Mesenchymal Stromal Cells Are Required for Regeneration and Homeostatic Maintenance of Skeletal Muscle

The necessity of mesenchymal stromal cells, called fibroadipogenic progenitors (FAPs), in skeletal muscle regeneration and maintenance remains unestablished. We report the generation of a PDGFRαCreER knockin mouse model that provides a specific means of labeling and targeting FAPs. Depletion of FAPs...

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Vydáno v:Cell reports (Cambridge) Ročník 27; číslo 7; s. 2029 - 2035.e5
Hlavní autoři: Wosczyna, Michael N., Konishi, Colin T., Perez Carbajal, Edgar E., Wang, Theodore T., Walsh, Rachel A., Gan, Qiang, Wagner, Mark W., Rando, Thomas A.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 14.05.2019
Elsevier
Témata:
3T3 Cells
Animals
FAP
fibroadipogenic progenitor
Homeostasis
local recombination
Mesenchymal
Mesenchymal Stem Cells - metabolism
Mice
Mice, Transgenic
muscle
Muscle Development
Muscle, Skeletal
niche
PDGFRα
Regeneration
satellite cell
stem cell
stromal
PDGFRα
stromal
satellite cell
FAP
stem cell
local recombination
fibroadipogenic progenitor
muscle
niche
Mesenchymal
ISSN:2211-1247, 2211-1247
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Shrnutí:The necessity of mesenchymal stromal cells, called fibroadipogenic progenitors (FAPs), in skeletal muscle regeneration and maintenance remains unestablished. We report the generation of a PDGFRαCreER knockin mouse model that provides a specific means of labeling and targeting FAPs. Depletion of FAPs using Cre-dependent diphtheria toxin expression results in loss of expansion of muscle stem cells (MuSCs) and CD45+ hematopoietic cells after injury and impaired skeletal muscle regeneration. Furthermore, FAP-depleted mice under homeostatic conditions exhibit muscle atrophy and loss of MuSCs, revealing that FAPs are required for the maintenance of both skeletal muscle and the MuSC pool. We also report that local tamoxifen metabolite delivery to target CreER activity in a single muscle, removing potentially confounding systemic effects of ablating PDGFRα+ cells distantly, also causes muscle atrophy. These data establish a critical role of FAPs in skeletal muscle regeneration and maintenance. [Display omitted] •A method to target or deplete FAPs locally in skeletal muscle is described•Depletion of FAPs results in a regenerative deficit in skeletal muscle•Depletion of FAPs results in skeletal muscle atrophy•MuSC number declines in muscles in which FAPs have been depleted Wosczyna et al. develop genetic models to target and deplete fibroadipogenic progenitors (FAPs) in skeletal muscle (SkM). Following injury of FAP-depleted SkM, muscle stem cell (MuSC) expansion is impaired, leading to a regenerative deficit. Under homeostatic conditions, FAP-depleted SkM undergoes muscle fiber atrophy, and MuSC numbers decline.
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content type line 23
M.N.W. designed and oversaw all experiments. T.A.R. provided guidance throughout. M.N.W., C.T.K., E.E.P.C., T.T.W., Q.G., R.A.W., and M.W.W. planned and performed experiments and interpreted results. M.N.W. and T.A.R. interpreted experimental results and wrote the manuscript.
AUTHOR CONTRIBUTIONS
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2019.04.074