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

Liu,Xiaozhi; Ren,Wenbo; Jiang,Zhongmin; Su,Zhiguo; Ma,Xiaofang; Li,Yanxia; Jiang,Rongcai; Zhang,Jianning; Yang,Xinyu

doi:10.3892/ijmm.2017.3167

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

Authors:
- Xiaozhi Liu
- Wenbo Ren
- Zhongmin Jiang
- Zhiguo Su
- Xiaofang Ma
- Yanxia Li
- Rongcai Jiang
- Jianning Zhang
- Xinyu Yang
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Affiliations: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China, Department of Neurology, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China, Department of Pathology, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China, Department of Neurosurgery, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China, Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China
Published online on: September 29, 2017 https://doi.org/10.3892/ijmm.2017.3167
Pages: 1631-1638
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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