Melatonin Pretreatment Improves the Survival and Function of Transplanted Mesenchymal Stem Cells after Focal Cerebral Ischemia

Abstract

Mesenchymal stem cell (MSC) transplantation has been shown to be beneficial in treating cerebral ischemia. However, such benefit is limited by the low survival of transplanted MSCs in an ischemic microenvironment. Previous studies showed that melatonin pretreatment can increase MSC survival in the ischemic kidney. However, whether it will improve MSC survival in cerebral ischemia is unknown. Our study examined the effect of melatonin pretreatment on MSCs under ischemia-related conditions in vitro and after transplantation into ischemic rat brain. Results showed that melatonin pretreatment greatly increased survival of MSCs in vitro and reduced their apoptosis after transplantation into ischemic brain. Melatonin-treated MSCs (MT-MSCs) further reduced brain infarction and improved neurobehavioral outcomes. Angiogenesis, neurogenesis, and the expression of vascular endothelial growth factor (VEGF) were greatly increased in the MT-MSC-treated rats. Melatonin treatment increased the level of p-ERK1/2 in MSCs, which can be blocked by the melatonin receptor antagonist luzindole. ERK phosphorylation inhibitor U0126 completely reversed the protective effects of melatonin, suggesting that melatonin improves MSC survival and function through activating the ERK1/2 signaling pathway. Thus, stem cells pretreated by melatonin may represent a feasible approach for improving the beneficial effects of stem cell therapy for cerebral ischemia.

Melatonin pretreatment of human adipose tissue-derived mesenchymal stromal cells enhances their prosurvival and protective effects on human kidney cells

“…Melatonin pretreatment of cells therefore has the potential to improve their use in different disease models and not just for kidney injury. For instance, a recent investigation by Tang et al (37) showed that pretreatment of rat bone marrow MSCs with melatonin augmented their survival in vitro in oxidative stress models and decreased their apoptosis following transplantation into ischemic rat brain. The expression of P-Erk 1/2 was found to be raised twofold by melatonin treatment (37).…”

Rola błonowych receptorów melatoniny w zależnym od melatoniny uwalnianiu oksytocyny z układu podwzgórze-część nerwowa przysadki szczura — badania in vitro oraz in vivo

“…Three concentrations (10 -9 M, 10 -7 M, and 10 -3 M) of the hormone were employed for the study because previous in vitro experiments have PRACE ORYGINALNE (10 -3 M ) concentration melatonin had the opposite effect on the studied process [8][9][10][11][12]. On the other hand, the concentrations of both antagonists (10 -6 M and 10 -5 M) were chosen for our present experiments because they were demonstrated to be the most effective in action [24][25][28][29][30][31]. Several studies have shown that luzindole antagonises the effects of melatonin.…”

Activity of mesenchymal stem cells in therapies for chronic skin wound healing

“…81 Therefore, a significant barrier to successful use of MSCs in any potential cell therapy has been post-implant cell survival in a variety of ischemic injury models. Past studies have shown marginal MSC preservation in various models including cardiac infarct 101 or cerebral injury, 102 but still MSC use in any of these models is limited by MSC death due to the harsh wound environment. As all of the benefits of MSC therapy for any type of wound healing are dependent on cell survival in the wound, strategies to improve survival following implantation are of interest in future research efforts.…”