Neuroprotection by mesenchymal stem cell (MSC) administration is enhanced by local cooling infusion (LCI) in ischemia.

Abstract

OBJECTIVE:

The present study aimed to determine if hypothermia augments the neuroprotection conferred by MSC administration by providing a conducive micro-environment.

METHODS:

Sprague-Dawley rats were subjected to 1.5 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h of reperfusion for molecular analyses, as well as 1, 14 and 28 days for brain infarction or functional outcomes. Rats were treated with either MSC (1 × 105), LCI (cold saline, 0.6 ml/min, 5 min) or both. Brain damage was determined by Infarct volume and neurological deficits. Long-term functional outcomes were evaluated using foot-fault and Rota-rod testing. Human neural SHSY5Y cells were investigated in vitro using 2 h oxygen-glucose deprivation (OGD) followed by MSC with or without hypothermia (HT) (34 °C, 4 h). Mitochondrial transfer was assessed by confocal microscope, and cell damage was determined by cell viability, ATP, and ROS level. Protein levels of IL-1β, BAX, Bcl-2, VEGF and Miro1 were measured by Western blot following 6 h and 24 h of reperfusion and reoxygenation.

RESULTS:

MSC, LCI, and LCI + MSC significantly reduced infarct volume and deficit scores. Combination therapy of LCI + MSC precipitated better long-term functional outcomes than monotherapy. Upregulation of Miro1 in the combination group increased mitochondrial transfer and lead to a greater increase in neuronal cell viability and ATP, as well as a decrease in ROS. Further, combination therapy significantly decreased expression of IL-1β and BAX while increasing Bcl-2 and VEGF expression.

CONCLUSION:

Therapeutic hypothermia upregulated Miro1 and enhanced MSC mitochondrial transfer-mediated neuroprotection in ischemic stroke. Combination of LCI with MSC therapy may facilitate clinical translation of this approach.

• Authors: Wenjing Wei, Di Wu, Yunxia Duan, Kenneth B Elkin, Ankush Chandra, Longfei Guan, Changya Peng, Xiaoduo He, Chuanjie Wu, Xunming Ji, Yuchuan Ding
• Journal: Brain research (Brain Res) Vol. 1724 Pg. 146406 (12 01 2019) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 31454517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Topics

• Animals
• Brain Injuries (metabolism)
• Brain Ischemia (metabolism, therapy)
• Disease Models, Animal
• Hypothermia (metabolism)
• Hypothermia, Induced (methods)
• Infarction, Middle Cerebral Artery (metabolism)
• Ischemia (metabolism, therapy)
• Male
• Mesenchymal Stem Cell Transplantation (methods)
• Mesenchymal Stem Cells (metabolism)
• Neurons (metabolism)
• Neuroprotection (physiology)
• Rats
• Rats, Sprague-Dawley
• Reperfusion
• Reperfusion Injury (metabolism)
• Stroke (metabolism)