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.
Highlights
Multipotent mesenchymal stromal cells (MSCs) are non-hematopoietic, perivascular cells that can be found in virtually all organs and tissues in the body
We found that silencing of glycoprotein A repetitions predominant (GARP) in adipose-derived MSCs (ASCs) (GARP−/lowASCs) increased the activation of transforming growth factor-β (TGF-β) and induced an increase in basal mitochondrial reactive oxygen species and γ-H2AX levels, indicating higher levels of DNA damage
In MSCs, ROS is mainly produced by the mitochondrial complexes I and III and, to a lesser extent, by the NADPH oxidase (NOX)-4.52 We showed that GARP−/lowASCs produced higher levels of mitochondrial reactive oxygen species (mtROS)
Summary
Multipotent mesenchymal stromal cells (MSCs) are non-hematopoietic, perivascular cells that can be found in virtually all organs and tissues in the body. The expansion of MSCs is associated with several problems including the loss of homing capacity,[11] onset of cellular senescence,[12] decrease in differentiation capacity,[13] and susceptibility to genomic instability and malignant transformation,[14,15] limiting the utility of MSCs as a cell-based therapy Another problem is the low survival and engraftment of injected cells in vivo,[16] and it has been estimated that up to 99% of the injected MSCs will die shortly after administration.[17,18] Several of the above obstacles can be circumvented using the MSC-derived secretome which has shown beneficial effects in inflammatory/autoimmune diseases and in regenerative medicine. GARP expression in HeLa cells correlated positively with their proliferative capacity, whereas silencing of GARP in the NmuMG breast cancer cell line did not affect their proliferation,[32,33]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
