Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived ß cells.
Cell Stem Cell
; 31(6): 850-865.e10, 2024 Jun 06.
Article
in En
| MEDLINE
| ID: mdl-38697109
ABSTRACT
Human pluripotent stem cell-derived ß cells (hPSC-ß cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-ß cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-ß 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-ß 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 ß cell maturation. Limiting intracellular accumulation of ceramides in hPSC-ß 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 ß cells and highlight the importance of ceramide homeostasis in function acquisition.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Differentiation
/
Ceramides
/
Pluripotent Stem Cells
/
Insulin-Secreting Cells
/
Homeostasis
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Stem Cell
Year:
2024
Document type:
Article