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2.
Cell Stem Cell ; 30(8): 1028-1042.e7, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37541209

RESUMO

Impaired differentiation of alveolar stem cells has been identified in a variety of acute and chronic lung diseases. In this study, we investigate the mechanisms that modulate alveolar regeneration and understand how aging impacts this process. We have discovered that the process of alveolar type II (AT2) cells differentiating into AT1 cells is an energetically costly process. During alveolar regeneration, activated AMPK-PFKFB2 signaling upregulates glycolysis, which is essential to support the intracellular energy expenditure that is required for cytoskeletal remodeling during AT2 cell differentiation. AT2 cells in aged lungs exhibit reduced AMPK-PFKFB2 signaling and ATP production, resulting in impaired alveolar regeneration. Activating AMPK-PFKFB2 signaling in aged AT2 cells can rescue defective alveolar regeneration in aged mice. Thus, beyond demonstrating that cellular energy metabolism orchestrates with stem cell differentiation during alveolar regeneration, our study suggests that modulating AMPK-PFKFB2 signaling promotes alveolar repair in aged lungs.


Assuntos
Proteínas Quinases Ativadas por AMP , Células Epiteliais Alveolares , Camundongos , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Células Epiteliais Alveolares/metabolismo , Pulmão , Células-Tronco , Diferenciação Celular , Glicólise
3.
Proc Natl Acad Sci U S A ; 120(2): e2215449120, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36595691

RESUMO

Fluid clearance mediated by lymphatic vessels is known to be essential for lung inflation and gas-exchange function during the transition from prenatal to postnatal life, yet the molecular mechanisms that regulate lymphatic function remain unclear. Here, we profiled the molecular features of lymphatic endothelial cells (LECs) in embryonic and postnatal day (P) 0 lungs by single-cell RNA-sequencing analysis. We identified that the expression of c-JUN is transiently upregulated in P0 LECs. Conditional knockout of Jun in LECs impairs the opening of lung lymphatic vessels at birth, leading to fluid retention in the lungs and neonatal death. We further demonstrated that increased mechanical pressure induces the expression of c-JUN in LECs. c-JUN regulates the opening of lymphatic vessels by modulating the remodeling of the actin cytoskeleton in LECs. Our study established the essential regulatory function of c-JUN-mediated transcriptional responses in facilitating lung lymphatic fluid clearance at birth.


Assuntos
Células Endoteliais , Vasos Linfáticos , Humanos , Recém-Nascido , Células Endoteliais/metabolismo , Pulmão/metabolismo , Vasos Linfáticos/metabolismo
4.
Cell Prolif ; 55(4): e13211, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35274784

RESUMO

OBJECTIVES: Short telomeres in alveolar type 2 (AT2) cells have been associated with many lung diseases. The study aimed to investigate the regeneration capacity of AT2 cells with short telomeres by knocking out Tert in mice (G4 Tert-/- ) from the whole to the cellular level. MATERIALS AND METHODS: The lung injury model of mice was established by left pneumonectomy (PNX). The proliferation and differentiation of AT2 cells were observed by immunofluorescence staining in vivo and in vitro. The difference of the gene expression between control and G4 Tert-/- group during the regeneration of AT2 cells was compared by RNA sequencing. The expression of tubulin polymerization promoting protein 3 (TPPP3) was reduced by adeno-associated virus delivery. RESULTS: The alveolar regeneration in G4 Tert-/- mice was impaired after PNX-induced lung injury. The regulation of cytoskeleton remodelling was defective in G4 Tert-/- AT2 cells. The expression of TPPP3 was gradually increased during AT2 cell differentiation. The expression level of TPPP3 was reduced in G4 Tert-/- AT2 cells. Reducing TPPP3 expression in AT2 cells limits the microtubule remodelling and differentiation of AT2 cells. CONCLUSION: Short telomeres in AT2 cells result in the reduced expression level of TPPP3, leading to impaired regeneration capacity of AT2 cells.


Assuntos
Lesão Pulmonar , Células Epiteliais Alveolares/metabolismo , Animais , Diferenciação Celular/fisiologia , Lesão Pulmonar/metabolismo , Camundongos , Telômero/genética , Encurtamento do Telômero
6.
Cell ; 180(1): 107-121.e17, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31866069

RESUMO

Fibrosis can develop in most organs and causes organ failure. The most common type of lung fibrosis is known as idiopathic pulmonary fibrosis, in which fibrosis starts at the lung periphery and then progresses toward the lung center, eventually causing respiratory failure. Little is known about the mechanisms underlying the pathogenesis and periphery-to-center progression of the disease. Here we discovered that loss of Cdc42 function in alveolar stem cells (AT2 cells) causes periphery-to-center progressive lung fibrosis. We further show that Cdc42-null AT2 cells in both post-pneumonectomy and untreated aged mice cannot regenerate new alveoli, resulting in sustained exposure of AT2 cells to elevated mechanical tension. We demonstrate that elevated mechanical tension activates a TGF-ß signaling loop in AT2 cells, which drives the periphery-to-center progression of lung fibrosis. Our study establishes a direct mechanistic link between impaired alveolar regeneration, mechanical tension, and progressive lung fibrosis.


Assuntos
Células-Tronco Adultas/metabolismo , Fibrose Pulmonar Idiopática/etiologia , Alvéolos Pulmonares/metabolismo , Células-Tronco Adultas/patologia , Idoso , Células Epiteliais Alveolares/patologia , Animais , Fenômenos Biomecânicos/fisiologia , Feminino , Fibrose/patologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Alvéolos Pulmonares/patologia , Regeneração , Transdução de Sinais , Células-Tronco/patologia , Estresse Mecânico , Estresse Fisiológico/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismo
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