ArticleStem cell research & therapy2023
CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs.
Article in Stem cell research & therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 13 citations in OpenAlex.
- Scale up manufacturing approach for production of human induced pluripotent stem cell-derived islets using Vertical Wheel® bioreactors.NPJ Regenerative medicine · 2025Article
- Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming.Journal of molecular medicine (Berlin, Germany) · 2025Article
- Cyclin-dependent protein kinases and cell cycle regulation in biology and disease.Signal transduction and targeted therapy · 2025Review
- Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming.Research square · 2024Article
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTransplantation of differentiated cells from human-induced pluripotent stem cells (hiPSCs) holds great promise for clinical treatments. Eliminating the risk factor of malignant cell transformation is essential for ensuring the safety of such cells. This study was aimed at assessing and mitigating mutagenicity that may arise during the cell culture process in the protocol of pancreatic islet cell (iPIC) differentiation from hiPSCs.
methodsWe evaluated the mutagenicity of differentiation factors used for hiPSC-derived pancreatic islet-like cells (iPICs). We employed Ames mutagenicity assay, flow cytometry analysis, immunostaining, time-resolved fluorescence resonance energy transfer-based (TR-FRET) cell-free dose-response assays, single-cell RNA-sequencing and in vivo efficacy study.
resultsWe observed a mutagenic effect of activin receptor-like kinase 5 inhibitor II (ALK5iII). ALK5iII is a widely used β-cell inducer but no other tested ALK5 inhibitors induced β-cells. We obtained kinase inhibition profiles and found that only ALK5iII inhibited cyclin-dependent kinases 8 and 19 (CDK8/19) among all ALK5 inhibitors tested. Consistently, CDK8/19 inhibitors efficiently induced β-cells in the absence of ALK5iII. A combination treatment with non-mutagenic ALK5 inhibitor SB431542 and CDK8/19 inhibitor senexin B afforded generation of iPICs with in vitro cellular composition and in vivo efficacy comparable to those observed with ALK5iII.
conclusionOur findings suggest a new risk mitigation approach for cell therapy and advance our understanding of the β-cell differentiation mechanism.
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