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Non–fibro-adipogenic pericytes from human embryonic stem cells attenuate degeneration of the chronically injured mouse muscle
Gina M. Mosich, … , Frank A. Petrigliano, Ayelet Dar
Gina M. Mosich, … , Frank A. Petrigliano, Ayelet Dar
Published December 19, 2019
Citation Information: JCI Insight. 2019;4(24):e125334. https://doi.org/10.1172/jci.insight.125334.
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Research Article Muscle biology Stem cells

Non–fibro-adipogenic pericytes from human embryonic stem cells attenuate degeneration of the chronically injured mouse muscle

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Abstract

Massive tears of the rotator cuff (RC) are associated with chronic muscle degeneration due to fibrosis, fatty infiltration, and muscle atrophy. The microenvironment of diseased muscle often impairs efficient engraftment and regenerative activity of transplanted myogenic precursors. Accumulating myofibroblasts and fat cells disrupt the muscle stem cell niche and myogenic cell signaling and deposit excess disorganized connective tissue. Therefore, restoration of the damaged stromal niche with non–fibro-adipogenic cells is a prerequisite to successful repair of an injured RC. We generated from human embryonic stem cells (hES) a potentially novel subset of PDGFR-β+CD146+CD34–CD56– pericytes that lack expression of the fibro-adipogenic cell marker PDGFR-α. Accordingly, the PDGFR-β+PDGFR-α– phenotype typified non–fibro-adipogenic, non-myogenic, pericyte-like derivatives that maintained non–fibro-adipogenic properties when transplanted into chronically injured murine RCs. Although administered hES pericytes inhibited developing fibrosis at early and late stages of progressive muscle degeneration, transplanted PDGFR-β+PDGFR-α+ human muscle-derived fibro-adipogenic progenitors contributed to adipogenesis and greater fibrosis. Additionally, transplanted hES pericytes substantially attenuated muscle atrophy at all tested injection time points after injury. Coinciding with this observation, conditioned medium from cultured hES pericytes rescued atrophic myotubes in vitro. These findings imply that non–fibro-adipogenic hES pericytes recapitulate the myogenic stromal niche and may be used to improve cell-based treatments for chronic muscle disorders.

Authors

Gina M. Mosich, Regina Husman, Paras Shah, Abhinav Sharma, Kevin Rezzadeh, Temidayo Aderibigbe, Vivian J. Hu, Daniel J. McClintick, Genbin Wu, Jonathan D. Gatto, Haibin Xi, April D. Pyle, Bruno Péault, Frank A. Petrigliano, Ayelet Dar

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Figure 6

Transplanted LR-PCs maintained non-adipogenic properties and did not affect adipocyte content in chronically injured RC.

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Transplanted LR-PCs maintained non-adipogenic properties and did not aff...
H&E staining of RC sections demonstrated that injured muscle undergoes prominent morphological change from fat-free tissue characteristic of non-injured (A) or sham-operated muscle at 10 weeks after surgery (B) to atrophied muscle with robust fatty infiltration in non-injected (C and D), LR-PC–injected (E and F), and FAP-injected (G and H) RC at 6 weeks (C, E, and G) and 10 weeks (D, F, and H) after TTDN. (I) Quantification of adipocyte numbers in H&E-stained RC tissue sections. Data are expressed as mean ± SEM; n = 3–5 mice per group, 5 adipocyte containing regions per RC section. *P < 0.005 sham LR-PC– or FAP-injected mice in comparison with matched time points of saline or cell injections after TTDN. #P < 0.05 compared with FAP injected mice at 4 days after TTDN (1-way ANOVA). (J and K) CM-DiI (red) labels engrafted LR-PC in interstitial spaces but not fat tissue–repopulating adipocytes (K); white arrows indicate CM-DiI– adipocytes). (L) FAP-derived CM-DiI+ adipocytes (arrows) in injured RC. (Blue nuclear staining for DAPI.) A, adipocyte. Scale bars: 100 μm (A–H), 50 μm (J), and 20 μm (K and L).

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