GARP is a key molecule for mesenchymal stromal cell responses to TGF-β and fundamental to control mitochondrial ROS levels.

Stem cells translational medicine (2020-02-20)
Ana Belén Carrillo-Gálvez, Sheyla Gálvez-Peisl, Juan Elías González-Correa, Marina de Haro-Carrillo, Verónica Ayllón, Pedro Carmona-Sáez, Verónica Ramos-Mejía, Pablo Galindo-Moreno, Francisca E Cara, Sergio Granados-Principal, Pilar Muñoz, Francisco Martin, Per Anderson

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.

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Amyloid Protein Non-Aβ Component, ≥80% (HPLC)