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Chemically induced expansion of type 2 alveolar epithelial cell promotes regenerative lower airway repair

ABSTRACT: To evaluate the effect of DPP4 inhibitor on regenerative repair of the lung upon injury, we carried out a single cell RNA sequencing study. In this study, orally administered sitagliptin was tested in LPS-induced lung injury model, followed by longitudinal single cell transcriptomic analysis with lung cells harvested at indicated time points.

ORGANISM(S): Mus musculus

PROVIDER: GSE262393 | GEO | 2024/03/27

REPOSITORIES: GEO

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Chemically induced expansion of type 2 alveolar epithelial cell promotes regenerative lower airway repair [RNA-seq]

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2024-03-27 | GSE262398 | GEO

Repurposing DPP4-Inhibition to Improve Hair Follicle Activation and Regeneration

Project description:Skin-injury and several diseases elicit fibrosis and induce hair follicle (HF)-growth arrest and loss. Resulting alopecia and disfiguration represent a severe burden for patients both physically and psychologically. Reduction of pro-fibrotic factors such as DPP4 might be a strategy to tackle this issue. We demonstrate DPP4-overrepresentation in settings with HF-growth arrest (telogen), HF-loss and non-regenerative wound areas in mice skin and human scalp. Topical DPP4-inhibition (DPP4i) with FDA/EMA-approved Sitagliptin (Sit) on preclinical models of murine HF-activation/regeneration results in accelerated anagen-progress, while treatment of wounds with Sit results in reduced expression of fibrosis markers, increased induction of anagen around wounds, and HF-regeneration in the wound center. These effects are associated with higher expression of Wnt-target Lef1, known to be required for HF-anagen (HF-activation)/regeneration. Sit-treatment decreases pro-fibrotic signaling in the skin, induce a differentiation trajectory of HF-cells, and activate Wnt-targets related to HF-activation/growth but not those supporting fibrosis. Taken together, our study demonstrates a role for DPP4 in HF biology and shows how DPP4i, currently used as oral medication to treat diabetes, could be repurposed into a topical treatment agent to potentially reverse HF-loss in alopecia and after injury.

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Chemically induced expansion of type 2 alveolar epithelial cell promotes regenerative lower airway repair

Project description:Chemically induced expansion of type 2 alveolar epithelial cell promotes regenerative lower airway repair

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Chemically induced expansion of type 2 alveolar epithelial cell promotes regenerative lower airway repair [RNA-seq]

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Qingda granules lower Angiotensin-II-induced blood pressure

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Single Cell RNA Sequencing Identifies TGFβ as a Key Regenerative Cue following LPS-induced Lung Injury

Project description:Many lung diseases result from a failure of efficient regeneration of damaged alveolar epithelial cells (AECs) after lung injury. During regeneration, AEC2s proliferate to replace lost cells, after which proliferation halts and some AEC2s transdifferentiate into AEC1s to restore normal alveolar structure and function. Although the mechanisms underlying AEC2 proliferation have been studied, the mechanisms responsible for halting proliferation and inducing transdifferentiation are poorly understood. To identify candidate signaling pathways responsible for halting proliferation and inducing transdifferentiation, we performed single cell RNA sequencing on AEC2s during regeneration in a murine model of lung injury induced by intratracheal LPS. Unsupervised clustering revealed distinct subpopulations of regenerating AEC2s: proliferating, cell cycle arrest, and transdifferentiating. Gene expression analysis of these transitional subpopulations revealed that TGFβ signaling was highly upregulated in the cell cycle arrest subpopulation and relatively downregulated in transdifferentiating cells. In cultured AEC2s, TGFβ was necessary for cell cycle arrest but impeded transdifferentiation. We conclude that during regeneration after LPS-induced lung injury, TGFβ is a critical signal halting AEC2 proliferation but must be inactivated to allow transdifferentiation. This study provides insight into the molecular mechanisms regulating alveolar regeneration and the pathogenesis of diseases resulting from a failure of regeneration.

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