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bioRxiv · 10.1101/2020.03.24.006270

Fibrinolytic niche is requested for alveolar type 2 cell-mediated alveologenesis and injury repair

Ali, G.·Zhao, R.·Zhang, M.·Jain, K. G.·Chang, J.·Komatsu, S.·Fang, X.·Zhou, B.·Liang, J.·Jiang, D.·Ikebe, M.·Matthay, M. A.·Ji, H.-L.
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Abstract

COVID-19, SARS, and MERS are featured by fibrinolytic dysfunction. To test the role of the fibrinolytic niche in the regeneration of alveolar epithelium, we compared the self-renewing capacity of alveolar epithelial type 2 (AT2) cells and its differentiation to AT1 cells between wild type (wt) and fibrinolytic niche deficient mice (Plau-/- and Serpine1Tg). A significant reduction in both proliferation and differentiation of deficient AT2 cells was observed in vivo and in 3D organoid cultures. This decrease was mainly restored by uPA derived A6 peptide, a binding fragment to CD44 receptors. The proliferative and differential rate of CD44+ AT2 cells was greater than that of CD44- controls. There was a reduction in transepithelial ion transport in deficient monolayers compared to wt cells. Moreover, we found a marked suppression in total AT2 cells and CD44+ subpopulation in lungs from brain dead patients with acute respiratory distress syndrome (ARDS) and a mouse model infected by influenza viruses. Thus, we demonstrate that the fibrinolytic niche can regulate AT2-mediated homeostasis and regeneration via a novel uPA-A6-CD44+-ENaC cascade.

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Ali, G., Zhao, R., Zhang, M., Jain, K. G., Chang, J., Komatsu, S., Fang, X., Zhou, B., Liang, J., Jiang, D., Ikebe, M., Matthay, M. A., Ji, H.-L.. 2020-03-25. Fibrinolytic niche is requested for alveolar type 2 cell-mediated alveologenesis and injury repair. https://doi.org/10.1101/2020.03.24.006270

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