Inhibition of Notch activity promotes pancreatic cytokeratin 5-positive cell differentiation to beta cells and improves glucose homeostasis following acute pancreatitis

Xiaoyi Zhang,Weixing Wang,Jing Tao,Dongqi Chai,Zhigang Tang,Jiarui Feng,Xuanzhe Zhang,Guirong Wang,Jia Yu,Ning Hu,Man Li,Qiao Shi,Yuping Rong,Zhiyong Peng,Xingcheng Xiong,Hanjun Li

doi:10.1038/s41419-021-04160-2

Abstract

Some individuals develop prediabetes and/or diabetes following acute pancreatitis (AP). AP-induced beta-cell injury and the limited regenerative capacity of beta cells might account for pancreatic endocrine insufficiency. Previously, we found that only a few pancreatic cytokeratin 5 positive (Krt5+) cells differentiated into beta cells in the murine AP model, which was insufficient to maintain glucose homeostasis. Notch signaling determines pancreatic progenitor differentiation in pancreas development. This study aimed to examine whether Notch signaling inhibition could promote pancreatic Krt5+ cell differentiation into beta cells and improve glucose homeostasis following AP. Pancreatic tissues from patients with acute necrotizing pancreatitis (ANP) were used to evaluate beta-cell injury, Krt5+ cell activation and differentiation, and Notch activity. The murine AP model was induced by cerulein, and the effect of Notch inhibition on Krt5+ cell differentiation was evaluated both in vivo and in vitro. The results demonstrated beta-cell loss in ANP patients and AP mice. Krt5+ cells were activated in ANP pancreases along with persistently elevated Notch activity, which resulted in the formation of massive duct-like structures. AP mice that received Notch inhibitor showed that impaired glucose tolerance was reversed 7 and 15 days following AP, and increased numbers of newborn small islets due to increased differentiation of Krt5+ cells to beta cells to some extent. In addition, Krt5+ cells isolated from AP mice showed increased differentiation to beta cells by Notch inhibition. Collectively, these findings suggest that beta-cell loss contributes to pancreatic endocrine insufficiency following AP, and inhibition of Notch activity promotes pancreatic Krt5+ cell differentiation to beta cells and improves glucose homeostasis. The findings from this study may shed light on the potential treatment of prediabetes/diabetes following AP.

Highlights

Diabetes mellitus (DM) affectes over 300 million people worldwide and poses an enormous burden on society [1]
In the present study, we provided direct evidence of beta-cell loss with acute necrotizing pancreatitis (ANP) human specimens and an acute pancreatitis (AP) model, which contributes to pancreatic endocrine insufficiency following AP
We established for the first time that Krt5+ cells are activated in injured pancreases of ANP patients and AP mice, and can differentiate into functional beta cells

Summary

Introduction

Diabetes mellitus (DM) affectes over 300 million people worldwide and poses an enormous burden on society [1]. Unlike the exocrine pancreas, which possesses an extensive regenerative capacity, studies have indicated the limited capacity of beta-cell regeneration in the natural course of pancreatic diseases [6, 7]. Promoting beta-cell regeneration and the recovery of endocrine function following AP is of great importance. Among the strategies to promote beta-cell regeneration, facilitating beta-cell proliferation, converting other endocrine lineages to beta cells and seeking pancreatic stem cells or progenitors to stimulate the regeneration of beta cells in vivo appear to be reliable and promising [1, 8, 9]. Krt5+ cells have been demonstrated to play a role as stem cells and to facilitate regeneration in the lung and submandibular gland [10,11,12]. Strategies promoting Krt5+ cell differentiation to functional beta cells would be promising to avoid/delay the onset of DM following AP

Objectives

Methods

Results

Conclusion