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胰蛋白酶介导胰腺祖细胞分化为功能性胰岛样簇的机制。

Mechanism of trypsin-mediated differentiation of pancreatic progenitor cells into functional islet-like clusters.

作者信息

Gao Ling, Lai Jia-Shuang, Chen Han, Qian Li-Xia, Hong Wan-Jin, Li Liang-Cheng

机构信息

Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China.

Department of Pharmacology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom.

出版信息

World J Diabetes. 2025 Jun 15;16(6):102727. doi: 10.4239/wjd.v16.i6.102727.

DOI:10.4239/wjd.v16.i6.102727
PMID:40548274
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12179872/
Abstract

BACKGROUND

Endogenous regeneration of pancreatic islet β-cells is a path to cure both type 1 and advanced type 2 diabetes. Pancreatic cancer cell line-1 (PANC-1), a human pancreatic islet progenitor cell line, can be induced by trypsin to differentiate into insulin-secreting islet-like aggregates (ILAs). However, the underlying mechanism has not been explored.

AIM

To explore the mechanism and signaling pathway of trypsin-induced differentiation of islet progenitor cells into insulin-secreting cells.

METHODS

PANC-1 cells were induced by trypsin to form ILAs and differentiate into insulin-secreting cells. Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 knockout and small interfering RNA knockdown techniques were used to investigate membrane proteins and downstream signaling pathways involved in the process.

RESULTS

The extracellular domain of membrane receptor E-cadherin hydrolyzed by trypsin induced the aggregation of PANC-1 cells and stimulated E-cadherin-recruited casein kinase-1γ3, which specifically phosphorylated the Ser655/Thr658 site of α-catenin in the cadherin-catenin complex, participating in the process of PANC-1 differentiation and affecting the maturation of differentiated ILAs.

CONCLUSION

The current study reveals the mechanism by which trypsin promotes PANC-1 cell differentiation into islet-like cells, providing a novel approach for endogenous islet β-cell regeneration.

摘要

背景

胰岛β细胞的内源性再生是治愈1型和晚期2型糖尿病的一条途径。胰腺癌细胞系-1（PANC-1），一种人胰岛祖细胞系，可被胰蛋白酶诱导分化为分泌胰岛素的胰岛样聚集体（ILA）。然而，其潜在机制尚未被探索。

目的

探索胰蛋白酶诱导胰岛祖细胞分化为胰岛素分泌细胞的机制和信号通路。

方法

用胰蛋白酶诱导PANC-1细胞形成ILA并分化为胰岛素分泌细胞。采用成簇规律间隔短回文重复序列（CRISPR）相关蛋白9敲除和小干扰RNA敲低技术研究该过程中涉及的膜蛋白和下游信号通路。

结果

胰蛋白酶水解膜受体E-钙黏蛋白的胞外结构域诱导PANC-1细胞聚集，并刺激E-钙黏蛋白招募的酪蛋白激酶-1γ3，其特异性磷酸化钙黏蛋白-连环蛋白复合物中α-连环蛋白的Ser655/Thr658位点，参与PANC-1分化过程并影响分化的ILA的成熟。

结论

本研究揭示了胰蛋白酶促进PANC-1细胞分化为胰岛样细胞的机制，为内源性胰岛β细胞再生提供了一种新方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/387c722d0efa/wjd-16-6-102727-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/e55bc46dc70a/wjd-16-6-102727-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/dd1190b88ed3/wjd-16-6-102727-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/c381d1a6aea8/wjd-16-6-102727-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/307a4789b0c3/wjd-16-6-102727-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/cd63ba87b0bb/wjd-16-6-102727-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/387c722d0efa/wjd-16-6-102727-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/e55bc46dc70a/wjd-16-6-102727-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/dd1190b88ed3/wjd-16-6-102727-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/c381d1a6aea8/wjd-16-6-102727-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/307a4789b0c3/wjd-16-6-102727-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/cd63ba87b0bb/wjd-16-6-102727-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fed9/12179872/387c722d0efa/wjd-16-6-102727-g006.jpg

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本文引用的文献

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Differentiation of Uc-MSCs into insulin secreting islet-like clusters by trypsin through TGF-beta signaling pathway.通过胰蛋白酶经转化生长因子-β信号通路将脐带间充质干细胞分化为分泌胰岛素的胰岛样簇。
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Fibronectin fragments generated by pancreatic trypsin act as endogenous inhibitors of pancreatic tumor growth.
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