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iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease modeling

Guo, Dongsheng
Daman, Katelyn
Chen, Jennifer Jc
Shi, Meng-Jiao
Yan, Jing
Matijasevic, Zdenka
Maehr, Rene
King, Oliver D.
Hayward, Lawrence J.
Emerson, Charles P. Jr.
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Abstract

Skeletal muscle myoblasts (iMyoblasts) were generated from human induced pluripotent stem cells (iPSCs) using an efficient and reliable transgene-free induction and stem cell selection protocol. Immunofluorescence, flow cytometry, qPCR, digital RNA expression profiling, and scRNA-Seq studies identify iMyoblasts as a PAX3+/MYOD1+ skeletal myogenic lineage with a fetal-like transcriptome signature, distinct from adult muscle biopsy myoblasts (bMyoblasts) and iPSC-induced muscle progenitors. iMyoblasts can be stably propagated for > 12 passages or 30 population doublings while retaining their dual commitment for myotube differentiation and regeneration of reserve cells. iMyoblasts also efficiently xenoengrafted into irradiated and injured mouse muscle where they undergo differentiation and fetal-adult MYH isoform switching, demonstrating their regulatory plasticity for adult muscle maturation in response to signals in the host muscle. Xenograft muscle retains PAX3+ muscle progenitors and can regenerate human muscle in response to secondary injury. As models of disease, iMyoblasts from individuals with Facioscapulohumeral Muscular Dystrophy revealed a previously unknown epigenetic regulatory mechanism controlling developmental expression of the pathological DUX4 gene. iMyoblasts from Limb-Girdle Muscular Dystrophy R7 and R9 and Walker Warburg Syndrome patients modeled their molecular disease pathologies and were responsive to small molecule and gene editing therapeutics. These findings establish the utility of iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease pathogenesis and for the development of muscle stem cell therapeutics.

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Guo D, Daman K, Chen JJ, Shi MJ, Yan J, Matijasevic Z, Rickard AM, Bennett MH, Kiselyov A, Zhou H, Bang AG, Wagner KR, Maehr R, King OD, Hayward LJ, Emerson CP Jr. iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease modeling. Elife. 2022 Jan 25;11:e70341. doi: 10.7554/eLife.70341. PMID: 35076017; PMCID: PMC8789283. Link to article on publisher's site

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10.7554/eLife.70341
PubMed ID
35076017
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Full author list omitted for brevity. For the full list of authors, see article.

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Copyright © 2022, Guo et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.