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Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype

Fibroblast-to-myofibroblast transition (FMT) leads to excessive extracellular matrix (ECM) deposition—a well-known hallmark of fibrotic disease. Transforming growth factor-β (TGF-β) is the primary cytokine driving FMT, and this phenotypic conversion is associated with mitochondrial dysfunction, nota...

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Autores principales: Baudo, Gherardo, Wu, Suhong, Massaro, Matteo, Liu, Haoran, Lee, Hyunho, Zhang, Aijun, Hamilton, Dale J., Blanco, Elvin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10342003/
https://www.ncbi.nlm.nih.gov/pubmed/37446100
http://dx.doi.org/10.3390/ijms241310913
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author Baudo, Gherardo
Wu, Suhong
Massaro, Matteo
Liu, Haoran
Lee, Hyunho
Zhang, Aijun
Hamilton, Dale J.
Blanco, Elvin
author_facet Baudo, Gherardo
Wu, Suhong
Massaro, Matteo
Liu, Haoran
Lee, Hyunho
Zhang, Aijun
Hamilton, Dale J.
Blanco, Elvin
author_sort Baudo, Gherardo
collection PubMed
description Fibroblast-to-myofibroblast transition (FMT) leads to excessive extracellular matrix (ECM) deposition—a well-known hallmark of fibrotic disease. Transforming growth factor-β (TGF-β) is the primary cytokine driving FMT, and this phenotypic conversion is associated with mitochondrial dysfunction, notably a metabolic reprogramming towards enhanced glycolysis. The objective of this study was to examine whether the establishment of favorable metabolic phenotypes in TGF-β-stimulated fibroblasts could attenuate FMT. The hypothesis was that mitochondrial replenishment of TGF-β-stimulated fibroblasts would counteract a shift towards glycolytic metabolism, consequently offsetting pro-fibrotic processes. Isolated mitochondria, functionalized with a dextran and triphenylphosphonium (TPP) (Dex-TPP) polymer conjugate, were administered to fibroblasts (MRC-5 cells) stimulated with TGF-β, and effects on bioenergetics and fibrotic programming were subsequently examined. Results demonstrate that TGF-β stimulation of fibroblasts led to FMT, which was associated with enhanced glycolysis. Dex-TPP-coated mitochondria (Dex-TPP/Mt) delivery to TGF-β-stimulated fibroblasts abrogated a metabolic shift towards glycolysis and led to a reduction in reactive oxygen species (ROS) generation. Importantly, TGF-β-stimulated fibroblasts treated with Dex-TPP/Mt had lessened expression of FMT markers and ECM proteins, as well as reduced migration and proliferation. Findings highlight the potential of mitochondrial transfer, as well as other strategies involving functional reinforcement of mitochondria, as viable therapeutic modalities in fibrosis.
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spelling pubmed-103420032023-07-14 Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype Baudo, Gherardo Wu, Suhong Massaro, Matteo Liu, Haoran Lee, Hyunho Zhang, Aijun Hamilton, Dale J. Blanco, Elvin Int J Mol Sci Article Fibroblast-to-myofibroblast transition (FMT) leads to excessive extracellular matrix (ECM) deposition—a well-known hallmark of fibrotic disease. Transforming growth factor-β (TGF-β) is the primary cytokine driving FMT, and this phenotypic conversion is associated with mitochondrial dysfunction, notably a metabolic reprogramming towards enhanced glycolysis. The objective of this study was to examine whether the establishment of favorable metabolic phenotypes in TGF-β-stimulated fibroblasts could attenuate FMT. The hypothesis was that mitochondrial replenishment of TGF-β-stimulated fibroblasts would counteract a shift towards glycolytic metabolism, consequently offsetting pro-fibrotic processes. Isolated mitochondria, functionalized with a dextran and triphenylphosphonium (TPP) (Dex-TPP) polymer conjugate, were administered to fibroblasts (MRC-5 cells) stimulated with TGF-β, and effects on bioenergetics and fibrotic programming were subsequently examined. Results demonstrate that TGF-β stimulation of fibroblasts led to FMT, which was associated with enhanced glycolysis. Dex-TPP-coated mitochondria (Dex-TPP/Mt) delivery to TGF-β-stimulated fibroblasts abrogated a metabolic shift towards glycolysis and led to a reduction in reactive oxygen species (ROS) generation. Importantly, TGF-β-stimulated fibroblasts treated with Dex-TPP/Mt had lessened expression of FMT markers and ECM proteins, as well as reduced migration and proliferation. Findings highlight the potential of mitochondrial transfer, as well as other strategies involving functional reinforcement of mitochondria, as viable therapeutic modalities in fibrosis. MDPI 2023-06-30 /pmc/articles/PMC10342003/ /pubmed/37446100 http://dx.doi.org/10.3390/ijms241310913 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Baudo, Gherardo
Wu, Suhong
Massaro, Matteo
Liu, Haoran
Lee, Hyunho
Zhang, Aijun
Hamilton, Dale J.
Blanco, Elvin
Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype
title Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype
title_full Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype
title_fullStr Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype
title_full_unstemmed Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype
title_short Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype
title_sort polymer-functionalized mitochondrial transplantation to fibroblasts counteracts a pro-fibrotic phenotype
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10342003/
https://www.ncbi.nlm.nih.gov/pubmed/37446100
http://dx.doi.org/10.3390/ijms241310913
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