Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes

Show full item record



Permalink

http://hdl.handle.net/10138/288196

Citation

Balboa , D , Saarimäki-Vire , J , Borshagovski , D , Survila , M , Lindholm , P , Galli , E , Eurola , S , Ustinov , J , Grym , H , Huopio , H , Partanen , J , Wartiovaara , K & Otonkoski , T 2018 , ' Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes ' , eLife , vol. 7 , 38519 . https://doi.org/10.7554/eLife.38519

Title: Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes
Author: Balboa, Diego; Saarimäki-Vire, Jonna; Borshagovski, Daniel; Survila, Mantas; Lindholm, Päivi; Galli, Emilia; Eurola, Solja; Ustinov, Jarkko; Grym, Heli; Huopio, Hanna; Partanen, Juha; Wartiovaara, Kirmo; Otonkoski, Timo
Contributor: University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Helsinki Institute of Life Science HiLIFE, Joint Activities
University of Helsinki, Biosciences
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Molecular and Integrative Biosciences Research Programme
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
Date: 2018-11-09
Language: eng
Number of pages: 35
Belongs to series: eLife
ISSN: 2050-084X
URI: http://hdl.handle.net/10138/288196
Abstract: Insulin gene mutations are a leading cause of neonatal diabetes. They can lead to proinsulin misfolding and its retention in endoplasmic reticulum (ER). This results in increased ER-stress suggested to trigger beta-cell apoptosis. In humans, the mechanisms underlying beta-cell failure remain unclear. Here we show that misfolded proinsulin impairs developing beta-cell proliferation without increasing apoptosis. We generated induced pluripotent stem cells (iPSCs) from people carrying insulin (INS) mutations, engineered isogenic CRISPR-Cas9 mutation-corrected lines and differentiated them to beta-like cells. Single-cell RNA-sequencing analysis showed increased ER-stress and reduced proliferation in INS-mutant beta-like cells compared with corrected controls. Upon transplantation into mice, INS-mutant grafts presented reduced insulin secretion and aggravated ER-stress. Cell size, mTORC1 signaling, and respiratory chain subunits expression were all reduced in INS-mutant beta-like cells, yet apoptosis was not increased at any stage. Our results demonstrate that neonatal diabetes-associated INS-mutations lead to defective beta-cell mass expansion, contributing to diabetes development.
Subject: ENDOPLASMIC-RETICULUM STRESS
UNFOLDED PROTEIN RESPONSE
PANCREATIC PROGENITORS
MUTANT PROINSULIN
GENE-EXPRESSION
ER STRESS
IN-VITRO
REVEALS
DYSFUNCTION
GENERATION
3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
elife_38519_v2.pdf 8.514Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record