Xu, L.;Chen, K.;Dash, B.;Yao, B.;Li, R.;Wang, X.;Zhou, Z.;Yu, V.;Salamon, R.;Bawa, P.;Guo, M.;Borok, Z.;Kotton, D.;Eickelberg, O.;Bueno, M.;Sun, X.

SUMMARY Following injury, predisposition towards regenerative repair and away from degenerative remodeling is central to organismal health, yet the upstream determinants that instruct this fate choice remain poorly understood. Here, we identify mesothelial cell plasticity as a central determinant between regeneration and degeneration by comparing mouse models of pneumonectomy (PNX) versus chronic lung allograft dysfunction (CLAD). While mesothelial cells expand in both settings, following PNX, these cells undergo differentiation through multiple transitional states, culminating in an inflammatory population that orchestrates monocyte recruitment and subsequent tissue regeneration. In contrast, in CLAD, mesothelial cells enrich in an extracellular matrix-enriched state that lacks pro-regenerative signaling capacity. Using single cell epigenomic profiling and in vivo genetics, we define a mesothelium-specific TWIST1-CCL2 axis that governs mesothelium plasticity and signaling, monocyte recruitment and lung regrowth. Together, these findings demonstrate that context-dependent reprogramming of a pleural population, known to protect organs, can be leveraged to drive regeneration.