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

Abstract 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 ind...

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Autores principales:	Heidrun Vethe, Yngvild Bjørlykke, Luiza M. Ghila, Joao A. Paulo, Hanne Scholz, Steven P. Gygi, Simona Chera, Helge Ræder
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/91757cd6189546db8502a9227b934527
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spelling	oai:doaj.org-article:91757cd6189546db8502a9227b9345272021-12-02T11:40:50ZProbing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells10.1038/s41598-017-04979-w2045-2322https://doaj.org/article/91757cd6189546db8502a9227b9345272017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04979-whttps://doaj.org/toc/2045-2322Abstract 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.Heidrun VetheYngvild BjørlykkeLuiza M. GhilaJoao A. PauloHanne ScholzSteven P. GygiSimona CheraHelge RæderNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Heidrun Vethe Yngvild Bjørlykke Luiza M. Ghila Joao A. Paulo Hanne Scholz Steven P. Gygi Simona Chera Helge Ræder Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells
description	Abstract 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.
format	article
author	Heidrun Vethe Yngvild Bjørlykke Luiza M. Ghila Joao A. Paulo Hanne Scholz Steven P. Gygi Simona Chera Helge Ræder
author_facet	Heidrun Vethe Yngvild Bjørlykke Luiza M. Ghila Joao A. Paulo Hanne Scholz Steven P. Gygi Simona Chera Helge Ræder
author_sort	Heidrun Vethe
title	Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells
title_short	Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells
title_full	Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells
title_fullStr	Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells
title_full_unstemmed	Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells
title_sort	probing the missing mature β-cell proteomic landscape in differentiating patient ipsc-derived cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/91757cd6189546db8502a9227b934527
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Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells

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