Gene-Edited Human Stem Cell-Derived β Cells From a Patient with Monogenic Diabetes Reverse Preexisting Diabetes in Mice
Publication: Science Translational Medicine | Publication Date: April 22, 2020
Authors: Kristina G. Maxwell, Punn Augsornworawat, Leonardo Velazco-Cruz, Michelle H. Kim, Rie Asada, Nathaniel J. Hogrebe, Shuntaro Morikawa, Fumihiko Urano, Jeffrey R. Millman
Abstract
Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Our results indicate that molecular pathways regulated by MANF are promising therapeutic targets for regenerative therapy of ER stress-related disorders, including diabetes, retinal degeneration, neurodegeneration, and Wolfram syndrome.
Introduction
Growing evidence indicates that endoplasmic reticulum (ER) stress plays a critical role in β cell death in type 1 and type 2 diabetes, as well as in neurodegenerative disorders, including Parkinson’s disease and amyotrophic lateral sclerosis [1,2,3,4,5]. Despite the underlying importance of ER stress in β cell death, there is currently no diabetes treatment targeting the ER due to the complex nature of type 1 and type 2 diabetes. Our strategy for overcoming this challenge is to focus on a monogenic form of diabetes, Wolfram syndrome. Wolfram syndrome is a rare disease characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, and neurodegeneration [6, 7]. As this syndrome is caused by mutations in the WFS1 gene which is involved in ER calcium homeostasis and ER stress-mediated cell death, it is ideal for testing potential new treatments targeting the ER [8,9,10,11,12,13,14].
Mahadevan, J., Morikawa, S., Yagi, T. et al. A soluble endoplasmic reticulum factor as regenerative therapy for Wolfram syndrome. Lab Invest 100, 1197–1207 (2020). Retrieved February 13, 2024, from https://doi.org/10.1038/s41374-020-0436-1.