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Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling

2023Journal article Unknown
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dc.contributor.authorRodrigues, Joana S.
dc.contributor.authorFaria-Pereira, Andreia
dc.contributor.authorCamões, Sérgio P.
dc.contributor.authorSerras, Ana S.
dc.contributor.authorMorais, Vanessa A.
dc.contributor.authorRuas, Jorge Lira
dc.contributor.authorMiranda, Joana P
dc.date.accessioned2025-05-30T13:30:39Z
dc.date.available2025-05-30T13:30:39Z
dc.date.issued2023
dc.descriptionCopyright © 2023 Rodrigues, Faria-Pereira, Camões, Serras, Morais, Ruas and Miranda. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.pt_PT
dc.description.abstractIntroduction: The development of reliable hepatic in vitro models may provide insights into disease mechanisms, linking hepatocyte dysmetabolism and related pathologies. However, several of the existing models depend on using high concentrations of hepatocyte differentiation-promoting compounds, namely glucose, insulin, and dexamethasone, which is among the reasons that have hampered their use for modeling metabolism-related diseases. This work focused on modulating glucose homeostasis and glucocorticoid concentration to improve the suitability of a mesenchymal stem-cell (MSC)-derived hepatocyte-like cell (HLC) human model for studying hepatic insulin action and disease modeling. Methods: We have investigated the role of insulin, glucose and dexamethasone on mitochondrial function, insulin signaling and carbohydrate metabolism, namely AKT phosphorylation, glycogen storage ability, glycolysis and gluconeogenesis, as well as fatty acid oxidation and bile acid metabolism gene expression in HLCs. In addition, we evaluated cell morphological features, albumin and urea production, the presence of hepatic-specific markers, biotransformation ability and mitochondrial function. Results: Using glucose, insulin and dexamethasone levels close to physiological concentrations improved insulin responsiveness in HLCs, as demonstrated by AKT phosphorylation, upregulation of glycolysis and downregulation of Irs2 and gluconeogenesis and fatty acid oxidation pathways. Ammonia detoxification, EROD and UGT activities and sensitivity to paracetamol cytotoxicity were also enhanced under more physiologically relevant conditions. Conclusion: HLCs kept under reduced concentrations of glucose, insulin and dexamethasone presented an improved hepatic phenotype and insulin sensitivity demonstrating superior potential as an in vitro platform for modeling energy metabolism-related disorders, namely for the investigation of the insulin signaling pathway.pt_PT
dc.description.sponsorshipThe work was financially supported by Fundação para a Ciência e a Tecnologia (FCT) through SFRH/BD/144130/2019 to JRo; PD/BD/114113/2015 and IMM/BI/76-2019 to AF-P; IF/01693/2014 and IMM/CT/27-2020 to VM; PTDC/MED-TOX/29183/2017; UIDB/04138/2020; UIDP/04138/2020 and PTDC/BIACEL/31230/2017. This project has received funding from the European Horizon´s research and innovation programme HORIZON-HLTH-2022-STAYHLTH-02 under agreement No 101095679; from the European Molecular Biology Organization (EMBO-IG#3309); and was also supported by COST actions CA17112, CA20121 and CA20140.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront Endocrinol (Lausanne). 2023 Jan 13:13:1043543pt_PT
dc.identifier.doi10.3389/fendo.2022.1043543pt_PT
dc.identifier.eissn1664-2392
dc.identifier.urihttp://hdl.handle.net/10400.5/101159
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontierspt_PT
dc.relationIMM/BI/76-2019pt_PT
dc.relationIMM/CT/27-2020pt_PT
dc.relationMaintaining Mitochondria Healthy: The Molecular Checkpoints involved in Mitochondrial Quality Control in Neurons
dc.relationUnderstanding the underlying mechanisms by which mesenchymal stem cells promote liver regeneration: the specific role of exosomes
dc.relation101095679pt_PT
dc.relationEMBO-IG#3309pt_PT
dc.relationCA17112pt_PT
dc.relationCA20121pt_PT
dc.relationCA20140pt_PT
dc.relation.publisherversionhttps://www.frontiersin.org/journals/endocrinologypt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAlternative hepatic in vitro modelspt_PT
dc.subjectDexamethasonept_PT
dc.subjectGlucosept_PT
dc.subjectHepatocyte-like cellspt_PT
dc.subjectInsulinpt_PT
dc.subjectMesenchymal stem cellspt_PT
dc.subjectMetabolismpt_PT
dc.titleImproving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signalingpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMaintaining Mitochondria Healthy: The Molecular Checkpoints involved in Mitochondrial Quality Control in Neurons
oaire.awardTitleUnderstanding the underlying mechanisms by which mesenchymal stem cells promote liver regeneration: the specific role of exosomes
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F144130%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F114113%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/IF%2F01693%2F2014%2FCP1236%2FCT0003/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-TOX%2F29183%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Concurso de avaliação no âmbito do Programa Plurianual de Financiamento de Unidades de I&D (2017%2F2018) - Financiamento Base/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Concurso de avaliação no âmbito do Programa Plurianual de Financiamento de Unidades de I&D (2017%2F2018) - Financiamento Programático/UIDP%2F04138%2F2020/PT
oaire.citation.titleFrontiers in Endocrinologypt_PT
oaire.citation.volume13pt_PT
oaire.fundingStreamOE
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream3599-PPCDT
oaire.fundingStreamConcurso de avaliação no âmbito do Programa Plurianual de Financiamento de Unidades de I&D (2017/2018) - Financiamento Base
oaire.fundingStreamConcurso de avaliação no âmbito do Programa Plurianual de Financiamento de Unidades de I&D (2017/2018) - Financiamento Programático
person.familyNameRodrigues
person.familyNameFaria Pereira
person.familyNameSerras
person.familyNameMorais
person.familyNameMiranda
person.givenNameJoana
person.givenNameAndreia Sofia
person.givenNameAna
person.givenNameVanessa
person.givenNameJoana P G
person.identifier666699
person.identifier793336
person.identifier507820
person.identifier.ciencia-id6419-AE71-2FA4
person.identifier.ciencia-idB41D-2E23-CD07
person.identifier.ciencia-id001A-6278-C231
person.identifier.orcid0000-0002-1772-9813
person.identifier.orcid0000-0002-0097-1160
person.identifier.orcid0000-0002-7941-9511
person.identifier.orcid0000-0002-0830-0548
person.identifier.orcid0000-0002-7804-4068
person.identifier.ridJ-3698-2013
person.identifier.scopus-author-id12798235300
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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