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

The epithelial lining of regeneratively quiescent lungs is composed of alveolar type 2 (AT2) progenitor and differentiated alveolar type 1 (AT1) cells. To replace aged AT1 cells, AT2 cells undergo self-renewal to maintain alveolar epithelial homeostasis1. The regenerative potential of AT2 cells could be activated for timely recovery from lung epithelial injury2-4, including lobectomy and infections5 , 6. A marked suppression in fibrinolytic activity in local respiratory illnesses (e.g., inhaled smoke and aspirated gastric juice) and pulmonary complications of systemic diseases (e.g., sepsis) has been reported clinically and in animal models7 , 8. Migration and differentiation of mesenchymal stem cells (MSCs) in inflamed tissues are regulated by dynamic fibrinolytic niche9-12. The proteolysis of extracellular matrix substrates by urokinase plasminogen activator (uPA) could be involved in the benefit of the fibrinolytic niche to the regeneration of skeletal muscles and fractured cartilage13-17. For example, uPA and plasmin, two critical components of the fibrinolytic niche, cleave epithelial sodium channels (ENaC)18 , 19. In addition, functionally multifaceted uPA regulates alveolar epithelial function20 and possesses an A6 motif with a high affinity to CD44 receptors21 , 22. CD44 + AT2 cells show a higher proliferative capacity in fibrotic lungs23. The fibrinolytic niche in alveolar epithelial homeostasis and regeneration mediated by AT2 cells, however, has not been studied systematically. Our results have tested the potential novel contribution of uPA-PAI1-A6-CD44-ENaC cascade to the fibrinolytic niche in regulating the fate of AT2 cells.