DOCUMENT
DATASET
1/1
Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells
figure
posted on 2022-01-18, 20:20 authored by Ada 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 RæderStudies 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.