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MODY1 is a maturity-onset monogenic diabetes, caused by heterozygous mutations of the  HNF4A  gene. To date the cellular and molecular mechanisms leading to disease onset remain largely unknown. In this study, we demonstrate that insulin-positive cells can be generated  in vitro  from human induced pluripotent stem cells (hiPSCs) derived from patients carrying a non-sense  HNF4A  mutation, proving for the first time, that a human  HNF4A  mutation is neither blocking the expression of the insulin genes nor the development of insulin-producing cells  in vitro . However, regardless of the mutation or diabetes status, these insulin-producing cells are immature, a common downfall off most current β-cell differentiation protocols. To further address the immature state of the cells,  in vitro  differentiated cells and adult human islets were compared by global proteomic analysis. We report the predicted upstream regulators and signalling pathways characterizing the proteome landscape of each entity. Subsequently, we focused on the molecular components absent or misregulated in the  in vitro  differentiated cells, to probe the components involved in the deficient  in vitro  maturation towards fully functional β-cells. This analysis identified the modulation of key developmental signalling pathways representing potential targets for improving the efficiency of the current differentiation protocols.

Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells