Hypothermia inhibits the proliferation of bone marrow-derived mesenchymal stem cells and increases tolerance to hypoxia by enhancing SUMOylation

Abstract

Hypothermia therapy has a positive effect on patients with severe brain injury. Recent studies have shown that mild hypothermia increases the survival of bone marrow-derived mesenchymal stem cells (BMSCs) in a hypoxic environment; however, the underlying mechanisms are not yet fully understood. Small ubiquitin-like modifiers (SUMOs) are sensitive to temperature stress reactions and are considered to exert a protective effect. In this study, we examined the protective effects of hypothermia on BMSCs in terms of SUMO protein modification. First, we found that mild hypothermia inhibited the proliferation and differentiation of BMSCs and increased cell tolerance to a hypoxic environment. Second, hypothermia significantly increased the levels of SUMO modification of multiple proteins in BMSCs. The knockdown of SUMO1/2/3 induced the rapid aging of the BMSCs, while the inhibition of the SUMO-conjugating enzyme, Ubc9, reduced cell proliferation and increased the proportion of BMSCs differentiating into nerve cells. Moreover, the tolerance of BMSCs to the hypoxic environment was significantly decreased. Lastly, we investigated 4 reported SUMO target proteins, anti-proliferating cell nuclear antigen, octamer-binding transcription factor 4, p53 and hypoxia-inducible factor-1α, to confirm that SUMO modification was indeed involved in maintaining the proliferation, inhibiting differentiation and enhancing the resistance of BMSCs against adverse conditions. Taken together, our results indicate that the SUMO pathway is involved in the response to hypothermic stress, and that SUMOylation may be an important protective mechanism against hypothermia for the survival of BMSCs under unfavorable conditions.

Overexpression of SENP1 reduces the stemness capacity of osteosarcoma stem cells and increases their sensitivity to HSVtk/GCV

“…However, although overexpression of SENP1 induced the transition from G 0 /G 1 to S/G 2 phase, the effects on cell apoptosis and migration were small. Liu et al recently reported that SUMO silencing can lead to growth arrest and rapid aging of bone marrow mesenchymal stem cells ( 56 ). Notably, SUMO silencing may induce marked side effects on normal stem cells, whereas SENP1 overexpression-induced deSUMOylation may significantly reduce the degree of side effects.…”

“…A previous study indicated that Connexin 43 (Cx43), which is a protein involved in gap junctional intercellular communication, can be covalently modified and regulated by SUMO1 in liver cancer stem cells ( 57 ). In addition, Cx43 SUMOylation can improve gap junction functions and enhance cell sensitivity to HSVtk/GCV ( 56 ). It seems contradictory that increasing protein SUMOylation levels in liver cancer stem cells and inducing deSUMOylation in osteosarcoma stem cells can both increase chemosensitivity.…”

Hypothermia-Induced Ubiquitination of Voltage-Dependent Anion Channel 3 Protects BV2 Microglia Cells From Cytotoxicity Following Oxygen-Glucose Deprivation/Recovery

“…were high in all organs tested (Yang et al, 2009). Moderate hypothermia-induced SUMO conjugation also reduced damage to bone marrow stromal cells (BMSCs) following OGD and improved BMSC survival following transplantation into the penumbra (Liu et al, 2017;Ren et al, 2017). Similarly, hibernation-like hypothermia induced by opioid receptor agonists protected the brain from ischemic injury FIGURE 9 | Effect of hypothermia on VDAC3 mRNA expression in microglial cells.…”

Moderate hypothermia induces protection against hypoxia/reoxygenation injury by enhancing SUMOylation in cardiomyocytes

“…Previous studies have described the link between hypothermia and SuMoylation in the brain, and indicated that hypothermia may regulate SuMoylation to provide protection to the nervous system during hypoxic ischemia (23,24). However, it is unknown whether hypothermia alters SUMOylation modifications in the heart.…”