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dc.contributor.authorPezzolla, Daniela-
dc.contributor.authorLópez-Beas, Javier-
dc.contributor.authorLachaud, Christian C.-
dc.contributor.authorDomínguez-Rodríguez, Alejandro-
dc.contributor.authorSmani, Tarik-
dc.contributor.authorHmadcha, Abdelkrim-
dc.contributor.authorSoria Escoms, Bernat-
dc.identifierdoi: 10.1371/journal.pone.0119904-
dc.identifierissn: 1932-6203-
dc.identifier.citationPLoS ONE 10(3): e0119904 (2015)-
dc.description.abstractHuman 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 glucosestimulated 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 insulinsecreting 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.-
dc.description.sponsorshipAuthors are supported by the nonprofit Foundation (Fundación Progreso y Salud) Consejería de Salud, Junta de Andalucía (Grant PI-0022/2008); FEDER co-funded grants from Consejería de Innovación Ciencia y Empresa, Junta de Andalucía (Grant CTS-6505; INP-2011-1615-900000 and P10- CVI-6095); FEDER co-funded grants from Instituto de Salud Carlos III (Red TerCel-Grant RD06/0010/0025, RD12/0019/0028 and RD12/0042/0041; PI10/00964, PI14/01015 and PI10/00871) and the Ministry of Health and Consumer Affairs (Advanced Therapies Program Grant TRA-120)-
dc.publisherPublic Library of Science-
dc.relation.isversionofPublisher's version-
dc.titleResveratrol ameliorates the maturation process of β-cell-like cells obtained from an optimized differentiation protocol of human embryonic stem cells-
dc.description.versionPeer Reviewed-
dc.contributor.funderFundación Progreso y Salud-
dc.contributor.funderJunta de Andalucía-
dc.contributor.funderEuropean Commission-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderRed de Terapia Celular (España)-
dc.contributor.funderMinisterio de Sanidad y Consumo (España)-
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