Human placental mesenchymal stem cells improve stroke outcomes via extracellular vesicles-mediated preservation of cerebral blood flow.

Mansoureh Barzegar,Randa S Eshaq,Roger E Kelley,Xiao-Hong Lu,Alireza Minagar,Jonathan S Alexander,Luke A White,Sergio G Cananzi,Yuping Wang,Christen J Boyer,J Winny Yun,Oleg Chernyshev,Karen Y Stokes

doi:10.1016/j.ebiom.2020.103161

Abstract

BackgroundBesides long-term trans-differentiation into neural cells, benefits of stem cell therapy (SCT) in ischemic stroke may include secretion of protective factors, which partly reflects extracellular vesicle (EVs) released by stem cell. However, the mechanism(s) by which stem cells/EVs limit stroke injury have yet to be fully defined.MethodsWe evaluated the protection effect of human placenta mesenchymal stem cells (hPMSC) as a potential form of SCT in experimental ischemic stroke ‘transient middle cerebral artery occusion (MCAO)/reperfusion’ mice model.FindingsWe found for the first time that intraperitoneal administration of hPMSCs or intravenous hPMSC-derived EVs, given at the time of reperfusion, significantly protected the ipsilateral hemisphere from ischemic injury. This protection was associated with significant restoration of normal blood flow to the post-MCAO brain. More importantly, EVs derived from hPMSC promote paracrine-based protection of SCT in the MCAO model in a cholesterol/lipid-dependent manner.InterpretationTogether, our results demonstrated beneficial effects of hPMSC/EVs in experimental stroke models which could permit the rapid “translation” of these cells into clinical trials in the near-term.

Highlights

In the US, stroke remains the leading cause of neurologicallymediated disability, and the 3rd leading cause of mortality in adults [1] with stroke incidence and occurrence increasing proportionately with aging in both developed and developing nations
The conceptual advance provided by our current study is to show that intraperitoneal administration of human placenta mesenchymal stem cells in middle cerebral artery occusion (MCAO) model are powerfully protective against acute stroke injury
We found that intraperitoneal (IP) administration of human placenta mesenchymal stem cells (hPMSC) at the beginning of reperfusion produced remarkable and highly significant preservation of ipsilateral hemispheric blood flow, tissue structure and neurological recovery following MCAO compared to untreated group

Summary

Introduction

In the US, stroke remains the leading cause of neurologicallymediated disability, and the 3rd leading cause of mortality in adults [1] with stroke incidence and occurrence increasing proportionately with aging in both developed and developing nations. The act of restoring local blood perfusion can triggers ischemia/reperfusion injury (IRI) that intensifies stroke severity. Methods: We evaluated the protection effect of human placenta mesenchymal stem cells (hPMSC) as a potential form of SCT in experimental ischemic stroke ‘transient middle cerebral artery occusion (MCAO)/reperfusion’ mice model. Findings: We found for the first time that intraperitoneal administration of hPMSCs or intravenous hPMSCderived EVs, given at the time of reperfusion, significantly protected the ipsilateral hemisphere from ischemic injury. This protection was associated with significant restoration of normal blood flow to the postMCAO brain. Interpretation: Together, our results demonstrated beneficial effects of hPMSC/EVs in experimental stroke models which could permit the rapid “translation” of these cells into clinical trials in the near-term

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