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Babaeijandaghi, Farshad

University of British Columbia

Fibrosis causes nearly 45% of all deaths in industrialized nations. Currently, no efficient antifibrotic therapy exists. Detailed understanding of the mechanisms governing efficient tissue regeneration and of how they go awry in fibrotic pathologies will likely inform therapeutic approaches. The remarkable healing capacity of skeletal muscle and development of rodent models for muscular dystrophies, in which fibrosis is a common outcome, makes skeletal muscle an excellent candidate to study tissue regeneration and fibrosis. In contrast to infiltrating macrophages, the role of tissue resident macrophages (RMs) during regeneration or fibrosis is not well-understood, mainly due to the lack of a specific marker for their identification. In the first part of this study, using a combination of parabiosis, lineage tracing, and single-cell transcriptomics we identified a population of muscle resident LYVE1+TIM4+ macrophages that locally self-renew (self-renewing resident macrophages, SRRMs). Using a Colony Stimulating Factor 1 Receptor (CSF1R) inhibition/withdrawal approach to specifically deplete SRRMs, we showed that SRRMs provide a non-redundant function in clearing damage-induced apoptotic cells. We further found that depletion of RMs through CSF1R inhibition changed muscle fiber composition from damage-sensitive glycolytic fibers towards damage-resistant oxidative fibers, protecting dystrophic muscle against contraction induced injury. This finding has therapeutic potential in light of the ongoing clinical testing of CSF1R inhibitors. As a well-known pro-inflammatory cytokine with diverse roles in antimicrobial and antitumor immunity, a small amount of conflicting evidence exists regarding the source and function of IFNγ during the regeneration process following a sterile injury. In the second part of this study, we showed that a population of natural killer cells is the main source of IFNγ in regenerating muscle. We found that the absence of IFNγ per se has no effect on regeneration. However, the role of IFNγ gets unmasked when TNFα is neutralized. Using three different transgenic mice strains to conditionally deplete the IFNγ receptor 1 on the surface of satellite cells, fibro-adipogenic progenitors (FAPs), or macrophages, we found that IFNγ acts through macrophages and FAPs to support muscle regeneration. In contrast to the common belief, we found that IFNγ peaks when pro-inflammatory macrophages are switching to an anti-inflammatory phenotype.

Text

2023-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/79414

Experimental Medicine

University of British Columbia

UBCV

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