Transplantation of Human Umbilical Cord Mesenchymal Stem Cells-Derived Neural Stem Cells Pretreated with Neuregulin1β Ameliorate Cerebral Ischemic Reperfusion Injury in Rats

Abstract

Ischemic stroke is a common cerebrovascular disease and recovering blood flow as early as possible is essential to reduce ischemic damage and maintain neuronal viability, but the reperfusion process usually causes additional damage to the brain tissue in the ischemic area, namely ischemia reperfusion injury. The accumulated studies have revealed that transplantation of exogenous neural stem cells (NSCs) is an ideal choice for the treatment of ischemia reperfusion injury. At present, the source and efficacy of exogenous NSCs after transplantation is still one of the key issues that need to be resolved. In this study, human umbilical cord mesenchymal stem cells (hUC-MSCs) were obtained and induced into NSCs byadding growth factor and neuregulin1β (NRG1β) was introduced during the differentiation process of NSCs. Then, the rat middle cerebral artery occlusion/reperfusion (MCAO/R) models were established, and the therapeutic effects were evaluated among groups treated by NRG1β, NSCs and NSCs pretreated with 10 nM NRG1β (NSCs-10 nM NRG1β) achieved through intra-arterial injection. Our data show that the NSCs-10 nM NRG1β group significantly improves neurobehavioral function and infarct volume after MCAO/R, as well as cerebral cortical neuron injury, ferroptosis-related indexes and mitochondrial injury. Additionally, NSCs-10 nM NRG1β intervention may function through regulating the p53/GPX4/SLC7A11 pathway, and reducing the level of ferroptosis in cells, further enhance the neuroprotective effect on injured cells.

Blocking P2RX7 Attenuates Ferroptosis in Endothelium and Reduces HG-induced Hemorrhagic Transformation After MCAO by Inhibiting ERK1/2 and P53 Signaling Pathways

“…Ferroptosis has been suggested to be involve in the process of endothelial cell damage and BBB disruption [27,28]. Some drugs were showed protective effect by inhibiting ferroptosis via SLC7A11/GPX4 signaling pathway after MCAO [27,29,30]. Our result showed the existence of ferroptosis in infract brain tissue after MCAO and in HUVECs after OGD/R, with lipid peroxidation, iron concentration and decreased expression of SLC7A11 and GPX4, which indicated that ferroptosis of endothelium is a potential pathogenic mechanism.…”

Human umbilical cord mesenchymal stem cell‐derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin‐mediated mitophagy

“…HucMSC exhibits strong proliferative ability, low immunogenicity, and multi‐potential differentiation 8 . Exogenous HucMSC can stimulate repair processes, suppress astrocyte activation, inhibit inflammatory factors, and decrease neuron loss after brain injury, resulting in improvement of behavioral outcomes and cerebral lesion volumes after brain damage 9 . It has been found that the therapeutic effects of HucMSC were depend on the release of exosome.…”

Ferroptosis—A New Dawn in the Treatment of Organ Ischemia–Reperfusion Injury

“…In tert-butyl-hydroxyperoxide-treated neurons, activation of the SSAT1/ALOX15 axis downregulated the expression of GPX4 and SLC7A11, which triggered neuronal death and worsened IRI [ 118 ]. Neural stem cell transplantation treated with neuregulin1β can regulate ferroptosis in I/R by promoting GPX4/SLC7A11 expression [ 119 ].…”