Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells

Studies of monogenic diabetes are particularly useful because we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a form of monogenic diabetes caused by a mutation in the HNF4A gene. Human-induced pluripotent stem cells (hiPSC...

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Main Authors: Abadpour, S. (Author), Bjørlykke, Y. (Author), Carrasco, M. (Author), Chera, S. (Author), Ghabayen, J. (Author), Ghila, L.M (Author), Lyssenko, V. (Author), Nermoen, I. (Author), Njølstad, P. (Author), Paulo, J.A (Author), Ræder, H. (Author), Scholz, H. (Author), Søviknes, A.M (Author), Tjora, E. (Author), Vaudel, M. (Author), Wang, C. (Author)
Format: Article
Language:English
Published: NLM (Medline) 2022
Online Access:View Fulltext in Publisher
LEADER 02454nam a2200325Ia 4500
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008 220420s2022 CNT 000 0 und d
020 |a 1939327X (ISSN) 
245 1 0 |a Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells 
260 0 |b NLM (Medline)  |c 2022 
300 |a 8 
856 |z View Fulltext in Publisher  |u https://doi.org/10.2337/db20-1279 
520 3 |a Studies of monogenic diabetes are particularly useful because we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a form of monogenic diabetes caused by a mutation in the HNF4A gene. Human-induced pluripotent stem cells (hiPSCs) provide an excellent tool for disease modeling by subsequently directing differentiation toward desired pancreatic islet cells, but cellular phenotypes in terminally differentiated cells are notoriously difficult to detect. Re-creating a spatial (three-dimensional [3D]) environment may facilitate phenotype detection. We studied MODY1 by using hiPSC-derived pancreatic β-like patient and isogenic control cell lines in two different 3D contexts. Using size-adjusted cell aggregates and alginate capsules, we show that the 3D context is critical to facilitating the detection of mutation-specific phenotypes. In 3D cell aggregates, we identified irregular cell clusters and lower levels of structural proteins by proteome analysis, whereas in 3D alginate capsules, we identified altered levels of glycolytic proteins in the glucose sensing apparatus by proteome analysis. Our study provides novel knowledge on normal and abnormal function of HNF4A, paving the way for translational studies of new drug targets that can be used in precision diabetes medicine in MODY. © 2022 by the American Diabetes Association. 
700 1 0 |a Abadpour, S.  |e author 
700 1 0 |a Bjørlykke, Y.  |e author 
700 1 0 |a Carrasco, M.  |e author 
700 1 0 |a Chera, S.  |e author 
700 1 0 |a Ghabayen, J.  |e author 
700 1 0 |a Ghila, L.M.  |e author 
700 1 0 |a Lyssenko, V.  |e author 
700 1 0 |a Nermoen, I.  |e author 
700 1 0 |a Njølstad, P.  |e author 
700 1 0 |a Paulo, J.A.  |e author 
700 1 0 |a Ræder, H.  |e author 
700 1 0 |a Scholz, H.  |e author 
700 1 0 |a Søviknes, A.M.  |e author 
700 1 0 |a Tjora, E.  |e author 
700 1 0 |a Vaudel, M.  |e author 
700 1 0 |a Wang, C.  |e author 
773 |t Diabetes