Cargando…
Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling
INTRODUCTION: 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, nam...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9880320/ https://www.ncbi.nlm.nih.gov/pubmed/36714559 http://dx.doi.org/10.3389/fendo.2022.1043543 |
_version_ | 1784878882242953216 |
---|---|
author | Rodrigues, Joana Saraiva Faria-Pereira, Andreia Camões, Sérgio Póvoas Serras, Ana Sofia Morais, Vanessa Alexandra Ruas, Jorge Lira Miranda, Joana Paiva |
author_facet | Rodrigues, Joana Saraiva Faria-Pereira, Andreia Camões, Sérgio Póvoas Serras, Ana Sofia Morais, Vanessa Alexandra Ruas, Jorge Lira Miranda, Joana Paiva |
author_sort | Rodrigues, Joana Saraiva |
collection | PubMed |
description | INTRODUCTION: 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. |
format | Online Article Text |
id | pubmed-9880320 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98803202023-01-28 Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling Rodrigues, Joana Saraiva Faria-Pereira, Andreia Camões, Sérgio Póvoas Serras, Ana Sofia Morais, Vanessa Alexandra Ruas, Jorge Lira Miranda, Joana Paiva Front Endocrinol (Lausanne) Endocrinology INTRODUCTION: 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. Frontiers Media S.A. 2023-01-13 /pmc/articles/PMC9880320/ /pubmed/36714559 http://dx.doi.org/10.3389/fendo.2022.1043543 Text en Copyright © 2023 Rodrigues, Faria-Pereira, Camões, Serras, Morais, Ruas and Miranda https://creativecommons.org/licenses/by/4.0/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. |
spellingShingle | Endocrinology Rodrigues, Joana Saraiva Faria-Pereira, Andreia Camões, Sérgio Póvoas Serras, Ana Sofia Morais, Vanessa Alexandra Ruas, Jorge Lira Miranda, Joana Paiva Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling |
title | Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling |
title_full | Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling |
title_fullStr | Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling |
title_full_unstemmed | Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling |
title_short | Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling |
title_sort | improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9880320/ https://www.ncbi.nlm.nih.gov/pubmed/36714559 http://dx.doi.org/10.3389/fendo.2022.1043543 |
work_keys_str_mv | AT rodriguesjoanasaraiva improvinghumanmesenchymalstemcellderivedhepaticcellenergymetabolismbymanipulatingglucosehomeostasisandglucocorticoidsignaling AT fariapereiraandreia improvinghumanmesenchymalstemcellderivedhepaticcellenergymetabolismbymanipulatingglucosehomeostasisandglucocorticoidsignaling AT camoessergiopovoas improvinghumanmesenchymalstemcellderivedhepaticcellenergymetabolismbymanipulatingglucosehomeostasisandglucocorticoidsignaling AT serrasanasofia improvinghumanmesenchymalstemcellderivedhepaticcellenergymetabolismbymanipulatingglucosehomeostasisandglucocorticoidsignaling AT moraisvanessaalexandra improvinghumanmesenchymalstemcellderivedhepaticcellenergymetabolismbymanipulatingglucosehomeostasisandglucocorticoidsignaling AT ruasjorgelira improvinghumanmesenchymalstemcellderivedhepaticcellenergymetabolismbymanipulatingglucosehomeostasisandglucocorticoidsignaling AT mirandajoanapaiva improvinghumanmesenchymalstemcellderivedhepaticcellenergymetabolismbymanipulatingglucosehomeostasisandglucocorticoidsignaling |