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Published on: November 18, 2009
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Selective GSK3α Inhibition Promotes Self-Renewal Across Different Stem Cell States.
Duo Wang1, Xiukun Wang2, Shuling Wang3
1Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Biorxiv : the Preprint Server for Biology
|June 4, 2025
Summary
Selective inhibition of GSK3α with BRD0705 promotes stem cell self-renewal independently of WNT/β-catenin signaling. This approach, combined with IWR1, maintains diverse stem cell states and enables co-culture of naive and primed cells.
Area of Science:
- Stem cell biology
- Molecular and Cellular Biology
- Developmental Biology
Background:
- Pan-GSK3α/β inhibition promotes stem cell self-renewal via WNT/β-catenin signaling.
- Broad GSK3 inhibition complicates precise control of stem cell states.
Purpose of the Study:
- To investigate the effects of selective GSK3α inhibition on stem cell self-renewal.
- To establish a culture system for maintaining diverse pluripotent stem cell states.
Main Methods:
- Selective GSK3α inhibition using BRD0705.
- Combination therapy with tankyrase inhibitor IWR1.
- Single-cell transcriptomics, epigenomic profiling, and functional assays.
Main Results:
- BRD0705 supports long-term self-renewal of mouse embryonic stem cells (ESCs), epiblast stem cells (EpiSCs), and neural stem cells (NSCs) independent of β-catenin.
- The BRD0705/IWR1 cocktail maintains diverse pluripotent stem cell states (ESCs, EpiSCs, formative), enabling co-culture of naive and primed cells while preserving identities.
- Single-cell analyses confirmed sustained lineage-specific features across stem cell types.
Conclusions:
- Selective GSK3α inhibition enhances stemness by promoting intrinsic self-renewal capacity and buffering against differentiation.
- GSK3α is identified as a key regulator of self-renewal across distinct stem cell states.
- A versatile culture system for broad stem cell applications is established.
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