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Hedgehog-interacting protein orchestrates alveologenesis and protects against BPD and emphysema by modulating hedgehog-IGF1 signaling axis

ABSTRACT: Hedgehog-interacting protein orchestrates alveologenesis and protects against BPD and emphysema by modulating hedgehog-IGF1 signaling axis

PROVIDER: PRJNA1131365 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29695383_1.fastq.gz	Fastqsanger.gz
	SRR29695383_2.fastq.gz	Fastqsanger.gz
	SRR29695384_1.fastq.gz	Fastqsanger.gz
	SRR29695384_2.fastq.gz	Fastqsanger.gz

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Hedgehog-interacting protein orchestrates alveologenesis and protects against BPD and emphysema by modulating hedgehog-IGF1 signaling axis

Project description:A majority of the gas-exchange surface is generated during alveologenesis, and disruption of this process causes bronchopulmonary dysplasia (BPD) in preterm infants, characterized by alveolar simplification. BPD is a significant risk factor for adult emphysema, marked by alveolar loss. A comprehensive molecular understanding of alveologenesis and effective treatments for BPD and emphysema are still lacking. Here, we show that the cells expressing Hhip, a gene associated with both BPD and emphysema, expand within the alveoli during alveologenesis, followed by hedgehog (Hh) inhibition and myofibroblast transition. Stromal-specific deletion of Hhip leads to aberrant persistence of SMA+ alveolar myofibroblasts, mediated by a hyperactive Hh-IGF1 axis. Conditional knockout animal and 3D stroma-stem cell organoid models demonstrate that loss of Hhip induces alveolar stem/progenitor cell senescence in a non–cell-autonomous manner. Alveolar simplification and BPD phenotypes induced by Hhip deletion can be partially rescued by IGF1 signaling blockade. We also observe the downregulation of Hhip expression and hyperactivation of Hh-IGF1 signaling in hyperoxia-induced BPD animal models. In addition, adult mice deficient in Hhip expression develop emphysema phenotype with abnormal alveolar myofibroblasts. Finally, we develop a therapeutic Fc-fused HHIP recombinant protein that attenuates BPD phenotypes in postnatal mice and emphysema in adult mice. These findings underscore the critical role of HHIP in coordinating alveologenesis and preventing BPD and emphysema by restricting Hh-IGF1 signaling.

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Hedgehog-Responsive PDGFRa(+) Fibroblasts are Necessary for Maintenance of a Unique Pool of Alveolar Epithelial Progenitor Cells During Alveologenesis

Project description:The adult lung alveolus is a flexible 3D structure composed of multiple epithelial, endothelial, and mesenchymal cell types. Two highly specialized alveolar type I (AT1) and type II (AT2) cells, derived from epithelial progenitors, form the inner lining of the alveolus. During alveologenesis, the increasing demand for epithelial cells to cover the surface of the expansive number of alveoli is met by proliferating progenitor cells. There is presently little information about the identity of this population, and the niche microenvironment that controls its proliferation. We show that during alveologenesis genetic inactivation of TGFreceptors in hedgehog-responsive, PDGFRa(+) mesodermal cells previously identified as secondary crest myofibroblasts or SCMF reduces their number, and depletes a unique pool of proliferative epithelial progenitors, without significantly impacting differentiation of cells existing the pool. SCMF are a source of both extracellular matrix and secreted trophic molecules and may thus constitute a key component of the epithelial progenitor niche during alveologenesis. Paralleling the mouse model, we found evidence of reduced proliferation of SFTPC(+) progenitors in lungs of human preterm infants who died with bronchopulmonary dysplasia or BPD. SCMF are a transient cell population, which are depleted at completion of alveologenesis, making them a unique stage-dependent niche mesodermal cell type in mammalian organs.

