Modeling different types of diabetes using human pluripotent stem cells
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Cellular and Molecular Life Sciences
REVIEW
Modeling different types of diabetes using human pluripotent stem cells Essam M. Abdelalim1,2 Received: 28 July 2020 / Revised: 19 October 2020 / Accepted: 11 November 2020 © Springer Nature Switzerland AG 2020
Abstract Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia as a result of progressive loss of pancreatic β cells, which could lead to several debilitating complications. Different paths, triggered by several genetic and environmental factors, lead to the loss of pancreatic β cells and/or function. Understanding these many paths to β cell damage or dysfunction could help in identifying therapeutic approaches specific for each path. Most of our knowledge about diabetes pathophysiology has been obtained from studies on animal models, which do not fully recapitulate human diabetes phenotypes. Currently, human pluripotent stem cell (hPSC) technology is a powerful tool for generating in vitro human models, which could provide key information about the disease pathogenesis and provide cells for personalized therapies. The recent progress in generating functional hPSC-derived β cells in combination with the rapid development in genomic and genome-editing technologies offer multiple options to understand the cellular and molecular mechanisms underlying the development of different types of diabetes. Recently, several in vitro hPSC-based strategies have been used for studying monogenic and polygenic forms of diabetes. This review summarizes the current knowledge about different hPSC-based diabetes models and how these models improved our current understanding of the pathophysiology of distinct forms of diabetes. Also, it highlights the progress in generating functional β cells in vitro, and discusses the current challenges and future perspectives related to the use of the in vitro hPSC-based strategies. Keywords hPSCs · Diabetes · Pathogenesis · β cells · Insulin · Genome editing · Precision medicine Abbreviations C-PEP C-PEPTIDE Ctr-iPSCs Control iPSCs DE Definitive endoderm DM Diabetes mellitus ER Endoplasmic reticulum GSIS Glucose-stimulated insulin secretion GWAS Genome-wide association studies hESCs Human embryonic stem cells Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03710-9) contains supplementary material, which is available to authorized users. * Essam M. Abdelalim [email protected] 1
Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Education City, Doha, Qatar
2
INS Insulin INSR Insulin receptor iPSCs Induced pluripotent stem cells IR Insulin resistance KO Knockout MD Monogenic diabetes NDM Neonatal diabetes mellitus ND Non-diabetic PBMCs Peripheral blood mononuclear cells PNDM Permanent neonatal diabetes RNA-seq High-throughput R
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