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Mesodermal iPSC–derived progenitor cells functionally regenerate cardiac and skeletal muscle
Mattia Quattrocelli, … , Stefan Janssens, Maurilio Sampaolesi
Mattia Quattrocelli, … , Stefan Janssens, Maurilio Sampaolesi
Published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4463-4482. https://doi.org/10.1172/JCI82735.
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Research Article Muscle biology Article has an altmetric score of 15

Mesodermal iPSC–derived progenitor cells functionally regenerate cardiac and skeletal muscle

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Abstract

Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles.

Authors

Mattia Quattrocelli, Melissa Swinnen, Giorgia Giacomazzi, Jordi Camps, Ines Barthélemy, Gabriele Ceccarelli, Ellen Caluwé, Hanne Grosemans, Lieven Thorrez, Gloria Pelizzo, Manja Muijtjens, Catherine M. Verfaillie, Stephane Blot, Stefan Janssens, Maurilio Sampaolesi

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Figure 1

Analysis of myogenic propensity of iPSCs in fetal chimeric tissues.

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Analysis of myogenic propensity of iPSCs in fetal chimeric tissues.
(A–H...
(A–H) Isogenic GFP+ f- and MAB-iPSCs contributed at comparable rates to chimeric morulae and blastocysts (A and B) and to chimeric fetuses (E14.5) and fertile adults (C and D). Rates of GFP+ chimeric embryos are reported for each stage (n = 5/iPSC line). However, immunofluorescence analysis of fetal tissues at E14.5 revealed comparable levels of GFP contribution to brain and liver (E and F) and unequal contribution levels (higher for MAB-iPSCs) to nascent somitic myofibers (G and H) (n = 6 embryos/iPSC type for fetal tissue analyses). Scale bars: ~50 μm (A and B) and ~100 μm (C–H). (I) At E14.5, qPCR analyses of dissected tissues from chimeric fetuses showed significantly higher GFP expression levels in the trunk muscles of MAB-iPSC chimeric fetuses compared with levels detected in f-iPSC chimeric fetuses (*P < 0.05, n ≥3/iPSC type, Mann-Whitney U test). Error bars represent SD. αFP, α-fetoprotein.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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