 N-叔丁氧羰基六肽（Box5）均可改变 AT2 细胞的谱系。本研究表明，升高的 PAI-1 通过 Wnt5a/β 连环蛋白级联反应调节 AT2 的增殖和分化。PAI-1 可能作为肺损伤修复的自分泌信号。
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