Unlocking cellular plasticity: enhancing human iPSC reprogramming through bromodomain inhibition and extracellular matrix gene expression regulation

The transformation from a fibroblast mesenchymal cell state to an epithelial-like state is critical for induced pluripotent stem cell (iPSC) reprogramming. In this report, we describe studies with PFI-3, a small-molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 sub...

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Veröffentlicht in:Stem cells (Dayton, Ohio) Jg. 42; H. 8; S. 706
Hauptverfasser: Yang, Jun, Kinyamu, H Karimi, Ward, James M, Scappini, Erica, Muse, Ginger, Archer, Trevor K
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England 01.08.2024
Schlagworte:
Cell Plasticity - drug effects
Cell Plasticity - genetics
Cellular Reprogramming - drug effects
Cellular Reprogramming - genetics
Epithelial-Mesenchymal Transition - drug effects
Epithelial-Mesenchymal Transition - genetics
Extracellular Matrix - metabolism
Fibroblasts - cytology
Fibroblasts - metabolism
Gene Expression Regulation - drug effects
Humans
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
PFI-3
reprogramming efficiency
SWI/SNF
iPSC
cellular plasticity
bromodomain inhibitor
MET
extracellular matrix
ISSN:1549-4918, 1549-4918
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Zusammenfassung:The transformation from a fibroblast mesenchymal cell state to an epithelial-like state is critical for induced pluripotent stem cell (iPSC) reprogramming. In this report, we describe studies with PFI-3, a small-molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 subunits of SWI/SNF complex, as an enhancer of iPSC reprogramming efficiency. Our findings reveal that PFI-3 induces cellular plasticity in multiple human dermal fibroblasts, leading to a mesenchymal-epithelial transition during iPSC formation. This transition is characterized by the upregulation of E-cadherin expression, a key protein involved in epithelial cell adhesion. Additionally, we identified COL11A1 as a reprogramming barrier and demonstrated COL11A1 knockdown increased reprogramming efficiency. Notably, we found that PFI-3 significantly reduced the expression of numerous extracellular matrix (ECM) genes, particularly those involved in collagen assembly. Our research provides key insights into the early stages of iPSC reprogramming, highlighting the crucial role of ECM changes and cellular plasticity in this process.
Bibliographie:ObjectType-Article-1
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ISSN:1549-4918
1549-4918
DOI:10.1093/stmcls/sxae039