iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease modeling
© 2022, Guo et al..
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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2022 |
---|---|
Erschienen: |
2022 |
Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
---|---|
Enthalten in: |
eLife - 11(2022) vom: 25. Jan. |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Guo, Dongsheng [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 04.03.2022 Date Revised 05.04.2024 published: Electronic Citation Status MEDLINE |
---|
doi: |
10.7554/eLife.70341 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM336105150 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM336105150 | ||
003 | DE-627 | ||
005 | 20240405232747.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2022 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.7554/eLife.70341 |2 doi | |
028 | 5 | 2 | |a pubmed24n1366.xml |
035 | |a (DE-627)NLM336105150 | ||
035 | |a (NLM)35076017 | ||
035 | |a (PII)e70341 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Guo, Dongsheng |e verfasserin |4 aut | |
245 | 1 | 0 | |a iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease modeling |
264 | 1 | |c 2022 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 04.03.2022 | ||
500 | |a Date Revised 05.04.2024 | ||
500 | |a published: Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2022, Guo et al. | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a developmental biology | |
650 | 4 | |a human | |
650 | 4 | |a human ipsc myogenesis | |
650 | 4 | |a iMyoblasts | |
650 | 4 | |a mouse | |
650 | 4 | |a muscle stem cells | |
650 | 4 | |a regenerative medicine | |
650 | 4 | |a stem cells | |
650 | 4 | |a xenograft | |
650 | 7 | |a Dux4 protein, mouse |2 NLM | |
650 | 7 | |a Homeodomain Proteins |2 NLM | |
650 | 7 | |a PAX3 Transcription Factor |2 NLM | |
650 | 7 | |a Pax3 protein, mouse |2 NLM | |
650 | 7 | |a 138016-91-8 |2 NLM | |
700 | 1 | |a Daman, Katelyn |e verfasserin |4 aut | |
700 | 1 | |a Chen, Jennifer Jc |e verfasserin |4 aut | |
700 | 1 | |a Shi, Meng-Jiao |e verfasserin |4 aut | |
700 | 1 | |a Yan, Jing |e verfasserin |4 aut | |
700 | 1 | |a Matijasevic, Zdenka |e verfasserin |4 aut | |
700 | 1 | |a Rickard, Amanda M |e verfasserin |4 aut | |
700 | 1 | |a Bennett, Monica H |e verfasserin |4 aut | |
700 | 1 | |a Kiselyov, Alex |e verfasserin |4 aut | |
700 | 1 | |a Zhou, Haowen |e verfasserin |4 aut | |
700 | 1 | |a Bang, Anne G |e verfasserin |4 aut | |
700 | 1 | |a Wagner, Kathryn R |e verfasserin |4 aut | |
700 | 1 | |a Maehr, René |e verfasserin |4 aut | |
700 | 1 | |a King, Oliver D |e verfasserin |4 aut | |
700 | 1 | |a Hayward, Lawrence J |e verfasserin |4 aut | |
700 | 1 | |a Emerson, Charles P |c Jr |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t eLife |d 2012 |g 11(2022) vom: 25. Jan. |w (DE-627)NLM221831460 |x 2050-084X |7 nnns |
773 | 1 | 8 | |g volume:11 |g year:2022 |g day:25 |g month:01 |
856 | 4 | 0 | |u http://dx.doi.org/10.7554/eLife.70341 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 11 |j 2022 |b 25 |c 01 |