Bone Marrow Stromal Cells Alleviate Secondary Damage in the Substantia Nigra After Focal Cerebral Infarction in Rats.

Jizi Jin,Lixuan Zhan,Xialin Zuo,Weiwen Sun,En Xu,Kongping Li,Yanyan Tang

doi:10.3389/fncel.2019.00338

Abstract

Transplantation of bone marrow stromal cells (BMSCs) is a promising therapy for ischemic stroke. Previously, we had reported that the secondary degeneration occurred in the ipsilateral substantia nigra (SN) after permanent distal branch of middle cerebral artery occlusion (dMCAO) in Sprague-Dawley rats. However, whether BMSCs have neurorestorative effects on the secondary damage in the SN after focal cerebral infarction has not known. In this study, rats were subjected to dMCAO followed by intravenous administration of BMSCs 1 day later. We found that transplanted BMSCs survived and migrated to cortical infarct areas and ipsilateral SN. Furthermore, BMSCs promoted neurogenesis through proliferation and differentiation in the SN after dMCAO. Rats implanted with BMSCs showed significant improvement in their performance of modified neurological severity scores and adhesive-removal test. Engrafted BMSCs enhanced survival of dopaminergic neuron, reduced gliosis in the ipsilateral SN, and increased contents of dopamine (DA) and its metabolites in the ipsilateral striatum after dMCAO. With pseudorabies virus-152 as a retrograde tracer, we also demonstrated that BMSCs could effectively enhance the cortico-striatum-nigral connections. These results suggest that BMSCs transplantation exerts neurorestorative effects after cortical infarction through promoting endogenous neurogenesis, increasing contents of DA and its metabolites, alleviating the secondary neuronal damage in the SN, enhancing the cortico-striatum-nigral projections pathway, and finally improving the neurological functional outcome.

Highlights

Stroke has been the leading cause of mortality and disability in China, the current mortality rate in China is 157 per 100,000, constituting almost 1/3 of the total number of deaths from stroke worldwide (Liu et al, 2011; Wang et al, 2017)
Secondary Degeneration Was Observed in the Ipsilateral Substantia Nigra After Focal Cortical Infarction
The in vivo fluorescence imaging showed that the transplanted bone marrow stromal cells (BMSCs)-dioctadecyltetramethyl indotricarbocyanine iodide (DiR)+ could migrate from peripheral blood to the ipsilateral brain after distal middle cerebral artery occlusion (dMCAO)

Summary

Introduction

Stroke has been the leading cause of mortality and disability in China, the current mortality rate in China is 157 per 100,000, constituting almost 1/3 of the total number of deaths from stroke worldwide (Liu et al, 2011; Wang et al, 2017). It has been accepted that cortical cerebral infarction leads to neuropathologic damages at primary lesion site, and in nonischemic remote regions such as hippocampus, thalamus, substantia nigra (SN), distal pyramidal tract, peripheral nerves and muscles (Forno, 1983; Zhang et al, 2012; Dang et al, 2016; Zuo et al, 2016, 2018). This phenomenon is termed as post-stroke secondary degeneration. Alleviating secondary neurodegeneration can be a promising target of neuroprotection and neurorestoration beyond the therapeutic time window for acute stroke

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