Olfactory Mucosa Mesenchymal Stem Cells Ameliorate Cerebral Ischemic/Reperfusion Injury Through Modulation of UBIAD1 Expression.

Jianyang Liu,Ming Lu,Yi Zhuo,Lite Ge,Da Duan,Wei Chen,Zhiping Hu,Jialin He,Yan Huang

doi:10.3389/fncel.2020.580206

Abstract

Mesenchymal stem cells (MSCs) have presented a promising neuroprotective effect in cerebral ischemia/reperfusion (I/R). Olfactory mucosa MSCs (OM-MSCs), a novel source of MSCs located in the human nasal cavity, are easy to obtain and situated for autologous transplantation. The present study was designed to evaluate the neuroprotective effects of OM-MSCs on cerebral I/R injury and the possible mechanisms. In the transient middle cerebral artery occlusion (t-MCAO) model, excessive oxidative stress and increased swollen mitochondria were observed in the peri-infarct cortex. Intravenous injection of OM-MSCs ameliorated mitochondrial damage and restored oxidant/antioxidant imbalance. Using the oxygen glucose deprivation/reperfusion (OGD/R) model in vitro, we discovered that the exposure of mouse neuroblastoma N2a cells to OGD/R triggers excessive reactive oxygen species (ROS) generation and induces mitochondrial deterioration with decreased mitochondrial membrane potential and reduces ATP content. OM-MSC transwell coculture attenuated the above perturbations accompanied with increased UbiA prenyltransferase domain-containing 1 (UBIAD1) expression, whereas these protective effects of OM-MSCs were blocked when UBIAD1 was knocked down. UBIAD1-specific small interfering RNA (siRNA) reversed the increased membrane potential and ATP content promoted by OM-MSCs. Additionally, UBIAD1-specific siRNA blocked the oxidant/antioxidant balance treated by OM-MSCs. Overall, our results suggested that OM-MSCs exert neuroprotective effects in cerebral I/R injury by attenuating mitochondrial dysfunction and enhancing antioxidation via upregulation of UBIAD1.

Highlights

Stroke is the third leading cause of death according to the systematic analysis for the Global Burden of Disease Study 2017 (GBD 2017 Causes of Death Collaborators, 2018), and someone has a stroke approximately every 40 s in the United States (Virani et al, 2020)
Using the oxygen-glucose deprivation/reperfusion (OGD/R) model in vitro and transient middle cerebral artery occlusion (t-MCAO) model in vivo, the present study investigated the protective effects of OM-Mesenchymal stem cells (MSCs) in cerebral I/R injury and whether Olfactory mucosa MSCs (OM-MSCs) protect neurons by attenuating mitochondrial dysfunction and enhancing antioxidant activity via upregulation of UbiA prenyltransferase domaincontaining 1 (UBIAD1)
Three behavior tests were performed to test the protective effects of OM-MSCs on cerebral I/R injury, including the rotarod test, balance beam test, and modified neurological severity score (mNSS)

Summary

Introduction

Stroke is the third leading cause of death according to the systematic analysis for the Global Burden of Disease Study 2017 (GBD 2017 Causes of Death Collaborators, 2018), and someone has a stroke approximately every 40 s in the United States (Virani et al, 2020). Restoration of cerebral blood flow by mechanical or chemical therapies is essential to prevent irreversible brain damage, reestablishing blood flow paradoxically amplifies the initial brain tissue damage. This phenomenon is termed as cerebral ischemia/reperfusion (I/R) injury (Al-Mufti et al, 2018). The result of reactive oxygen species (ROS) overproduction, is regarded as the primary event in cerebral I/R injury (Janardhan and Qureshi, 2004; Granger and Kvietys, 2015). Previous studies have suggested that cerebral I/R produces oxygen free radicals, mostly secreted by the mitochondria, thereby resulting in excessive oxidative damage in neurons (Christophe and Nicolas, 2006; Zhao et al, 2018). Oxidant/antioxidant imbalance and mitochondrial dysfunction are fundamental triggers to neuronal injury in cerebral I/R

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