2021-04-15 | GSE172059 | GEO

Recombinant FGF10-induced de novo alveologenesis in neonatal mice after hyperoxia exposure is associated with enhanced AT2’s resident mesenchymal cell niche activity

Project description:Recombinant FGF10 improved hemodynamic measurements and alveologenesis. Alveolosphere assays indicate that the activity of rMC-Sca1Pos is negatively impacted by HYX and partially rescued by FGF10 treatment. scRNAseq results identified clusters expressing Fgf10, Fgf7, Pdgfra, Axin2 which could represent the rMC niche cells for the AT2 stem cells. In this syudy, we demonstrate that FGF10 administration is curative for BPD and identified a subpopulation of rMC-Sca1Pos niche cells which could represent its cellular target.

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miRNA expression in tracheal aspirates [ICS-BPD vs. ICS-BPD-PH]

Project description:Tracheal aspirate (TAs) samples were collected from intubated preterm infants with hemodynamically significant intracardiac shunt (ICS), and a diagnosis of ICS-BPD/ICS-BPD-PH. 36 TA samples were analyzed. Small RNAs were extracted and the expression miRNAs was detected with PCR arrays.

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Targeting p16-induced Senescence Prevents Cigarette Smoke-Induced Emphysema by Promoting IGF1/Akt1 Signaling in mice

Project description:Increased IGF1 signaling in p16 -/- lungs

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Targeting p16-induced Senescence Prevents Cigarette Smoke-Induced Emphysema by Promoting IGF1/Akt1 Signaling in mice

Project description:Targeting p16-induced Senescence Prevents Cigarette Smoke-Induced Emphysema by Promoting IGF1/Akt1 Signaling in mice

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miRNA expression in tracheal aspirates [ICS-BPD vs. ICS-BPD-PH]

Project description:miRNA expression in tracheal aspirates [ICS-BPD vs. ICS-BPD-PH]

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Eosinophils promote lung emphysema via CTSL

Project description:Patients with chronic obstructive pulmonary disease (COPD) having higher blood eosinophil levels exhibit worse lung function and more severe emphysema, implying the potential role of eosinophils in emphysema development. However, the specific mechanism underlying eosinophil-mediated emphysema development is not fully elucidated. In this study, single-cell RNA sequencing was used to identify eosinophil subgroups in mouse models of asthma and emphysema and analyze their functions. Analysis of the accumulated eosinophils revealed differential transcriptomes between the mouse lungs of elastase-induced emphysema and ovalbumin-induced asthma., Eosinophil depletion alleviated elastase-induced emphysema. Notably, eosinophil-derived cathepsin L (CTSL) degraded the extracellular matrix (ECM), causing emphysema in the pulmonary tissue. Eosinophils were positively correlated with serum CTSL levels, which were increased in patients with emphysema than in those without emphysema. Collectively, these results suggest that CTSL expression in eosinophils plays an important role in ECM degradation and remodeling and is related to emphysema in patients with COPD. Therefore, eosinophil-derived CTSL may serve as a potential therapeutic target for patients with emphysema.

2023-10-17 | GSE237749 | GEO

Expression data from E18.5 Igf1 -/- (homozygous mutant) and Igf1+/+ (normal wild type control) mouse lungs

Project description:Insight into the role of Insulin-like Growth Factor (IGF) in development of lungs has come from the study of genetically modified mice. IGF1 is a key factor during lung development. IGF1 deficiency in the neonatal mouse causes respiratory failure collapsed alveoli and altered alveolar septa. To further characterize IGF1 function during lung development we analyzed Igf1-/- mouse prenatal lungs in a C57Bl/6 genetic background. Mutant lungs showed disproportional hypoplasia, disorganized extracellular matrix and dilated alveolar capillaries. IGF1 target genes during lung maturation were identified by analyzing RNA differential expression in Igf1-/- lungs using microarrays. Lungs from E18.5 were isolated from both Igf1+/+ wild type and Igf1-/- null mice and pooled to obtain RNA. Heterozygous male and female with a genetic background C57BL/6J were mated to obtain embryos at embrionic (E) stage 18.5 days post coitum (E18.5). 3 biological replicates per genotype.

2014-03-31 | E-GEOD-17157 | biostudies-arrayexpress

Emphysema Lung Tissue Gene Expression Profiling

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