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

Ali Gibran; Runzhen Zhao; Mo Zhang; Krishan G. Jain; Jianjun Chang; Satoshi Komatsu; Xiaohui Fang; Beiyun Zhou; Jiurong Liang; Dianhua Jiang; Mistuo Ikebe; Michael A Matthay; Hong-Long Ji

CD44 is a crucial mediator for the regulation of re-alveologenesis by AT2 cells. We previously demonstrated that CD44 receptors govern cell survival and the progression of lung fibrosis via the Toll-like receptors and hyaluronan54. The connective domain of uPA has an eight L-amino acid sequence (Ac-KPSSPPEE-NH2), known as A6 peptide55. Binding of the A6 peptide with the link domain of CD44 receptors initiates the downstream signaling56. CD44 -/mice demonstrate an inflammatory phenotype characterized by increased inflammatory cell recruitment and are more susceptible to LPS induced injury. CD44 deficiency leads to impaired expression of negative regulators of TLR signaling in macrophages, an essential event in the prevention of LPS induced inflammatory responses57. Our study demonstrates a new mechanism that the CD44 receptors at the plasma membrane of AT2 cells are a key player for AT2 cell-mediated re-alveolarization. In addition to the reduction in AT2 cells in injured mouse and human lungs associated with aberrant fibrinolytic niche, both Plau -/and Serpine1 Tg AT2 cells cannot develop organoids equal to those of wt mice in vitro, mostly likely due to the author/funder. All rights reserved. No reuse allowed without permission.