The MicroRNA-92a/Sp1/MyoD Axis Regulates Hypoxic Stimulation of Myogenic Lineage Differentiation in Mouse Embryonic Stem Cells

Hypoxic microenvironments exist in developing embryonic tissues and determine stem cell fate. We previously demonstrated that hypoxic priming plays roles in lineage commitment of embryonic stem cells. In the present study, we found that hypoxia-primed embryoid bodies (Hyp-EBs) efficiently differenti...

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Published in:Molecular therapy 2020-01, Vol.28 (1), p.142-156
Main Authors: Lee, Seo-Yeon, Yang, Jimin, Park, Jung Hwa, Shin, Hwa Kyoung, Kim, Woo Jean, Kim, Su-Yeon, Lee, Eun Ju, Hwang, Injoo, Lee, Choon-Soo, Lee, Jaewon, Kim, Hyo-Soo
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Angiogenesis
Animals
Apoptosis
Binding sites
Cell differentiation
Cell Differentiation - genetics
Cell fate
Cell Hypoxia - genetics
Cell Lineage - genetics
Cells, Cultured
Embryo cells
embryoid bodies
Embryos
Gene expression
Gene Knockdown Techniques
Hypoxia
Hypoxia-inducible factor 1a
hypoxic microenvironment
Mice
Mice, Inbred C57BL
Microenvironments
microRNA
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
Mouse Embryonic Stem Cells - metabolism
Muscle Development - genetics
MyoD protein
MyoD Protein - metabolism
Myogenesis
myogenic differentiation
Original
Plasmids
Point mutation
Promoter Regions, Genetic
Proteins
Sp1 Transcription Factor - genetics
Sp1 Transcription Factor - metabolism
Stem cell transplantation
Stem cells
transcription factor
Transfection
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Summary:Hypoxic microenvironments exist in developing embryonic tissues and determine stem cell fate. We previously demonstrated that hypoxic priming plays roles in lineage commitment of embryonic stem cells. In the present study, we found that hypoxia-primed embryoid bodies (Hyp-EBs) efficiently differentiate into the myogenic lineage, resulting in the induction of the myogenic marker MyoD, which was not mediated by hypoxia-inducible factor 1α (HIF1α) or HIF2α, but rather by Sp1 induction and binding to the MyoD promoter. Knockdown of Sp1 in Hyp-EBs abrogated hypoxia-induced MyoD expression and myogenic differentiation. Importantly, in the cardiotoxin-muscle injury mice model, Hyp-EB transplantation facilitated muscle regeneration in vivo, whereas transplantation of Sp1-knockdown Hyp-EBs failed to do. Moreover, we compared microRNA (miRNA) expression profiles between EBs under normoxia versus hypoxia and found that hypoxia-mediated Sp1 induction was mediated by the suppression of miRNA-92a, which directly targeted the 3′ untranslated region (3′ UTR) of Sp1. Further, the inhibitory effect of miRNA-92a on Sp1 in luciferase assay was abolished by a point mutation in specific sequence in the Sp1 3′ UTR that is required for the binding of miRNA-92a. Collectively, these results suggest that hypoxic priming enhances EB commitment to the myogenic lineage through miR-92a/Sp1/MyoD regulatory axis, suggesting a new pathway that promotes myogenic-lineage differentiation. [Display omitted] Lee et al. describe the enhanced differentiation of hypoxia-primed embryoid bodies (EBs) into the myogenic lineage. Interestingly, this process was not mediated by HIF1α or HIF2α, but rather by Sp1 induction, via binding to the MyoD promoter. Moreover, the transplantation of hypoxia-primed EBs was found to facilitate muscle regeneration in vivo, and this was also found to depend on Sp1. By analyzing miRNA expression profiles, the authors demonstrate that hypoxia induced Sp1 in EBs via suppression of miRNA-92a that was found to directly target the 3′ UTR of Sp1.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2019.08.014