A novel therapeutic approach using peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation

Masahiro Hatakeyama,Yasuko Kimura,Tetsuya Takahashi,Masato Kanazawa,Takayoshi Shimohata,Itaru Ninomiya,Osamu Onodera,Masanori Fukushima,Kaoru Omae

doi:10.1038/s41598-019-53418-5

Abstract

Cell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke. Based on previous experiments using microglia preconditioned by oxygen-glucose deprivation, we hypothesized that the administration of peripheral blood mononuclear cells (PBMCs) preconditioned by oxygen-glucose deprivation (OGD-PBMCs) to be a therapeutic strategy for ischemic stroke. Here, OGD-PBMCs were identified to secrete remodelling factors, including the vascular endothelial growth factor and transforming growth factor-β in vitro, while intra-arterial administration of OGD-PBMCs at 7 days after focal cerebral ischemia prompted expression of such factors in the brain parenchyma at 28 days following focal cerebral ischemia in vivo. Furthermore, administration of OGD-PBMCs induced an increasing number of stage-specific embryonic antigen-3-positive cells both in vitro and in vivo. Finally, it was found to prompt angiogenesis and axonal outgrowth, and functional recovery after cerebral ischemia. In conclusion, the administration of OGD-PBMCs might be a novel therapeutic strategy against ischemic stroke.

Highlights

Cell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke
We investigated whether the primary rat and human oxygen-glucose deprivation (OGD)-peripheral blood mononuclear cells (PBMCs) polarised to the protective phenotype promoted functional recovery following focal cerebral ischemia in experimental ischemic stroke
Given that the 18 h OGD was previously shown to cause the protective switch in primary microglia[9], the OGD condition induced PBMCs to increase the secretion of both VEGF and TGF-β in vitro, indicating a polarisation into the protective phenotype (Fig. 1)

Summary

Introduction

Cell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke. Based on previous experiments using OGD-microglia, we hypothesised that intra-arterially administered OGD-PBMCs might cross the BBB, secrete remodelling factors in the brain parenchyma, increase SSEA-3-positive cells, and exert pleiotropic therapeutic effects against focal cerebral ischemia through the promotion of angiogenesis and axonal outgrowth, even in the subacute phase. To test this hypothesis, we investigated whether the primary rat and human OGD-PBMCs polarised to the protective phenotype promoted functional recovery following focal cerebral ischemia in experimental ischemic stroke

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