Submitted on March 9, 2007
Accepted on July 12, 2007
TISSUE-SPECIFIC STEM CELLS
|
Nitric Oxide Donor Upregulation of SDF1/CXCR4 Enhances BMSC, Migration into Ischemic Brain after Stroke
Xu Cui 1,
Jieli Chen 1,
Alex Zacharek 1,
Yi Li 1,
Cynthia Roberts 1,
Alissa Kapke 2,
Smita Savant-Bhonsale 3,
Michael Chopp 4*
1 Departments of Neurology
2 Biostatistics and Research Epidemiology, Henry Ford Health Sciences Center, Detroit, Michigan 48202
3 Neurobiology, Theradigm, Inc. Baltimore, MD 21227; and
4 Departments of Neurology, Department of Physics, Oakland University, Rochester, Michigan 48309
* To whom correspondence should be addressed. E-mail: chopp{at}neuro.hfh.edu.
 |
Abstract |
|---|
Stromal cell-Derived Factor-1 (SDF1) and its chemokine (CXC motif) receptor 4 (CXCR4) along with matrix metalloproteinases (MMPs) regulate bone marrow stromal cell (BMSC) migration. We tested the hypothesis that an NO donor, DETA-NONOate, increases endogenous ischemic brain SDF1 and BMSC CXCR4 and MMP9 expression, which promote BMSC migration into ischemic brain and thereby enhance functional outcome after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo) and 24h later the following were intravenously administered (n=9/group): 1. PBS; 2. BMSC (5x105); 3. 0.4 mg/kg DETA-NONOate; 4. Combination CXCR4-inhibition BMSC with DETA-NONOate; 5. Combination BMSC with DETA-NONOate. To elucidate the mechanisms underlying combination-enhanced BMSC migration, transwell co-cultures of BMSC with mouse brain endothelial cells (MBECs) or astrocytes were performed. Combination treatment significantly improved functional outcome after stroke compared to BMSC monotherapy and MCAo control, and increased SDF1 expression in the ischemic brain compared to DETA-NONOate monotherapy and MCAo control. The number of BMSCs in the ischemic brain is significantly increased after combination BMSC with DETA-NONOate treatment compared to monotherapy with BMSCs. The number of engrafted BMSCs was significantly correlated with functional outcome after stroke. DETA-NONOate significantly increased BMSC CXCR4 and MMP9 expression, and promoted BMSC adhesion and migration to MBECs and astrocytes compared with non-treatment BMSCs. Inhibition of CXCR4 or MMPs in BMSCs significantly decreased DETA-NONOate-induced BMSC adhesion and migration. Our data demonstrate that DETA-NONOate enhanced the therapeutic potency of BMSCs, possibly via upregulation of SDF1/CXCR4 and MMP pathways and increased BMSC engraftment into the ischemic brain.
Key Words.
DETA-NONOate, SDF1/CXCR4, MMPs, BMSC, migration, stroke
