Chemokine, vascular and therapeutic effects of combination Simvastatin and BMSC treatment of stroke.
We investigated the additive therapeutic effect of the combination treatment of stroke with sub-therapeutic doses of Simvastatin, a HMG-CoA reductase inhibitor, and bone marrow stromal cells (BMSCs). Rats were administered Simvastatin (0.5 mg/kg), BMSCs (1x10(6)) or combination of Simvastatin and BMSCs starting at 24 h after stroke. Combination treatment significantly improved neurological outcome, enhanced angiogenesis and arteriogenesis, and increased the number of engrafted-BMSCs in the ischemic brain. The number of engrafted-BMSCs and arteriogenesis was significantly correlated with functional outcome. Simvastatin significantly increased stromal cell-derived factor-1 (SDF1) expression in the ischemic brain and chemokine (CXC motif) receptor-4 (CXCR4) in BMSCs, and increased BMSC migration to RBMECs and astrocytes. Combination treatment of stroke upregulates the SDF1/CXCR4 axis and enhances BMSC migration into the ischemic brain, amplifies arteriogenesis and angiogenesis, and improves functional outcome after stroke.
Cui
Xu
X
Department of Neurology, E&R Bldg., Room 3091, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202, USA.
Chopp
Michael
M
Zacharek
Alex
A
Roberts
Cynthia
C
Lu
Mei
M
Savant-Bhonsale
Smita
S
Chen
Jieli
J
D000704:Analysis of Variance; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000379:methods; D001973:Bromodeoxyuridine / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000628:therapy*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D009460:Neurologic Examination / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*; D017154:Stromal Cells / Q000502:physiology
D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019718:Receptors, CXCR4; D019821:Simvastatin; D001973:Bromodeoxyuridine