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 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-/low ASCs 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. ; This work has been financed by the Instituto de Salud Carlos III, Spain (www.isciii.es) and Fondo Europeo de Desarrollo Regional (FEDER), from the European Union, through the research grants PI15/00794, PI18/00826, and the contract CPII15/00032 (P.A), PI15/02015, PI18/00337, and ISCIII Red de Terapia Celular (RD12/0019/0006) (F.M.). P.A. is supported by the Consejería de Salud - Junta de Andalucía through the contract "Nicolás Monardes (C-0013-2018). F.M. is supported by the Fundación Progreso y Salud (Consejería de Salud—Junta de Andalucía). A.B.C.-G. is supported by the Ministerio de Ciencia y Tecnología, through the contract PEJ-2014-A-46314. V.A. is funded by the L'Oréal-UNESCO For Women In Science Program. V.R.-M. is supported by a Miguel Servet II contract FIS/FEDER (CPII17/00032) and ISCIII/FEDER PI17/01574. S.G-P. is supported by a Miguel Servet I contract FIS/FEDER (CP14/00197). P.M. is supported by the Fundación Andaluza Progreso y Salud (Consejería de Salud—Junta de Andalucía). ; Yes