Journal
STEM CELLS TRANSLATIONAL MEDICINE
Volume 9, Issue 5, Pages 636-650Publisher
WILEY
DOI: 10.1002/sctm.19-0372
Keywords
DNA damage; mesenchymal stromal cells (MSCs); proliferation; ROS; TGF-beta
Categories
Funding
- Consejeria de Salud - Junta de Andealucia [C-0013-2018]
- L'Oreal-UNESCO For Women In Science Program
- Ministerio de Ciencia y Tecnologia [PEJ-2014-A-46314]
- Fundacion Progreso y Salud
- ISCIII Red de Terapia Celular [RD12/0019/0006]
- Fondo Europeo de Desarrollo Regional/Instituto de Salud Carlos III [PI18/00337, PI15/02015, CPII15/00032, PI18/00826, PI15/00794, CP14/00197, CPII17/00032, PI17/01574]
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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-beta (TGF-beta) activation. Silencing of GARP in human ASCs increased their activation of TGF-beta which augmented the levels of mitochondrial reactive oxygen species (mtROS), resulting in DNA damage, a block in proliferation and apoptosis. Inhibition of TGF-beta 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-beta-dependent manner. In summary, our data show that the presence or absence of GARP on ASCs gives rise to distinct TGF-beta responses with diametrically opposing effects on ASC proliferation and survival.
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