Bone marrow-derived mononuclear cells ameliorate neurological function in chronic cerebral infarction model mice via improvement of cerebral blood flow

Abstract

Background aims: Stroke is a frequently observed neurological disorder that might lead to permanent and severe disability. Recently, various regenerative therapies have been developed, some of which have already been applied clinically. However, their outcomes have not been fully satisfactory. In particular, the development of regenerative therapies for chronic ischemic stroke is greatly needed. Herein intracerebral administration of bone marrow-derived mononuclear cells (BM-MNCs) was assessed as a potential treatment for chronic ischemic stroke using a severe combined immunodeficiency mouse model characterized by minimal vascular variation unrelated to immunodeficiency.

Methods: A reproducible model of permanent middle cerebral artery occlusion was prepared, and intracerebral BM-MNC transplantation was performed 14 days after stroke induction in the infarcted brain.

Results: Sensorimotor behavioral function and cerebral blood flow were significantly improved upon treatment with BM-MNCs compared to control medium injection. The transplanted cells exhibited characteristics of the vascular endothelium and microglia/macrophages. Significant angiogenesis and suppression of astrogliosis and microgliosis were observed in the affected brain. Messenger RNA expression analysis showed significant increases in anti-inflammatory cytokines, A2 astrocyte/anti-inflammatory microglia markers and vascular endothelial markers such as vascular endothelial growth factor and significant decreases in pro-inflammatory cytokines and A1 astrocyte/pro-inflammatory microglia markers following BM-MNC transplantation.

Conclusions: These results suggest that intracerebral administration of BM-MNCs should be considered an effective cell therapy for chronic stroke.

Keywords: bone marrow-derived mononuclear cells; cerebral blood flow; chronic cerebral infarction; microglia; vascular endothelium.