Bone marrow-derived cells are the major source of MMP-9 contributing to blood-brain barrier dysfunction and infarct formation after ischemic stroke in mice

Brain Res. 2009 Oct 19;1294:183-92. doi: 10.1016/j.brainres.2009.07.070. Epub 2009 Jul 29.

Abstract

Matrix metalloproteinase (MMP)-9 has been shown to contribute to blood-brain barrier (BBB) disruption, infarct formation, and hemorrhagic transformation after ischemic stroke. The cellular source of MMP-9 detectable in the ischemic brain remains controversial since extracellular molecules in the brain may be derived from blood. We here demonstrate that bone marrow-derived cells are the major source of MMP-9 in the ischemic brain. We made bone marrow chimeric mice with MMP-9 null and wild-type as donor and recipient. After 90 min of transient focal cerebral ischemia, MMP-9 null mice receiving wild-type bone marrow showed comparable outcomes to wild-type in brain MMP-9 levels and BBB disruption (endogenous albumin extravasation) at 1 h post-reperfusion and infarct size at 24 h post-reperfusion. In contrast, wild-type animals replaced with MMP-9 null bone marrow showed barely detectable levels of MMP-9 in the ischemic brain, with attenuations in BBB disruption and infarct size. MMP-9 null mice receiving wild-type bone marrow showed enhanced Evans blue extravasation as early as 1 h post-reperfusion compared to wild-type mice replaced with MMP-9 null bone marrow. These findings suggest that MMP-9 released from bone marrow-derived cells influences the progression of BBB disruption in the ischemic brain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Blood-Brain Barrier / pathology
  • Blood-Brain Barrier / physiopathology*
  • Bone Marrow Cells / physiology*
  • Bone Marrow Transplantation
  • Brain / drug effects
  • Brain / pathology
  • Brain / physiopathology
  • Brain Infarction / pathology
  • Brain Infarction / physiopathology*
  • Brain Ischemia / pathology
  • Brain Ischemia / physiopathology*
  • Capillary Permeability
  • Gelatinases / metabolism
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Stroke / pathology
  • Stroke / physiopathology*
  • Time Factors
  • Transplantation Chimera

Substances

  • Gelatinases
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse