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CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs

ABSTRACT: CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs

PROVIDER: PRJNA888999 | ENA |

REPOSITORIES: ENA

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CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs

Project description:In this study, we demonstrate that we can obtain human iPSC-derived pancreatic islet-like cells (iPICs) with comparable transcriptomic profile by using a combination of an ALK5 inhibitor and a CDK8/19 inhibitor, instead of utilizing ALK5 inhibitor II.

2022-12-08 | GSE215152 | GEO

CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs.

Project description: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.

| S-EPMC9814340 | biostudies-literature

ARID1A plays an important role in skin inflammation.

Project description:ARID1A plays an important role in skin inflammation.

| PRJNA966998 | ENA

Peroxidase plays important roles in soybean tolerance to Al toxicity

Project description:Peroxidase plays important roles in soybean tolerance to Al toxicity

| PRJNA480265 | ENA

RNA-binding activity plays an important role in MYC function

Project description:RNA-binding activity plays an important role in MYC function

| PRJNA1062072 | ENA

Transcriptomic analysis of the effects of expression of CDK8/CDK19 and their kinase-inactive mutants in HEK293 cells (WT) and their CDK8/19 double-knockout (dKO) derivatives

Project description:RNA-Seq analysis was carried out to investigate the effects of expression of wild-type CDK8 (CDK8) or CDK19 (CDK19) or their kinase-inactive D173A mutants (CDK8M and CDK19M) in HEK293 cells (WT) and their CDK8/19 double-knockout (dKO) derivatives

2023-06-30 | GSE200753 | GEO

MtBZR1 plays an important role in nodule development in Medicago truncatula

Project description:MtBZR1 plays an important role in nodule development in Medicago truncatula

| PRJNA545836 | ENA

Gene Expresssion Analysis of Myometrium Stem Cells Treated with CDK8/19 Inhibitor

Project description:We report the gene expression changes in myometrial stem cells after 3hr treatment with CDK8/19 inhibitor (CCT251545).

2021-07-07 | GSE179494 | GEO

Effects of CDK8/19 Mediator Kinase inhibition by Senexin B on gene expression in HEK293 cells

Project description:RNA-Seq analysis was carried out to investigate the effects of selective CDK8/19 inhibitor Senexin B on gene expression in HEK293 cells (293-WT) or the CDK8/19 double-knockout (293-dKO) derivatives.

2023-06-30 | GSE221160 | GEO

CDK8/19 small molecule inhibition promotes naïve features in human and mouse pluripotent stem cells II

Project description:Pluripotent stem cells (PSCs) can transition between cell states in vitro, closely reflecting developmental changes in the early embryo. PSCs can be stabilized in their naive state by blocking extracellular differentiation stimuli, particularly FGF5 MEK signaling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF-MEK-signaling. Mechanistically, chemical inhibition of CDK8 and CDK19 kinases (CDK8/19i) removes their ability to repress the Mediator complex at enhancers. Thus CDK8/19i increases Mediator-driven recruitment of RNA Pol II to promoters and enhancers. This efficiently stabilizes the naive transcriptional program, and confers resistance to enhancer perturbation by BRD4 inhibition. Moreover, naive pluripotency during embryonic development coincides with reduction in CDK8/19. We conclude that global hyperactivation of enhancers drives naive pluripotency, and this can be captured in-vitro by inhibiting extracellular FGF-MEK-signaling, or downstream, by CDK8/19i. These principles may apply to other contexts of cellular plasticity.

2021-05-06 | GSE152378 | GEO

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