Jun Sung Kim1, Young Hyun Jung1, Hyun Jik Lee2,3, Chang Woo Chae1, Gee Euhn Choi1, Jae Ryong Lim1, Seo Yihl Kim1, Joo Eun Lee1, Ho Jae Han4. 1. Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul, 08826, Republic of Korea. 2. Laboratory of Veterinary Physiology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea. 3. Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea. 4. Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul, 08826, Republic of Korea. hjhan@snu.ac.kr.
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.
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 obesemice. 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.
Authors: Daniela S Masson-Meyers; Thiago A M Andrade; Guilherme F Caetano; Francielle R Guimaraes; Marcel N Leite; Saulo N Leite; Marco Andrey C Frade Journal: Int J Exp Pathol Date: 2020-03-30 Impact factor: 1.925
Authors: Alexis Stamatikos; Nagadhara Dronadula; Philip Ng; Donna Palmer; Ethan Knight; Bradley K Wacker; Chongren Tang; Francis Kim; David A Dichek Journal: Hum Gene Ther Date: 2018-10-02 Impact factor: 5.695
Authors: Karolina Szewczyk-Golec; Paweł Rajewski; Marcin Gackowski; Celestyna Mila-Kierzenkowska; Roland Wesołowski; Paweł Sutkowy; Marta Pawłowska; Alina Woźniak Journal: Oxid Med Cell Longev Date: 2017-09-21 Impact factor: 6.543
Authors: Hyun Jik Lee; Young Hyun Jung; Ji Young Oh; Gee Euhn Choi; Chang Woo Chae; Jun Sung Kim; Jae Ryong Lim; Seo Yihl Kim; Sei-Jung Lee; Je Kyung Seong; Ho Jae Han Journal: Cell Death Differ Date: 2018-11-21 Impact factor: 15.828