Enhanced mitophagy promotes lung repair and regeneration by restoring epithelial metabolic fitness
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE301256 | GEO | 2026/02/26
REPOSITORIES: GEO
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Project description:Alveolar Type II cells (AT2s) are the stem cells in the alveoli, responsible for both alveolar homeostasis and regeneration. Mitochondrial dysfunction has been reported in the AT2 cells from both chronic and acute injury induced alveolar diseases, including idiopathic pulmonary fibrosis (IPF) and viral pneumonia. Here, we demonstrate that genetic depletion of Ubiquitin Specific Peptidase 30 (USP30), a negative regulator of mitophagy, boosts mitophagy and restores mitochondrial function, leading to protection from injury induced AT2 apoptosis and increased AT2 stem cell activity. Both global Usp30 knockout (KO) and AT2-specific Usp30 KO protects the mice from bleomycin induced lung fibrosis and influenza puneumonia. Moreover, pharmaceutical inhibition of USP30 using a small molecule inhibitor effectively alleviates lung fibrosis and influenza pneumonia. Our study underscores a therapeutic potiential of USP30 inhibition for the treatment of injury induced alveolar diseases, offering a promising strategy for treating injury induced diseases
2026-02-26 | GSE317252 | GEO
Project description:Alveolar Type II cells (AT2s) are the stem cells in the alveoli, responsible for both alveolar homeostasis and regeneration. Mitochondrial dysfunction has been reported in the AT2 cells from both chronic and acute injury induced alveolar diseases, including idiopathic pulmonary fibrosis (IPF) and viral pneumonia. Here, we demonstrate that genetic depletion of Ubiquitin Specific Peptidase 30 (USP30), a negative regulator of mitophagy, boosts mitophagy and restores mitochondrial function, leading to protection from injury induced AT2 apoptosis and increased AT2 stem cell activity. Both global Usp30 knockout (KO) and AT2-specific Usp30 KO protects the mice from bleomycin induced lung fibrosis and influenza puneumonia. Moreover, pharmaceutical inhibition of USP30 using a small molecule inhibitor effectively alleviates lung fibrosis and influenza pneumonia. Our study underscores a therapeutic potiential of USP30 inhibition for the treatment of injury induced alveolar diseases, offering a promising strategy for treating injury induced diseases
2026-02-26 | GSE317253 | GEO
Project description:During influenza pneumonia, the alveolar epithelial cells of the lungs are targeted by influenza virus. The distal airway stem cells (DASCs) and proliferating alveolar type II (AT2) cells are reported to be putative lung repair cells. However, their relative spatial and temporal distribution is still unknown during influenza-induced acute lung injury. Here, we investigated the distribution of these cells, and concurrently performed global proteomic analysis of the infected lungs to elucidate and link the cellular and molecular events during influenza pneumonia recovery. BALB/c mice were infected with a sub-lethal dose of influenza H1N1 virus. From 5 to 25 days post-infection (dpi), mouse lungs were subjected to histopathologic and immunofluorescence analysis to probe for global distribution of lung repair cells (using P63 and KRT5 markers for DASCs; PCNA and SPC markers for AT2 cells). At 7 and 15 dpi, infected mouse lungs were also subjected to protein mass spectrometry for relative protein quantification. DASCs appeared only in the damaged area of the lung from 7 dpi onwards, reaching a peak at 21 dpi, and persisted at 25 dpi. However, no differentiation of DASCs to AT2 cells was observed by 25 dpi. In contrast, AT2 cells began proliferating from 7 dpi to replenish its population. Mass spectrometry and gene ontology analysis revealed prominent innate immune response at 7 dpi, which shifted towards adaptive immune responses by 15 dpi. Hence, proliferating AT2 cells but not DASCs contribute to AT2 cell regeneration following transition from innate to adaptive immune responses during the early phase of recovery from influenza pneumonia up to 25 dpi.
2020-04-17 | PXD014967 | Pride
Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate. To compare expression between ATII and E18 BP populations, RNA was isolated from either population purified by FACS. Two populations are analyzed with 3 biological replicates per population.
2014-03-07 | E-GEOD-49346 | biostudies-arrayexpress
Project description:Drug-induced lung injury rarely, but seriously leads to severe lung diseases such as interstitial pneumonia and pulmonary fibrosis. However, the mechanism underlying drug-induced lung injury remains unclear. Anticancer drugs frequently induce pulmonary damage compared to the other categories of the drugs. In this study, the effect of bleomycin and methotrexate, which are representative pulmonary toxic anticancer drugs, on the comprehensive protein expression levels in alveolar epithelial model cell line, A549.
2025-07-25 | PXD053298 | Pride
Project description:A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ are implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrated that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings established that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.
