Non–fibro-adipogenic pericytes from human embryonic stem cells attenuate degeneration of the chronically injured mouse muscle
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
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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Research Article Muscle biology Stem cells

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

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 5

Transplanted LR-PCs but not FAPs diminish the development of fibrosis in chronically injured RC.

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Transplanted LR-PCs but not FAPs diminish the development of fibrosis in...
(A–F) Representative images of picrosirius red staining for collagen of RC sections at the indicated settings. (G) Red pixel intensity quantification of picrosirius red–stained sections of non-injured, sham-operated, and injured RC at 6 or 10 weeks after operation that were injected with saline, LR-PCs, or FAPs at the indicated time points. LR-PCs significantly inhibited the development of fibrosis in injured muscle when injected at 2 and 6 weeks after TTDN. FAPs significantly increased fibrosis at all time points of injection. Data are expressed as mean ± SEM; n = 3–4 mice per group, 5 picrosirius red–stained regions per RC section. *P < 0.05 compared with matched time points of saline injections after TTDN. #P < 0.005 between cell injected TTDN mice and matched sham cell injected mice. §P < 0.05 between LR-PC–injected TTDN mice and matched FAP–injected TTDN mice (1-way ANOVA). (H–J) Transplanted CM-DiI–labeled LR-PCs (H and I, red) did not contribute to fat tissue infiltration (H, dark green autofluorescence) and did not differentiate into α-SMA+ myofibroblasts when engrafted in fibrotic scar (I, red arrows). α-SMA (green) was expressed by perivascular cells of large blood vessels (H–J) and engrafted FAPs (yellow arrows, J). Scale bars: 100 μm (A–F), 50 μm (H–J).