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

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.

Human mesenchymal stem cells–derived conditioned medium inhibits hypoxia‐induced death of neonatal porcine islets by inducing autophagy

“…Mesenchymal stem cells (MSCs), a class of pluripotent cells, have been proved to exert anti‐apoptosis, anti‐inflammatory and immunoregulatory effects, and they are an emerging and promising resource that may protect islets from hypoxia or other damage, thereby promoting graft survival . Interestingly, a growing body of research has indicated there may be a potential link between the protective role of MSCs and autophagy . However, it is currently unknown whether the favourable effect of MSCs on protecting islets subjected to hypoxia is related to the regulation of autophagy.…”

Melatonin suppresses ER stress-dependent proapoptotic effects via AMPK in bone mesenchymal stem cells during mitochondrial oxidative damage

“…2 a). LDH, which is retained in the cytoplasm of viable cells with intact plasma membranes and released from cells after membrane damage, is considered an important indicator of necrosis [ 28 ]. Spectrophotometric analysis demonstrated that the LDH level was significantly increased in the medium of cells treated with H 2 O 2 , especially those treated with 800 μM H 2 O 2 (Fig.…”

Grape Seed Proanthocyanidin Extract Down-Regulates Autophagic Proteins (LC3II and Beclin-1) in a Mouse Model of Neonatal Hypoxic-Ischemic Brain Injury

“…Autophagy is an intracellular degradation process and a cytoprotective response of cells in extreme environments, such as starvation, hypoxia, and physical stimulation [17]. Autophagy can be converted into the energy needs by removing metabolic substances from the body and damaged organelles.…”