Dedifferentiated early postnatal lung myofibroblasts redifferentiate in adult disease

• Published in: Frontiers in cell and developmental biology 2024-03, Vol.12, p.1335061
• Main Authors: Chandran, Rachana R, Adams, Taylor S, Kabir, Inamul, Gallardo-Vara, Eunate, Kaminski, Naftali, Gomperts, Brigitte N, Greif, Daniel M
• Format: Article
• Language: English
• Subjects: alveolarization; Cell and Developmental Biology; fate mapping; hypoxia; lung fibrosis; lung myofibroblasts; pulmonary hypertension
• ISSN: 2296-634X; 2296-634X
• DOI: 10.3389/fcell.2024.1335061

Alveolarization ensures sufficient lung surface area for gas exchange, and during bulk alveolarization in mice (postnatal day [P] 4.5-14.5), alpha-smooth muscle actin (SMA) myofibroblasts accumulate, secrete elastin, and lay down alveolar septum. Herein, we delineate the dynamics of the lineage of early postnatal SMA myofibroblasts during and after bulk alveolarization and in response to lung injury. SMA lung myofibroblasts first appear at ∼ P2.5 and proliferate robustly. Lineage tracing shows that, at P14.5 and over the next few days, the vast majority of SMA myofibroblasts downregulate smooth muscle cell markers and undergo apoptosis. Of note, ∼8% of these dedifferentiated cells and another ∼1% of SMA myofibroblasts persist to adulthood. Single cell RNA sequencing analysis of the persistent SMA cells and SMA myofibroblasts in the adult lung reveals distinct gene expression profiles. For instance, dedifferentiated SMA cells exhibit higher levels of tissue remodeling genes. Most interestingly, these dedifferentiated early postnatal myofibroblasts re-express SMA upon exposure of the adult lung to hypoxia or the pro-fibrotic drug bleomycin. However, unlike during alveolarization, these cells that re-express SMA do not proliferate with hypoxia. In sum, dedifferentiated early postnatal myofibroblasts are a previously undescribed cell type in the adult lung and redifferentiate in response to injury.