ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

Airway secretory cell-derived p63+progenitors contribute to alveolar regeneration after sterile lung injury

“…To understand the source and fate of p63 + progenitors during injury, we first used p63-CreER to label pre-existing p63 + basal cells and intrapulmonary p63 + progenitors before injury 25,31 . After bleomycin injury, we found these pre-labeled p63 + cells do not contribute appreciably to p63 + cells in damaged lung parenchyma, which is in stark contrast to multiple reports demonstrating that essentially all of the p63 + Krt5 + expansion after influenza can be attributed to pre-existing intrapulmonary p63 + progenitors 16,18,25 . Instead, the honeycomb-like p63 + cells appearing after bleomycin injury were de novo generated by p63 − cells.…”

“…It could also be explained by the intrinsic heterogeneity of the secretory cells, as the proximal secretory cell can dedifferentiate and reform basal stem cells when their parental basal stem cells are ablated 37 , while distal secretory cells convert to p63 + progenitors that preferentially differentiate into alveolar cells. Intriguingly, we demonstrate that adoption of a p63 + intermediate after bleomycin injury seems to empower club cells to participate in repair, whereas loss of p63 is also required for p63 + Krt5 + cells to appreciably contribute to alveolar repair after influenza 18 , reinforcing the notion that dynamics of p63 expression are critical for both injury responses but also the resolution of epithelial remodeling. However, what drives some secretory cells to activate the expression of p63 and their translocation into the injured lung parenchyma remains unclear.…”

“…1e-f). This suggests that pre-existing intrapulmonary p63 + LNEPs that expand upon influenza injury do not expand upon sterile injury with bleomycin 16,18,25 . By using K5-2A-CreER;R26-tdT mice, we did not detect significant contribution of pre-labeled K5 + cells to alveoli after injury (Extended Data Fig.…”

“…However, direct in vivo genetic lineage tracing evidence to demonstrate the endogenous fate and function of H2-K1 high progenitors is lacking 15 . Conversely, p63 + LNEPs represent a rare population of intrapulmonary basal-like cells that expand dramatically upon influenza injury but rarely give rise to alveolar cell types, instead representing a dysplastic repair response [16][17][18] . In spite of these advances, the origins and lineage relationships of these various progenitor populations remain unclear, and whether their relative fate potential is dictated by the nature of the injury is similarly understudied.…”

Respiratory viruses: New frontiers—a Keystone Symposia report

“…They showed that the deletion of p63 increases the conversion of Krt5 + cells into AT2 cells. 8 They have also looked at the impact of chronic inflammation that persists even after the virus is cleared. Vaughan focused on the impact of tuft cells, which are implicated in intestinal damage and repair, where they play a role in type 2 mucosal immunity, characterized by IL-13, IL-25, and metaplasia.…”