GARP is a key molecule for mesenchymal stromal cell responses to TGF-? 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-? (TGF-?) activation. Silencing of GARP in human ASCs increased their activation of TGF-? which augmented the levels of mitochondrial reactive oxygen species (mtROS), resulting in DNA damage, a block in proliferation and apoptosis. Inhibition of TGF-? 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-?-dependent manner. In summary, our data show that the presence or absence of GARP on ASCs gives rise to distinct TGF-? responses with diametrically opposing effects on ASC proliferation and survival.

SUBMITTER: Carrillo-Galvez AB 

PROVIDER: S-EPMC7180295 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature