Mesenchymal Stem Cells Protect Against Hypoxia-Ischemia Brain Damage by Enhancing Autophagy Through Brain Derived Neurotrophic Factor/Mammalin Target of Rapamycin Signaling Pathway

Overview

Journal Stem Cells

Publisher Oxford University Press

Specialties Cell Biology
Reproductive Medicine

Date 2018 Feb 17

PMID 29451335

Citations 32

Authors

Zhen Zheng

Li Zhang

Yi Qu

Guoguang Xiao

Shiping Li

Shan Bao

Q Richard Lu

Dezhi Mu

Affiliations

Soon will be listed here.

Abstract

Hypoxic-ischemic encephalopathy (HIE) is a serious disease for neonates. However, present therapeutic strategies are not effective enough for treating HIE. Previous study showed that mesenchymal stem cells (MSCs) can exert neuroprotective effects for brain damage, but its mechanism remains elusive. Using in vitro coculture of rat cortical primary neurons and MSCs in HI conditions, we demonstrated that MSCs help increase brain derived neurotrophic factor (BDNF) and autophagy markers (LC3II and Beclin1) in the cultures and decrease cells death (lactate dehydrogenase levels). We demonstrated a similar mechanism using an in vivo rat model of HI in combination with MSCs transplantation. Using a behavioral study, we further showed that MSCs transplantation into the rat brain after HI injury can attenuate behavioral deficits. Finally, we found that the increase in BDNF and autophagy related factors after HI injury combined with MSCs transplantation can be reversed by anti-BDNF treatment and strengthen the point that the protective effects of BDNF work through inhibition of the mammalin target of rapamycin (mTOR) pathway. Collectively, we proposed that coculture/transplantation of MSCs after HI injury leads to increased BDNF expression and a subsequent reduction in mTOR pathway activation that results in increased autophagy and neuroprotection. This finding gives a hint to explore new strategies for treating neonates with HIE. Stem Cells 2018;36:1109-1121.

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