The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2
Summary: 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 r...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-10-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723012342 |
| _version_ | 1797660290310995968 |
|---|---|
| author | Chiara Ninfali Laura Siles Anna Esteve-Codina Antonio Postigo |
| author_facet | Chiara Ninfali Laura Siles Anna Esteve-Codina Antonio Postigo |
| author_sort | Chiara Ninfali |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-11T18:28:38Z |
| format | Article |
| id | doaj.art-1f9f4cdb9d314484899e60d76dfee739 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-11T18:28:38Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1f9f4cdb9d314484899e60d76dfee7392023-10-13T13:53:24ZengElsevierCell Reports2211-12472023-10-014210113222The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2Chiara Ninfali0Laura Siles1Anna Esteve-Codina2Antonio Postigo3Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036 Barcelona, SpainGroup of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036 Barcelona, SpainNational Center of Genomic Analysis (CNAG), 08028 Barcelona, SpainGroup 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; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723012342CP: Stem cell researchCP: Developmental biology |
| spellingShingle | Chiara Ninfali Laura Siles Anna Esteve-Codina Antonio Postigo The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2 Cell Reports CP: Stem cell research CP: Developmental biology |
| title | The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2 |
| title_full | The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2 |
| title_fullStr | The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2 |
| title_full_unstemmed | The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2 |
| title_short | The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2 |
| title_sort | mesodermal and myogenic specification of hescs depend on zeb1 and are inhibited by zeb2 |
| topic | CP: Stem cell research CP: Developmental biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723012342 |
| work_keys_str_mv | AT chiaraninfali themesodermalandmyogenicspecificationofhescsdependonzeb1andareinhibitedbyzeb2 AT laurasiles themesodermalandmyogenicspecificationofhescsdependonzeb1andareinhibitedbyzeb2 AT annaestevecodina themesodermalandmyogenicspecificationofhescsdependonzeb1andareinhibitedbyzeb2 AT antoniopostigo themesodermalandmyogenicspecificationofhescsdependonzeb1andareinhibitedbyzeb2 AT chiaraninfali mesodermalandmyogenicspecificationofhescsdependonzeb1andareinhibitedbyzeb2 AT laurasiles mesodermalandmyogenicspecificationofhescsdependonzeb1andareinhibitedbyzeb2 AT annaestevecodina mesodermalandmyogenicspecificationofhescsdependonzeb1andareinhibitedbyzeb2 AT antoniopostigo mesodermalandmyogenicspecificationofhescsdependonzeb1andareinhibitedbyzeb2 |