Gao L, Lai JS, Chen H, Qian LX, Hong WJ, Li LC. Mechanism of trypsin-mediated differentiation of pancreatic progenitor cells into functional islet-like clusters. World J Diabetes 2025; 16(6): 102727 [DOI: 10.4239/wjd.v16.i6.102727]
Corresponding Author of This Article
Liang-Cheng Li, PhD, Professor, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, No. 4221-115 Xiangan South Road, Xiangan District, Xiamen 361102, Fujian Province, China. lchli2013@xmu.edu.cn
Research Domain of This Article
Cell & Tissue Engineering
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Diabetes. Jun 15, 2025; 16(6): 102727 Published online Jun 15, 2025. doi: 10.4239/wjd.v16.i6.102727
Mechanism of trypsin-mediated differentiation of pancreatic progenitor cells into functional islet-like clusters
Ling Gao, Jia-Shuang Lai, Han Chen, Li-Xia Qian, Wan-Jin Hong, Liang-Cheng Li
Ling Gao, Jia-Shuang Lai, Li-Xia Qian, Wan-Jin Hong, Liang-Cheng Li, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
Han Chen, Department of Pharmacology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom
Co-corresponding authors: Wan-Jin Hong and Liang-Cheng Li.
Author contributions: Gao L and Lai JS designed the study, conducted the experiments, and drafted the manuscript; Chen H reviewed the manuscript; Qian LX researched the data; Hong WJ and Li LC conceived the project, designed the experiments, reviewed the results, and wrote the manuscript.
Supported by the National Natural Science Foundation of China, No. 82073908.
Institutional review board statement: This study does not involve any human experiments, as is based on previous experiments, we conducted mechanistic studies using pancreatic cancer cell lines with pancreatic progenitor/progenitor cell properties.
Institutional animal care and use committee statement: This manuscript does not involve animal experiments.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The datasets generated from the current study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Liang-Cheng Li, PhD, Professor, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, No. 4221-115 Xiangan South Road, Xiangan District, Xiamen 361102, Fujian Province, China. lchli2013@xmu.edu.cn
Received: October 28, 2024 Revised: January 20, 2025 Accepted: March 28, 2025 Published online: June 15, 2025 Processing time: 229 Days and 11.2 Hours
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.
Core Tip: Trypsin induced pancreatic cancer cell line-1 cell differentiation into insulin-producing cells. Loss of E-cadherin, αE-catenin, and casein kinase-1γ3 (CK1γ3) blocked trypsin-induced differentiation. Hydrolysis of E-cadherin by trypsin recruited CK1γ3. CK1γ3 phosphorylated αE-catenin at Ser655/Thr658.
