Overexpression of VLA-4 in glial-restricted precursors enhances their endothelial docking and induces diapedesis in a mouse stroke model

Anna Jablonska, Daniel J. Shea, Suyi Cao, Jeff W.M. Bulte, Miroslaw Janowski, Konstantinos Konstantopoulos, Piotr Walczak

Research output: Contribution to journalArticlepeer-review

Abstract

The loss of oligodendrocytes after stroke is one of the major causes of secondary injury. Glial-restricted progenitors (GRPs) have remylenating potential after intraparenchymal cerebral transplantation. The intraarterial (IA) injection route is an attractive gateway for global brain delivery, but, after IA infusion, naive GRPs fail to bind to the cerebral vasculature. The aim of this study was to test whether overexpression of Very Late Antigen-4 (VLA-4) increases endothelial docking and cerebral homing of GRPs in a stroke model. Mouse GRPs were co-transfected with DNA plasmids encoding VLA-4 subunits (α4, β1). The adhesion capacity and migration were assessed using a microfluidic assay. In vivo imaging of the docking and homing of IA-infused cells was performed using two-photon microscopy in a mouse middle cerebral artery occlusion (MCAO) model. Compared to naïve GRPs, transfection of GRPs with VLA-4 resulted in >60% higher adhesion (p < 0.05) to both purified Vascular Cell Adhesion Molecule-11 (VCAM-11) and TNFα-induced endothelial VCAM-1. VLA-4 + GRPs displayed a higher migration in response to a chemoattractant gradient. Following IA infusion, VLA-4 + GRPs adhered to the vasculature at three-fold greater numbers than naïve GRPs. Multi-photon imaging confirmed that VLA-4 overexpression increases the efficiency of GRP docking and leads to diapedesis after IA transplantation. This strategy may be further exploited to increase the efficacy of cellular therapeutics.

Original languageEnglish (US)
Pages (from-to)835-846
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume38
Issue number5
DOIs
StatePublished - May 1 2018

Keywords

  • Stroke
  • adhesion molecules
  • cell transplantation
  • two-photon microscopy
  • white matter/oligodendrocytes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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