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Cheung, Chun Wai

University of British Columbia

Muscle regeneration is a highly orchestrated process in which multiple tissue-resident and infiltrating cells actively participate to ensure optimal repair and functional recovery. More than a decade ago, we reported a muscle resident, non-myogenic mesenchymal stromal cell type which we termed fibroadipogenic progenitors (FAPs) for their ability to spontaneously differentiate into mature fibroblasts or adipocytes. FAPs regulate multiple aspects of muscle biology, including maintenance of basement membrane, provide trophic support for muscle satellite cells, and recruitment of immune cells in response to injury. Recently, advent in single cell technologies unveiled previously unappreciated heterogeneity within FAPs. We and others identified dipeptidyl peptidase 4 (Dpp4) as a putative marker for one of the FAP subsets that is present in homeostasis. In this study, we first demonstrated a robust flow cytometry workflow to purify DPP4⁺ FAPs from steady state skeletal muscles, and implemented a variety of biological assays to comprehensively characterize this FAP subset. DPP4⁺ FAPs are more proliferative, display a stronger capacity of undergoing adipogenic differentiation without sacrificing their fibrogenic potential, and have a higher frequency of colony forming units (CFUs), compared with their DPP4-negative counterparts. In vitro culturing further showed that DPP4⁺ FAPs are the precursors of DPP4⁻ FAPs, while DPP4⁻ FAPs have negligible contribution to DPP4⁺ FAPs. We also revealed a potential role of DPP4+ FAPs as a niche for a recently discovered population of LYVE1⁺ skeletal muscle self-renewing resident macrophages. Lastly, we employed a newly developed transgenic DPP4CreERT2 mouse model to ablate DPP4-expressing cells and showed that they are critical for survival. Together, this project provided a detailed description of a novel FAP subset that has important roles in steady state muscles.

Text

2023-08-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85752

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/