2. Academic Validation
  3. The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2

The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2

  • Cell Rep. 2023 Oct 10;42(10):113222. doi: 10.1016/j.celrep.2023.113222.
Chiara Ninfali 1,  Laura Siles 1,  Anna Esteve-Codina 2,  Antonio Postigo 3
Affiliations

Affiliations

  • 1 Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036 Barcelona, Spain.
  • 2 National Center of Genomic Analysis (CNAG), 08028 Barcelona, Spain.
  • 3 Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036 Barcelona, Spain; Molecular Targets Program, J.G. Brown Center, Louisville University Healthcare Campus, Louisville, KY 40202, USA; ICREA, 08010 Barcelona, Spain. Electronic address: [email protected].
PMID: 37819755 DOI: 10.1016/j.celrep.2023.113222
Abstract

Human embryonic stem cells (hESCs) can differentiate into any cell lineage. Here, we report that ZEB1 and ZEB2 promote and inhibit mesodermal-to-myogenic specification of hESCs, respectively. Knockdown and/or overexpression experiments of ZEB1, ZEB2, or PAX7 in hESCs indicate that ZEB1 is required for hESC Nodal/Activin-mediated mesodermal specification and PAX7+ human myogenic progenitor (hMuP) generation, while ZEB2 inhibits these processes. ZEB1 downregulation induces neural markers, while ZEB2 downregulation induces mesodermal/myogenic markers. Mechanistically, ZEB1 binds to and transcriptionally activates the PAX7 promoter, while ZEB2 binds to and activates the promoter of the neural OTX2 marker. Transplanting ZEB1 or ZEB2 knocked down hMuPs into the muscles of a muscular dystrophy mouse model, showing that hMuP engraftment and generation of dystrophin-positive myofibers depend on ZEB1 and are inhibited by ZEB2. The mouse model results suggest that ZEB1 expression and/or downregulating ZEB2 in hESCs may also enhance hESC regenerative capacity for human muscular dystrophy therapy.

Keywords

CP: Developmental biology; CP: Stem cell research; EMT; OTX2; PAX7; ZEB1 and ZEB2; cellular therapy; epithelial-to-mesenchymal transition; hESC; hESCs differentiation; human embryonic stem cells; mesodermal precursors; myogenic precursors.

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