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Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells
- Source :
- Cell Stem Cell; June 2024, Vol. 31 Issue: 6 p850-865.e10
- Publication Year :
- 2024
-
Abstract
- Human pluripotent stem cell-derived β cells (hPSC-β cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-β cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-β cells post transplantation via single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we show that functional maturation of hPSC-β cells is an orderly multistep process during which cells sequentially undergo metabolic adaption, removal of negative regulators of cell function, and establishment of a more specialized transcriptome and epigenome. Importantly, remodeling lipid metabolism, especially downregulating the metabolic activity of ceramides, the central hub of sphingolipid metabolism, is critical for β cell maturation. Limiting intracellular accumulation of ceramides in hPSC-β cells remarkably enhanced their function, as indicated by improvements in insulin processing and glucose-stimulated insulin secretion. In summary, our findings provide insights into the maturation of human pancreatic β cells and highlight the importance of ceramide homeostasis in function acquisition.
Details
- Language :
- English
- ISSN :
- 19345909
- Volume :
- 31
- Issue :
- 6
- Database :
- Supplemental Index
- Journal :
- Cell Stem Cell
- Publication Type :
- Periodical
- Accession number :
- ejs66526045
- Full Text :
- https://doi.org/10.1016/j.stem.2024.04.010