Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria

Zhang, Kuan; Yao, Erica; Chen, Biao; Chuang, Ethan; Wong, Josephine; Seed, Robert; Nishimura, Stephen L.; Wolters, Paul J.; Chuang, Pao-Tien

doi:10.7554/elife.68598

Cited by 16 publications

(7 citation statements)

References 62 publications

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“…Li et al established the requirement of myofibroblasts during postnatal development by specifically ablating PDGFRα+ cells at the onset of alveologenesis and showing that these mice developed alveolar simplification 31 . Other work has identified essential functions of myofibroblasts during alveolar development, including contractility 37 and mitochondrial energetics 68 . Ricetti et al used bulk RNA sequencing to show a skewing from myofibroblast to matrix fibroblast phenotypes after hyperoxia exposure along with reduced Ki-67 uptake and contractility in myofibroblasts 36 .…”

Section: Discussionmentioning

confidence: 99%

Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification

Khan,

Molina,

Ren

et al. 2023

Preprint

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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 TGFb 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.

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Section: Discussionmentioning

confidence: 99%

Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification

Khan,

Molina,

Ren

et al. 2023

Preprint

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“…Immunofluorescence was performed as previously described [ 34 , 37 , 38 ]. In brief, mouse embryonic lungs were collected at the indicated time points and fixed with 4% paraformaldehyde (PFA) on ice for 1 h. The samples were embedded in OCT and sectioned at 7 μm.…”

Section: Methodsmentioning

confidence: 99%

Wnt5a–Vangl1/2 signaling regulates the position and direction of lung branching through the cytoskeleton and focal adhesions

et al. 2022

Self Cite

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Lung branching morphogenesis requires reciprocal interactions between the epithelium and mesenchyme. How the lung branches are generated at a defined location and projected toward a specific direction remains a major unresolved issue. In this study, we investigated the function of Wnt signaling in lung branching in mice. We discovered that Wnt5a in both the epithelium and the mesenchyme plays an essential role in controlling the position and direction of lung branching. The Wnt5a signal is mediated by Vangl1/2 to trigger a cascade of noncanonical or planar cell polarity (PCP) signaling. In response to noncanonical Wnt signaling, lung cells undergo cytoskeletal reorganization and change focal adhesions. Perturbed focal adhesions in lung explants are associated with defective branching. Moreover, we observed changes in the shape and orientation of the epithelial sheet and the underlying mesenchymal layer in regions of defective branching in the mutant lungs. Thus, PCP signaling helps define the position and orientation of the lung branches. We propose that mechanical force induced by noncanonical Wnt signaling mediates a coordinated alteration in the shape and orientation of a group of epithelial and mesenchymal cells. These results provide a new framework for understanding the molecular mechanisms by which a stereotypic branching pattern is generated.

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“…In lung morphogenesis, the mTOR signaling pathway participates in the regulation of alveologenesis by controlling mitochondrial function [ 100 ]. For instance, in the postnatal period (P10), Raptor inactivation in mice leads to the loss of mitochondria and alveolar lung defects.…”

Section: Hippo-yap Signaling In Lung Cellsmentioning

confidence: 99%

Influence of intersignaling crosstalk on the intracellular localization of YAP/TAZ in lung cells

Govorova,

Nikitochkina,

Vorotelyak

2024

Cell Commun Signal

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A cell is a dynamic system in which various processes occur simultaneously. In particular, intra- and intercellular signaling pathway crosstalk has a significant impact on a cell’s life cycle, differentiation, proliferation, growth, regeneration, and, consequently, on the normal functioning of an entire organ. Hippo signaling and YAP/TAZ nucleocytoplasmic shuttling play a pivotal role in normal development, homeostasis, and tissue regeneration, particularly in lung cells. Intersignaling communication has a significant impact on the core components of the Hippo pathway and on YAP/TAZ localization. This review describes the crosstalk between Hippo signaling and key lung signaling pathways (WNT, SHH, TGFβ, Notch, Rho, and mTOR) using lung cells as an example and highlights the remaining unanswered questions.

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Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria

Cited by 16 publications

References 62 publications

Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification

Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification

Wnt5a–Vangl1/2 signaling regulates the position and direction of lung branching through the cytoskeleton and focal adhesions

Influence of intersignaling crosstalk on the intracellular localization of YAP/TAZ in lung cells

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