Stem Cell Research & Therapy (Feb 2021)

Melatonin activates ABCA1 via the BiP/NRF1 pathway to suppress high-cholesterol-induced apoptosis of mesenchymal stem cells

  • Jun Sung Kim,
  • Young Hyun Jung,
  • Hyun Jik Lee,
  • Chang Woo Chae,
  • Gee Euhn Choi,
  • Jae Ryong Lim,
  • Seo Yihl Kim,
  • Joo Eun Lee,
  • Ho Jae Han

DOI
https://doi.org/10.1186/s13287-021-02181-4
Journal volume & issue
Vol. 12, no. 1
pp. 1 – 14

Abstract

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Abstract Background Retarded wound healing in patients with obesity contributes to a risk of complications associated with vascular insufficiency and oxidative stress. The high cholesterol levels of patients with obesity are associated with apoptosis of engrafted umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). Melatonin contributes to the prevention of cholesterol accumulation in patients with obesity via a mechanism that is poorly understood. We therefore investigated the regulatory mechanism of melatonin in cholesterol-induced apoptosis. Methods The protective effects of melatonin on cholesterol-induced apoptosis were investigated in UCB-MSCs. We used a mouse model of induced obesity to show that melatonin treatment restored the survival rate of transplanted UCB-MSCs and their wound-healing capacity. The mean values of the treatment groups were compared with those of the control group using Student’s t test, and differences among three or more groups were analyzed using one-way analysis of variance with Dunnett’s multiple comparison test. Results Melatonin treatment increased the expression of ATP-binding cassette subfamily A member 1 (ABCA1), which reduced cholesterol accumulation and cholesterol-induced apoptosis. The mouse skin wound healing model showed that melatonin treatment restored the survival rate of transplanted UCB-MSCs and the wound-healing capacity of obese mice. Melatonin inhibited the expression of binding immunoglobulin protein (BiP) through the regulation of MT2/Sp1-dependent microRNA-597-5p. Melatonin decreased the co-localization of BiP with nuclear factor erythroid 2-related factor 1 (NRF1), which resulted in increased ABCA1 expression. Conclusion Melatonin induced the efflux of intracellular cholesterol through ABCA1 to decrease apoptosis of UCB-MSCs via an MT2-dependent BiP/NRF1 pathway.

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