Unraveling Alveolar Fibroblast and Activated Myofibroblast Heterogeneity and Differentiation Trajectories During Lung Fibrosis Development and Resolution in Young and Old Mice.
Arun Lingampally, Marin Truchi, Xianrong Shi, Yuqing Zhou, Esmeralda Vasquez-Pacheco, Georgios-Dimitrios Panagiotidis, Stefan Hadzic, Janine Koepke, Ana Ivonne Vazquez-Armendariz, Susanne Herold, Christos Samakovlis, Hector A Cabrera-Fuentes, Xuran Chu, Werner Seeger, Jin-San Zhang, Elie El Agha, Bernard Mari, Saverio Bellusci, Chengshui Chen
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引用次数: 0
Abstract
Idiopathic pulmonary fibrosis (IPF) is an age-associated disease characterized by the irreversible accumulation of excessive extracellular matrix components by activated myofibroblasts (aMYFs). Following bleomycin administration in young mice, fibrosis formation associated with efficient resolution takes place limiting the clinical relevance of this model for IPF. In this study, we used aged mice in combination with bleomycin administration to trigger enhanced fibrosis formation and delayed resolution as a more relevant model for IPF. Alveolosphere assays were carried out to compare the alveolar resident mesenchymal niche activity for AT2 stem cells in young versus old mice. Lineage tracing of the Acta2+ aMYFs in old mice exposed to bleomycin followed by scRNAseq of the lineage-traced cells isolated during fibrosis formation and resolution was performed to delineate the heterogeneity of aMYFs during fibrosis formation and their fate during resolution. Integration of previously published similar scRNAseq results using young mice was carried out. Our results show that alveolar resident mesenchymal cells from old mice display decreased supporting activity for AT2 stem cells. Our findings suggest that the cellular and molecular mechanisms underlying the aMYFs formation and differentiation towards the Lipofibroblast phenotype are mostly conserved between young and old mice. In addition to persistent fibrotic signaling in aMYF from old mice during resolution, we also identified differences linked to interleukin signaling in old versus young alveolar fibroblast populations before and during bleomycin injury. Importantly, our work confirms the relevance of a subcluster of aMYFs in old mice that is potentially relevant for future management of IPF.
Aging CellBiochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍:
Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health.
The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include:
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Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.