GARP is a key molecule for mesenchymal stromal cell responses to TGF‐β and fundamental to control mitochondrial ROS levels
Abstract Multipotent mesenchymal stromal cells (MSCs) have emerged as a promising cell therapy in regenerative medicine and for autoimmune/inflammatory diseases. However, a main hurdle for MSCs‐based therapies is the loss of their proliferative potential in vitro. Here we report that glycoprotein A...
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Online Access: | https://doi.org/10.1002/sctm.19-0372 |
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doaj-8ef05891c4e145d19d4652a49c2453822020-11-25T01:44:23ZengWileyStem Cells Translational Medicine2157-65642157-65802020-05-019563665010.1002/sctm.19-0372GARP is a key molecule for mesenchymal stromal cell responses to TGF‐β and fundamental to control mitochondrial ROS levelsAna Belén Carrillo‐Gálvez0Sheyla Gálvez‐Peisl1Juan Elías González‐Correa2Marina deHaro‐Carrillo3Verónica Ayllón4Pedro Carmona‐Sáez5Verónica Ramos‐Mejía6Pablo Galindo‐Moreno7Francisca E. Cara8Sergio Granados‐Principal9Pilar Muñoz10Francisco Martin11Per Anderson12Centre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainDepartment of Oral Surgery and Implant Dentistry School of Dentistry, University of Granada Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainCentre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalucian Regional Government Granada SpainServicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico Hospital Universitario Virgen de las Nieves Granada SpainAbstract Multipotent mesenchymal stromal cells (MSCs) have emerged as a promising cell therapy in regenerative medicine and for autoimmune/inflammatory diseases. However, a main hurdle for MSCs‐based therapies is the loss of their proliferative potential in vitro. Here we report that glycoprotein A repetitions predominant (GARP) is required for the proliferation and survival of adipose‐derived MSCs (ASCs) via its regulation of transforming growth factor‐β (TGF‐β) activation. Silencing of GARP in human ASCs increased their activation of TGF‐β which augmented the levels of mitochondrial reactive oxygen species (mtROS), resulting in DNA damage, a block in proliferation and apoptosis. Inhibition of TGF‐β signaling reduced the levels of mtROS and DNA damage and restored the ability of GARP−/lowASCs to proliferate. In contrast, overexpression of GARP in ASCs increased their proliferative capacity and rendered them more resistant to etoposide‐induced DNA damage and apoptosis, in a TGF‐β‐dependent manner. In summary, our data show that the presence or absence of GARP on ASCs gives rise to distinct TGF‐β responses with diametrically opposing effects on ASC proliferation and survival.https://doi.org/10.1002/sctm.19-0372DNA damagemesenchymal stromal cells (MSCs)proliferationROSTGF‐β |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ana Belén Carrillo‐Gálvez Sheyla Gálvez‐Peisl Juan Elías González‐Correa Marina deHaro‐Carrillo Verónica Ayllón Pedro Carmona‐Sáez Verónica Ramos‐Mejía Pablo Galindo‐Moreno Francisca E. Cara Sergio Granados‐Principal Pilar Muñoz Francisco Martin Per Anderson |
spellingShingle |
Ana Belén Carrillo‐Gálvez Sheyla Gálvez‐Peisl Juan Elías González‐Correa Marina deHaro‐Carrillo Verónica Ayllón Pedro Carmona‐Sáez Verónica Ramos‐Mejía Pablo Galindo‐Moreno Francisca E. Cara Sergio Granados‐Principal Pilar Muñoz Francisco Martin Per Anderson GARP is a key molecule for mesenchymal stromal cell responses to TGF‐β and fundamental to control mitochondrial ROS levels Stem Cells Translational Medicine DNA damage mesenchymal stromal cells (MSCs) proliferation ROS TGF‐β |
author_facet |
Ana Belén Carrillo‐Gálvez Sheyla Gálvez‐Peisl Juan Elías González‐Correa Marina deHaro‐Carrillo Verónica Ayllón Pedro Carmona‐Sáez Verónica Ramos‐Mejía Pablo Galindo‐Moreno Francisca E. Cara Sergio Granados‐Principal Pilar Muñoz Francisco Martin Per Anderson |
author_sort |
Ana Belén Carrillo‐Gálvez |
title |
GARP is a key molecule for mesenchymal stromal cell responses to TGF‐β and fundamental to control mitochondrial ROS levels |
title_short |
GARP is a key molecule for mesenchymal stromal cell responses to TGF‐β and fundamental to control mitochondrial ROS levels |
title_full |
GARP is a key molecule for mesenchymal stromal cell responses to TGF‐β and fundamental to control mitochondrial ROS levels |
title_fullStr |
GARP is a key molecule for mesenchymal stromal cell responses to TGF‐β and fundamental to control mitochondrial ROS levels |
title_full_unstemmed |
GARP is a key molecule for mesenchymal stromal cell responses to TGF‐β and fundamental to control mitochondrial ROS levels |
title_sort |
garp is a key molecule for mesenchymal stromal cell responses to tgf‐β and fundamental to control mitochondrial ros levels |
publisher |
Wiley |
series |
Stem Cells Translational Medicine |
issn |
2157-6564 2157-6580 |
publishDate |
2020-05-01 |
description |
Abstract Multipotent mesenchymal stromal cells (MSCs) have emerged as a promising cell therapy in regenerative medicine and for autoimmune/inflammatory diseases. However, a main hurdle for MSCs‐based therapies is the loss of their proliferative potential in vitro. Here we report that glycoprotein A repetitions predominant (GARP) is required for the proliferation and survival of adipose‐derived MSCs (ASCs) via its regulation of transforming growth factor‐β (TGF‐β) activation. Silencing of GARP in human ASCs increased their activation of TGF‐β which augmented the levels of mitochondrial reactive oxygen species (mtROS), resulting in DNA damage, a block in proliferation and apoptosis. Inhibition of TGF‐β signaling reduced the levels of mtROS and DNA damage and restored the ability of GARP−/lowASCs to proliferate. In contrast, overexpression of GARP in ASCs increased their proliferative capacity and rendered them more resistant to etoposide‐induced DNA damage and apoptosis, in a TGF‐β‐dependent manner. In summary, our data show that the presence or absence of GARP on ASCs gives rise to distinct TGF‐β responses with diametrically opposing effects on ASC proliferation and survival. |
topic |
DNA damage mesenchymal stromal cells (MSCs) proliferation ROS TGF‐β |
url |
https://doi.org/10.1002/sctm.19-0372 |
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