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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 1

Stage-specific degeneration of chronically injured RC muscle.

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Stage-specific degeneration of chronically injured RC muscle.
(A–F) Repr...
(A–F) Representative H&E images of changes in normal skeletal muscle of RC (A) at the indicated time points after transection of the tendons and nerve (TTDN) and compared with sham-operated RC (B). (C) A short transition phase of significant increase in muscle cellularity was seen at 4 days after TTDN. Within 2 weeks transient muscle regeneration was accompanied by developing fatty infiltration of adipocytes (D, arrows). At 6 weeks (E) and 10 weeks (F) after TTDN, chronic muscle damage was characterized by severe muscle atrophy and increasing amounts of adipose tissue (arrows) and fibrosis (arrowheads). (G–L) Representative images of picrosirius red staining of collagen in sections of non-operated (G) and sham-operated RC (H) or 4 days (I), 2 weeks (J), 6 weeks (K), and 10 weeks (L) after TTDN. (M) Muscle regeneration at 2 weeks after TTDN is indicated by the presence of central multinuclei, non-atrophied myofibers (arrowheads) surrounding developing fat tissue (arrow) and fibrotic scar (f). (N) Lateral to medial imaging (from left to right) of H&E-stained RC sections at 2 weeks or 10 weeks after TTDN. Scale bars: 100 μm.

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