title: Resveratrol ameliorates the maturation process of β-cell-like cells obtained from an optimized differentiation protocol of human embryonic stem cells.
abstract: Human embryonic stem cells (hESCs) retain the extraordinary capacity to differentiate into different cell types of an adult organism, including pancreatic β-cells. For this particular lineage, although a lot of effort has been made in the last ten years to achieve an efficient and reproducible differentiation protocol, it was not until recently that this aim was roughly accomplished. Besides, several studies evidenced the impact of resveratrol (RSV) on insulin secretion, even though the mechanism by which this polyphenol potentiates glucose-stimulated insulin secretion (GSIS) is still not clear. The aim of this study was to optimize an efficient differentiation protocol that mimics in vivo pancreatic organogenesis and to investigate whether RSV may improve the final maturation step to obtain functional insulin-secreting cells. Our results indicate that treatment of hESCs (HS-181) with activin-A induced definitive endoderm differentiation as detected by the expression of SOX17 and FOXA2. Addition of retinoic acid (RA), Noggin and Cyclopamine promoted pancreatic differentiation as indicated by the expression of the early pancreatic progenitor markers ISL1, NGN3 and PDX1. Moreover, during maturation in suspension culture, differentiating cells assembled in islet-like clusters, which expressed specific endocrine markers such as PDX1, SST, GCG and INS. Similar results were confirmed with the human induced Pluripotent Stem Cell (hiPSC) line MSUH-001. Finally, differentiation protocols incorporating RSV treatment yielded numerous insulin-positive cells, induced significantly higher PDX1 expression and were able to transiently normalize glycaemia when transplanted in streptozotocin (STZ) induced diabetic mice thus promoting its survival. In conclusion, our strategy allows the efficient differentiation of hESCs into pancreatic endoderm capable of generating β-cell-like cells and demonstrates that RSV improves the maturation process.
authors.affiliation: Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER)-Fundación Progreso y Salud (FPS), Sevilla, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pezzolla
authors.affiliation: Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER)-Fundación Progreso y Salud (FPS), Sevilla, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: López-Beas
authors.affiliation: Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER)-Fundación Progreso y Salud (FPS), Sevilla, Spain.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Lachaud
authors.affiliation: Cardiovascular Pathophysiology, Institute of Biomedicine of Seville (IBIS), Sevilla, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Domínguez-Rodríguez
authors.affiliation: Cardiovascular Pathophysiology, Institute of Biomedicine of Seville (IBIS), Sevilla, Spain.
authors.forename: Tarik
authors.initials: T
authors.lastname: Smani
authors.affiliation: Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER)-Fundación Progreso y Salud (FPS), Sevilla, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Hmadcha
authors.affiliation: Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER)-Fundación Progreso y Salud (FPS), Sevilla, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
authors.forename: Bernat
authors.initials: B
authors.lastname: Soria
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000637:transplantation*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D013267:Stilbenes; D000077185:Resveratrol