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Mesothelial Plasticity Specifies a Pleural Immune Circuit that Orchestrates Lung Regeneration

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE328025 | GEO | 2026/08/26

REPOSITORIES: GEO

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Project description:While aging leads to a reduction in the capacity for regeneration after pneumonectomy (PNX) in most mammals, this biological phenomenon has not been characterized over the lifetime of mice. We measured the age-specific (3, 9, 24 month) effects of PNX on physiology, morphometry, cell proliferation and apoptosis, global gene expression, and lung fibroblast phenotype and clonogenicity in female C57BL6 mice. The data show that only 3 month old mice were fully capable of restoring lung volumes by day 7 and total alveolar surface area. By 9 months, the rate of regeneration was slower (with incomplete regeneration by 21 days), and by 24 months there was no regrowth 21 days post-PNX. The early decline in regeneration rate was not associated with changes in alveolar epithelial cell type II (AECII) proliferation or apoptosis rate. However, significant apoptosis and lack of cell proliferation was evident after PNX in both total cells and AECII cells in 24 mo mice. Analysis of gene expression at several time points (1, 3 and 7 days) post-PNX in 3 versus 9 month mice was consistent with a myofibroblast signature (increased Tnc, Lox1, Col3A1, Eln and Tnfrsf12a) and more alpha smooth muscle actin (αSMA) positive myofibroblasts were present after PNX in 9 month than 3 month mice. Microarray analyses of mRNA expression patterns were performed on lung tissue from 9 month versus 3 month mice, before and after PNX. First, gene expression was compared in whole lungs tissues of young (3 month) vs. middle age (9 month) animals obtained at surgery (left, control lung). Second, the global gene expression responses of 3 vs. 9 mo mice were compared after PNX (1, 3 and 7 days) in the right lung. For each animal in the surgical study, the left (excised) lung lobe was used as a control for the corresponding right lung at the end of the study. This design was intended to increase the statistical power for detecting differences in gene expression by comparing pre- and post-PNX lung tissue from the same biological pools (2 animals/pool, 3 pools per group).

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Mesothelial Plasticity Specifies a Pleural Immune Circuit that Orchestrates Lung Regeneration

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