Odd skipped-related 1 controls the pro-regenerative response of Fibro-Adipogenic Progenitors

Abstract

Skeletal muscle regeneration requires the coordinated interplay of diverse tissue-resident- and infiltrating cells. Fibro-adipogenic progenitors (FAPs) are an interstitial cell population that provides a beneficial microenvironment for muscle stem cells (MuSCs) during muscle regeneration. Here we show that the transcription factor Osr1 is essential for FAPs to communicate with MuSCs and infiltrating macrophages, thus coordinating muscle regeneration. Conditional inactivation of Osr1 impaired muscle regeneration with reduced myofiber growth and formation of excessive fibrotic tissue with reduced stiffness. Osr1-deficient FAPs acquired a fibrogenic identity with altered matrix secretion and cytokine expression resulting in impaired MuSC viability, expansion and differentiation. Immune cell profiling suggested a novel role for Osr1-FAPs in macrophage polarization. In vitro analysis suggested that increased TGFβ signaling and altered matrix deposition by Osr1-deficient FAPs actively suppressed regenerative myogenesis. In conclusion, we show that Osr1 is central to FAP function orchestrating key regenerative events such as inflammation, matrix secretion and myogenesis.

Aging impairs skeletal muscle regeneration by promoting fibro/fatty degeneration and inhibiting inflammation resolution via fibro-adipogenic progenitors

“…Aging and fibrotic scar tissue formation during muscle regeneration have been associated with altered muscle stiffness, somewhat resembling the reduced muscle stiffness we observed in our Postn -/- mice (Figure S2F) 12,23 . During muscle regeneration, a transient decrease in tissue stiffness at the injury site around 5-dpi, which subsequently rebounds to normal stiffness levels in fully regenerated muscle, has been reported recently 61 .…”

“…When disrupted, for instance through loss of Periostin, this results in a delay of the pro-to antiinflammatory switch within the post-injury myogenic niche and is also observed in aging muscle. The crosstalk between FAPs and muscle-resident immune cell subsets to sustain adequate muscle regeneration has been reported on before 23,[26][27][28] . Nevertheless, the exact mechanisms of interaction between FAPs and macrophage polarization associated with muscle regeneration capacity, and their alterations during the aging process, remain largely unknown.…”

“…Muscle injury repair requires complex interactions between different cell types residing within the stem cell niche 47 . For instance, extensive evidence exists for FAP-MuSC interactions to ensure successful myogenic regeneration 10,13–15,23,24,66 . Aging and other pathologies result in defective myogenesis due to stem cell niche dysfunction by inhibiting different aspects of myogenic stem cell maintenance, activation and differentiation 4 .…”

“…Besides their role in ECM remodeling, FAPs secrete trophic factors that control MuSC activation through different mechanisms 14,[21][22][23] and aged FAPs display an aberrant secretory profile of WISP1, BMP3b or SMOC2, among others, that reduce MuSCs' regeneration capacity 10,11,24 . The contribution of aging to FAPs' dysregulation and fibro/fatty infiltration in skeletal muscle remains less well understood.…”

Granular hydrogels improve myogenic invasion and repair after volumetric muscle loss

“…This is in line with the expected trajectory of myogenic regenerative response where satellite cell activation peaks in the early stages after injury and declines thereafter. To evaluate differentiation of myogenic progenitors into new myofibers, we next stained muscle sections with embryonic myosin heavy chain (eMHC) antibody that marks newly regenerated myofibers (55). As expected, eMHC+ myofibers were not observed in the sham group but were readily observed in other groups around the injury region at 1 and 4 week timepoints (Fig.…”