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.
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.
Wang
Guangming
G
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30310, USA.
Guo
Qingmin
Q
Hossain
Mohammed
M
Fazio
Vince
V
Zeynalov
Emil
E
Janigro
Damir
D
Mayberg
Marc R
MR
Namura
Shobu
S
D000818:Animals; D030801:Animals, Genetically Modified; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology*; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020520:Brain Infarction / Q000473:pathology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002199:Capillary Permeability; D018093:Gelatinases / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D018183:Transplantation Chimera
D018093:Gelatinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse