Impaired myofibroblast proliferation is a central feature of pathologic post-natal alveolar simplification.

Autor:	Khan IS; Division of Neonatology, Department of Pediatrics, UCSF, San Francisco, United States.; Cardiovascular Research Institute, UCSF, San Francisco, United States., Molina C; Cardiovascular Research Institute, UCSF, San Francisco, United States.; Division of Pulmonary, Critical Care, Allergy, and Sleep, UCSF, San Francisco, United States.; Department of Medicine, UCSF, San Francisco, United States., Ren X; Cardiovascular Research Institute, UCSF, San Francisco, United States.; Division of Pulmonary, Critical Care, Allergy, and Sleep, UCSF, San Francisco, United States.; Department of Medicine, UCSF, San Francisco, United States., Auyeung VC; Cardiovascular Research Institute, UCSF, San Francisco, United States.; Division of Pulmonary, Critical Care, Allergy, and Sleep, UCSF, San Francisco, United States., Cohen M; Division of Pulmonary, Critical Care, Allergy, and Sleep, UCSF, San Francisco, United States.; Department of Medicine, UCSF, San Francisco, United States., Tsukui T; Cardiovascular Research Institute, UCSF, San Francisco, United States.; Division of Pulmonary, Critical Care, Allergy, and Sleep, UCSF, San Francisco, United States.; Department of Medicine, UCSF, San Francisco, United States., Atakilit A; Cardiovascular Research Institute, UCSF, San Francisco, United States.; Division of Pulmonary, Critical Care, Allergy, and Sleep, UCSF, San Francisco, United States.; Department of Medicine, UCSF, San Francisco, United States., Sheppard D; Cardiovascular Research Institute, UCSF, San Francisco, United States.; Division of Pulmonary, Critical Care, Allergy, and Sleep, UCSF, San Francisco, United States.; Department of Medicine, UCSF, San Francisco, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Dec 11; Vol. 13. Date of Electronic Publication: 2024 Dec 11.
DOI:	10.7554/eLife.94425
Abstrakt:	Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGFβ) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGFβ signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGFβ signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFβ signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD. Competing Interests: IK, CM, XR, VA, MC, TT, AA, DS No competing interests declared (© 2024, Khan et al.)
Databáze:	MEDLINE
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