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Research Paper|Volume 10, Issue 10|pp 2954—2972

Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress

Jia Fang1, Yuan Yan1, Xin Teng1, Xinyu Wen1, Na Li1, Sha Peng1, Wenshuai Liu2, F. Xavier Donadeu3, Shanting Zhao1, Jinlian Hua1
  • 1College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and Technology, Northwest A and F University, Yangling, Shaanxi Province, China
  • 2Department of Pathology, Yangling Demonstration Zone Hospital, Yangling, Shaanxi Province, China
  • 3Division of Developmental Biology, The Roslin Institute Reader, Royal (Dick) School of Veterinary Studies University of Edinburgh, Easter Bush, Midlothian, EH25 9RG Scotland, UK
Received: September 5, 2018Accepted: October 15, 2018Published: October 25, 2018
https://doi.org/10.18632/aging.101602

Copyright: © 2018 Fang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can aid in the treatment of numerous diseases in animals. However, natural aging during in vitro expansion of ADMSCs prior to their use in transplantation restricts their beneficial effects. Melatonin is reported to exert biorhythm regulation, anti-oxidation, and anti-senescence effects in various animal and cell models. Herein, by using a senescent canine ADMSCs (cADMSCs) cell model subjected to multiple passages in vitro, we investigated the effects of melatonin on ADMSCs senescence. We found that melatonin alleviates endoplasmic reticulum stress (ERS) and cell senescence. MT1/MT2 melatonin receptor inhibitor, luzindole, diminished the mRNA expression levels and rhythm expression amplitude of Bmal1 and Nrf2 genes. Nrf2 knockdown blocked the stimulatory effects of melatonin on endoplasmic reticulum-associated degradation (ERAD)-related gene expression and its inhibitory effects on ERS-related gene expression. At the same time, the inhibitory effects of melatonin on the NF-κB signaling pathway and senescence-associated secretory phenotype (SASP) were blocked by Nrf2 knockdown in cADMSCs. Melatonin pretreatment improved the survival of cADMSCs and enhanced the beneficial effects of cADMSCs transplantation in canine acute liver injury. These results indicate that melatonin activates Nrf2 through the MT1/MT2 receptor pathway, stimulates ERAD, inhibits NF-κB and ERS, alleviates cADMSCs senescence, and improves the efficacy of transplanted cADMSCs.