生物
细胞生物学
诱导多能干细胞
平衡
干细胞
神经酰胺
胚胎干细胞
遗传学
细胞凋亡
基因
作者
Huijuan Hua,Yaqi Wang,Xiaofeng Wang,Shusen Wang,Yun-Lu Zhou,Yinan Liu,Zhen Liang,Huixia Ren,Lu Shen,Shuangshuang Wu,Yong Jiang,Ying Pu,Xiaojing Zheng,Chao Tang,Zhongyang Shen,Cheng Li,Yuanyuan Du,Hongkui Deng
标识
DOI:10.1016/j.stem.2024.04.010
摘要
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.
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