重塑神经酰胺平衡促进人类多能干细胞衍生β细胞的功能成熟

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING
Huijuan Hua, Yaqi Wang, Xiaofeng Wang, Shusen Wang, Yunlu Zhou, Yinan Liu, Zhen Liang, Huixia Ren, Sufang Lu, Shuangshuang Wu, Yong Jiang, Yue Pu, Xiang Zheng, Chao Tang, Zhongyang Shen, Cheng Li, Yuanyuan Du, Hongkui Deng
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引用次数: 0

摘要

人类多能干细胞衍生的β细胞(hPSC-β细胞)具有恢复优生血糖的潜力。然而,hPSC-β细胞的不成熟功能限制了其应用效果。在这里,我们通过单细胞RNA测序(scRNA-seq)和单细胞转座酶可获取染色质测序(scATAC-seq)分析,破解了移植后hPSC-β细胞的持续成熟过程,结果表明,hPSC-β细胞的功能成熟是一个有序的多步骤过程,在这一过程中,细胞依次经历了代谢适应、细胞功能负调控因子的去除以及更特化的转录组和表观基因组的建立。重要的是,重塑脂质代谢,尤其是下调神经酰胺(鞘脂代谢的核心枢纽)的代谢活性,对β细胞的成熟至关重要。限制神经酰胺在 hPSC-β 细胞内的积累可显著增强其功能,这体现在胰岛素处理和葡萄糖刺激的胰岛素分泌的改善上。总之,我们的研究结果为人类胰腺β细胞的成熟提供了见解,并强调了神经酰胺平衡在功能获得中的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells

Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells

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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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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