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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human
human ipsc myogenesis
iMyoblasts
mouse
muscle stem cells
regenerative medicine
stem cells
xenograft
Cell Biology
Cellular and Molecular Physiology
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Developmental Biology
Disease Modeling
Musculoskeletal Diseases
Nervous System Diseases
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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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Full author list omitted for brevity. For the full list of authors, see article.