内质网
医学
β细胞
糖尿病
未折叠蛋白反应
BETA(编程语言)
内科学
细胞生物学
内分泌学
生物
小岛
计算机科学
程序设计语言
作者
Ahmed Mohamed Rashwan,Mohamed M. A. Abumandour,Ramadan M. Kandyel,Om Prakash Choudhary,Rofaida Mostafa Soliman,Ashraf El Sharaby,Ahmed G. Nomir
标识
DOI:10.1097/js9.0000000000001148
摘要
Background: Immunodeficient mice models have become increasingly important as in vivo models engrafted with human cells or tissues for research. The NOD-Rag1 null Ins2 Akita Il2r null (NRG Akita) mice is a model combined with immunodeficient NRG and monogenic diabetes Akita mice that develop spontaneous hyperglycemia with progressive loss of pancreatic insulin-producing beta-cells with age. This model is one of the monogenic diabetic models, which has been providing a powerful platform for transplantation experiments of stem cells-generated human β-cells. This research aimed to provide insights into the mechanisms underlying this monogenic diabetes, which remains incompletely understood. Methods: Histological and immunofluorescence analyses were conducted on endocrine pancreatic islets to compare NRG wild-type (Wt) controls with NRG-Akita mice. Our investigation focused on assessing the expression of endocrine hormones, transcription factors, proliferation, ER stress, and apoptosis. Results: Histological analyses on NRG-Akita mice revealed smaller islets at 6-weeks-old, due to fewer β-cells in the islets, compared to NRG-Wt controls, which further progressed with age. The proliferation rate decreased, and apoptosis was abundant in β-cells in NRG Akita mice. Interestingly, our mechanistic analyses revealed that β-cells in NRG-Akita mice progressively accumulated the endoplasmic reticulum (ER) stresses, leading to a decreased expression of pivotal β-cell transcriptional factor PDX1. Conclusions: Altogether, our mechanistic insight into β-cell loss in this model could shed light on essential links between ER stress, proliferation, and cell identity, which might open the door to new therapeutic strategies for various diseases since ER stress is one of the most common features not only in diabetes but also in other degenerative diseases.
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