Transplantation of iPS-derived vascular endothelial cells improves white matter ischemic damage.

Bin Xu,Hiroya Shimauchi‐Ohtaki,Yuhei Yoshimoto,Masashi Kurachi,Yasuki Ishizaki

doi:10.1111/jnc.14949

Abstract

White matter infarct induces demyelination and brain dysfunction. We previously reported that transplantation of brain microvascular endothelial cells improved the behavioral outcome and promoted remyelination by increasing the number of oligodendrocyte precursor cells in the rat model of white matter infarct. In this study, we investigated the effects of transplantation of vascular endothelial cells generated from human induced pluripotent stem cells (iPSCs) on the rat model of white matter infarct. Seven days after induction of ischemic demyelinating lesion by injection of endothelin‐1 into the internal capsule of a rat brain, iPSC‐derived vascular endothelial cells (iVECs) were transplanted into the site of demyelination. The majority of iVECs transplanted into the internal capsule survived for 14 days after transplantation when traced by immunohistochemistry for a human cytoplasmic protein. iVEC transplantation significantly recovered hind limb rotation angle as compared to human iPSC or rat meningeal cell transplantation when evaluated using footprint test. Fourteen days after iVEC transplantation, the infarct area remarkably decreased as compared to that just before the transplantation when evaluated using magnetic resonance imaging or luxol fast blue staining, and remyelination was promoted dramatically in the infarct when assessed using luxol fast blue staining. Transplantation of iVECs increased the number of oligodendrocyte lineage cells and suppressed the inflammatory response and reactive astrocytogenesis. These results suggest that iVEC transplantation may prove useful in treatment for white matter infarct.

Highlights

Ischemic stroke in white matter causes severe neurological disorder and brain dysfunction as a result of interruption of the blood flow (Otero-Ortega et al, 2015; Wang et al, 2016)
We previously reported that transplantation of brain microvascular endothelial cells (MVECs) improved the behavioral outcome and promoted remyelination in an endothelin-1 (ET-1)-injected white matter infarct model (Puentes et al, 2012)
Our results showed that the density of Olig2positive cells was significantly increased in ischemic demyelinating lesion of iPSC-derived vascular endothelial cell (iVEC)-transplanted rats, compared with human induced pluripotent stem cell (iPSC)- or rat meningeal cell (MC)-transplanted, or bovine serum albumin (BSA)-injected animals (Figure 6)

Summary

Introduction

Ischemic stroke in white matter causes severe neurological disorder and brain dysfunction as a result of interruption of the blood flow (Otero-Ortega et al, 2015; Wang et al, 2016). Acute-phase interventions, such as tissue-type plasminogen activator and mechanical thrombectomy, exist for ischemic stroke with dramatically improved outcomes. After the acute phase of stroke, the only available therapy to aid recovery is rehabilitation, but the extent of recovery and outcome may not achieve a level sufficient for functional independence (Love, Selim, Spector, & Lo, 2019). Ischemic stroke leads to extensive demyelination and defective remyelination in white matter (Fumagalli, Lecca, & Abbracchio, 2016; Maki, Liang, Miyamoto, Lo, & Arai, 2013). Promotion of remyelination in white matter ischemia is critical to the recovery of proper brain functions

Methods

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Conclusion