Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells.
Manuel CarrascoChencheng WangAnne M SøviknesYngvild BjørlykkeShadab AbadpourJoao A PauloErling TjoraPal Rasmus NjolstadJonas GhabayenIngrid NermoenValeriya LyssenkoSimona CheraLuiza M GhilaMarc VaudelHanne ScholzHelge RaederPublished in: Diabetes (2022)
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.
Keyphrases
- type diabetes
- cardiovascular disease
- single cell
- induced pluripotent stem cells
- cell therapy
- induced apoptosis
- glycemic control
- healthcare
- cell cycle arrest
- emergency department
- stem cells
- blood pressure
- cell death
- immune response
- oxidative stress
- cell proliferation
- endoplasmic reticulum stress
- transcription factor
- skeletal muscle
- insulin resistance
- case report
- quantum dots