2023-11-15 | GSE243135 | GEO
Project description:Rationale: Transdifferentiation of alveolar type 2 (AT2) epithelial cells into type 1 (AT1) cells is essential for maintaining lung homeostasis and facilitating repair following injury. However, the molecular mechanisms governing AT2-to-AT1 transdifferentiation remain unclear. Objectives: To investigate the role of the prostaglandin I2 receptor (IP) in regulating AT2-to-AT1 transdifferentiation and elucidate the underlying mechanisms. Methods: Alveolar organoid cultures and bleomycin- or lipopolysaccharide (LPS)-induced murine lung injury models were used to assess the role of IP in AT2-to-AT1 transdifferentiation and lung repair. Single-cell RNA sequencing (scRNA-seq), ATAC-seq, and biochemical assays were performed to explore the regulatory signaling pathways downstream of IP in AT2 cells. Measurements and Main Results: Among all prostaglandin receptors, IP exhibited the strongest association with AT1 gene enrichment in transitional AT2 cells from patients with idiopathic pulmonary fibrosis (IPF). Pharmacological inhibition or genetic deletion of IP significantly impaired the AT2-to-AT1 transition in organoid cultures. Conditional knockout of IP in AT2 cells exacerbated bleomycin- and lipopolysaccharide-induced lung injury by reducing epithelial regeneration and increasing fibrosis. Mechanistically, IP deficiency led to aberrant JUN activation, which suppressed p53-dependent AT1 gene expression. IP activation promoted PKA-mediated inhibition of MAP3K5, thereby suppressing the JNK/JUN axis and enhancing p53-driven AT2-to-AT1 transdifferentiation. Pharmacological activation of IP with selexipag promoted alveolar epithelial regeneration and reduced lung fibrosis in mice. IP agonist also enhanced AT2-to-AT1 transdifferentiation in primary AT2 cells from patients with IPF. Conclusions: IP is a key regulator of alveolar epithelial regeneration. Therapeutic activation of IP may be a promising strategy for promoting lung repair.
2026-01-14 | GSE313673 | GEO
Project description:Rationale: Transdifferentiation of alveolar type 2 (AT2) epithelial cells into type 1 (AT1) cells is essential for maintaining lung homeostasis and facilitating repair following injury. However, the molecular mechanisms governing AT2-to-AT1 transdifferentiation remain unclear. Objectives: To investigate the role of the prostaglandin I2 receptor (IP) in regulating AT2-to-AT1 transdifferentiation and elucidate the underlying mechanisms. Methods: Alveolar organoid cultures and bleomycin- or lipopolysaccharide (LPS)-induced murine lung injury models were used to assess the role of IP in AT2-to-AT1 transdifferentiation and lung repair. Single-cell RNA sequencing (scRNA-seq), ATAC-seq, and biochemical assays were performed to explore the regulatory signaling pathways downstream of IP in AT2 cells. Measurements and Main Results: Among all prostaglandin receptors, IP exhibited the strongest association with AT1 gene enrichment in transitional AT2 cells from patients with idiopathic pulmonary fibrosis (IPF). Pharmacological inhibition or genetic deletion of IP significantly impaired the AT2-to-AT1 transition in organoid cultures. Conditional knockout of IP in AT2 cells exacerbated bleomycin- and lipopolysaccharide-induced lung injury by reducing epithelial regeneration and increasing fibrosis. Mechanistically, IP deficiency led to aberrant JUN activation, which suppressed p53-dependent AT1 gene expression. IP activation promoted PKA-mediated inhibition of MAP3K5, thereby suppressing the JNK/JUN axis and enhancing p53-driven AT2-to-AT1 transdifferentiation. Pharmacological activation of IP with selexipag promoted alveolar epithelial regeneration and reduced lung fibrosis in mice. IP agonist also enhanced AT2-to-AT1 transdifferentiation in primary AT2 cells from patients with IPF. Conclusions: IP is a key regulator of alveolar epithelial regeneration. Therapeutic activation of IP may be a promising strategy for promoting lung repair.
2026-01-14 | GSE313672 | GEO
Project description:Rationale: Transdifferentiation of alveolar type 2 (AT2) epithelial cells into type 1 (AT1) cells is essential for maintaining lung homeostasis and facilitating repair following injury. However, the molecular mechanisms governing AT2-to-AT1 transdifferentiation remain unclear. Objectives: To investigate the role of the prostaglandin I2 receptor (IP) in regulating AT2-to-AT1 transdifferentiation and elucidate the underlying mechanisms. Methods: Alveolar organoid cultures and bleomycin- or lipopolysaccharide (LPS)-induced murine lung injury models were used to assess the role of IP in AT2-to-AT1 transdifferentiation and lung repair. Single-cell RNA sequencing (scRNA-seq), ATAC-seq, and biochemical assays were performed to explore the regulatory signaling pathways downstream of IP in AT2 cells. Measurements and Main Results: Among all prostaglandin receptors, IP exhibited the strongest association with AT1 gene enrichment in transitional AT2 cells from patients with idiopathic pulmonary fibrosis (IPF). Pharmacological inhibition or genetic deletion of IP significantly impaired the AT2-to-AT1 transition in organoid cultures. Conditional knockout of IP in AT2 cells exacerbated bleomycin- and lipopolysaccharide-induced lung injury by reducing epithelial regeneration and increasing fibrosis. Mechanistically, IP deficiency led to aberrant JUN activation, which suppressed p53-dependent AT1 gene expression. IP activation promoted PKA-mediated inhibition of MAP3K5, thereby suppressing the JNK/JUN axis and enhancing p53-driven AT2-to-AT1 transdifferentiation. Pharmacological activation of IP with selexipag promoted alveolar epithelial regeneration and reduced lung fibrosis in mice. IP agonist also enhanced AT2-to-AT1 transdifferentiation in primary AT2 cells from patients with IPF. Conclusions: IP is a key regulator of alveolar epithelial regeneration. Therapeutic activation of IP may be a promising strategy for promoting lung repair.
2026-01-14 | GSE313671 | GEO
Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate.
2014-03-07 | GSE49346 | GEO