Reactive Oxygen Species Are Required for Human Mesenchymal Stem Cells to Initiate Proliferation after the Quiescence Exit

Abstract

The present study focuses on the involvement of reactive oxygen species (ROS) in the process of mesenchymal stem cells “waking up” and entering the cell cycle after the quiescence. Using human endometrial mesenchymal stem cells (eMSCs), we showed that intracellular basal ROS level is positively correlated with the proliferative status of the cell cultures. Our experiments with the eMSCs synchronized in the G0 phase of the cell cycle revealed a transient increase in the ROS level upon the quiescence exit after stimulation of the cell proliferation. This increase was registered before the eMSC entry to the S-phase of the cell cycle, and elimination of this increase by antioxidants (N-acetyl-L-cysteine, Tempol, and Resveratrol) blocked G1–S-phase transition. Similarly, a cell cycle arrest which resulted from the antioxidant treatment was observed in the experiments with synchronized human mesenchymal stem cells derived from the adipose tissue. Thus, we showed that physiologically relevant level of ROS is required for the initiation of human mesenchymal stem cell proliferation and that low levels of ROS due to the antioxidant treatment can block the stem cell self-renewal.

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

“…We thus measured the ROS levels in GARP −/low ASCs and detected a significant increase in the levels of mtROS compared with control cells. Although physiological levels of ROS in MSCs are necessary for their proliferation and adipogenic/chondrogenic differentiation capacity, high endogenous ROS levels can have detrimental effects on MSCs, including the induction of DNA damage and premature senescence, impairment of MSC migration, and a reduction in their immunomodulatory and osteogenic capacities . We found that reducing the levels of mtROS in GARP −/low ASCs using the mitochondria‐targeted antioxidant mitoTEMPO, decreased the amount of DSBs, and partially reversed their block in proliferation.…”

Effects of Poor Maternal Nutrition during Gestation on Bone Development and Mesenchymal Stem Cell Activity in Offspring

“…A recent study conducted by Lyublinskaya and colleagues found that reactive oxygen species (ROS) are required for MSC to initiate proliferation [31]. Additionally, reduced level of basal oxidative phosphorylation will lead to a reduced ROS in MSC [21,32].…”

Two faces of the coin: Minireview for dissecting the role of reactive oxygen species in stem cell potency and lineage commitment

“…The enzymatic activity has been shown to decrease in response to ROS [47] . Furthermore, the addition of ROS to bone marrow-derived stromal cells or osteoblastic precursors inhibited the expression of different osteogenic markers in a dose dependent manner [34] , [48] . Thus, there is an inverse correlation between the level of ROS and bone differentiation.…”

“…With the basal level of ROS, MSCs would remain quiescent. The ROS level would increase before the cells enter the S phase of the cell cycle, and antioxidants block the G 1 -S transition [34] . Urao et al, in 2008, found that deletion of Nox2 causes reduced stem cell mobilization from the bone marrow to peripheral blood [35] .…”