posted on 2022-01-18, 20:20authored byAda AdminAda Admin, Manuel Carrasco, Chencheng Wang, Anne M. Søviknes, Yngvild Bjørlykke, Shadab Abadpour, Joao A. Paulo, Erling Tjora, Pål Njølstad, Jonas Ghabayen, Ingrid Nermoen, Valeriya Lyssenko, Simona Chera, Luiza M. Ghila, Marc Vaudel, Hanne Scholz, Helge Ræder
Studies of monogenic diabetes are particularly useful as we can gain
insight into the molecular events of pancreatic β-cell failure. Maturity-onset
diabetes of the young 1 (MODY1) is a monogenic diabetes form, caused by a
mutation in the HNF4A gene. Human induced
pluripotent stem cells (hiPSC) provide an excellent tool for disease modelling
by subsequent directed differentiation toward desired pancreatic islet cells,
but cellular phenotypes in terminally differentiated cells are notoriously
difficult to detect. Re-creating a spatial (3D) environment may facilitate
phenotype detection. In this study, we studied MODY1 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 showed
that the 3D context was critical to facilitate 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 of MODY.
Funding
Bergen Forskningsstiftelse BFS2014REK02 Diabetesforbundet Johan Selmer Kvanes legat NIH/NIGMS grant R01 GM132129 Norwegian Research Foundation 247577 Novo Nordisk Foundation NNF15OC0015054 Novo Nordisk Foundation Center for Basic Metabolic Research NNF17OC0027258 Research Council of Norway #262613 #301178 UiO:LifeScience Convergence environments II 247577 Western Norway Regional Health Authority 911985