Non-Canonical BMP Signaling Pathway Plays A Critical Role In Lung Repair And Regeneration

The distal part of adult lung in mammalian animals is comprised of functionally distinct regions including a branched network of respiratory airways and a dense web of alveolar sacs where gas exchange occurs.Homeostasis and repair of this highly complex structure after injury rely on distinct progenitor cell populations and these processes are regulated by signaling pathways including BMP,TGF-b,Wnt,and Notch.Several progenitor cell populations have been identified,including club cells and alveolar epithelial cells type ?(AEC-?),which are able to repopulate distal airway and alveolar epithelium,respectively.However,the lineage identity of the cells involved in regeneration of bronchiolar and alveolar epithelium and the underlying mechanisms remain incompletely understood.In this study,we aimed to identify and characterize the lineage identity of epithelial progenitor cell populations in the adult lung,and furthermore,to investigate the potential for the BMP pathway to repair/regenerate the bronchiolar and alveolar epithelium using conditional gene knock-out mouse models and naphthalene/bleomycin induced injury models.Here,using the Prrx1-Cre;Rosa-td Tomato mice,this study showed that Prrx1,a homeobox transcription factor,can mark club cells and AEC-? cells in adult mice during homeostasis and regeneration.Prrx1-Cre;Rosa-td Tomato mice were used to lineage trace the club cells and AEC-? cells after naphthalene and bleomycin induced injury,respectively.Using conditional gene knockout mouse models,it further showed that the non-canonical signaling pathway of BMPs,BMPR1A-Tak1-p38MAPK plays a critical role in club cell and AEC-? cell regeneration.Ablation of Bmpr1a,Tak1,or Mapk14(encoding p38a)in Prrx1~+club cells caused minimal effect on bronchiolar epithelium homeostasis,yet it resulted in severe defects in club cell regeneration and bronchiole repair in adult mice.In addition to these,depletion of these genes in Prrx1~+cells resulted in increased collagen deposition,severe fibrosis and delayed repair of alveolar epithelium after bleomycin induced injury.Findings of current study thus identify a marker for club cells and reveal a critical role for the BMP non-canonical pathway in club cell regeneration and restoration of alveolar epithelium.We strongly believe that findings of this study will potentially aid the design of practical cell-specific therapeutics targeted at inducing lung regeneration to fight against various lung diseases.