Intravenous Administration of Human Bone Marrow Stromal Cells Induces Angiogenesis in the Ischemic Boundary Zone After Stroke in Rats

Circulation Research - Tập 92 Số 6 - Trang 692-699 - 2003
Jieli Chen1, Zheng Gang Zhang2,1,3,4, Yi Li1, Lei Wang2,1,3,4, Yong Xu1, Subhash C. Gautam1, Mei Lü1, Zhenping Zhu5,1, Michael Chopp2,1,3,4
1From the Department of Neurology (J.C., Z.G.Z., Y.L., L.W., M.C.), Division of Hematology/Oncology (Y.X.X., S.C.G.), Biostatistics and Research Epidemiology (M.L.), Henry Ford Health Sciences Center, Detroit, Mich; the Department of Antibody Technology (Z.Z.), ImClone Systems Incorporated, New York, NY; and the Department of Physics (M.C.), Oakland University, Rochester, Mich.
2Department of Physics (M.C.), Oakland University, Rochester, Mich.
3ImClone Systems Incorporated, New York, NY;
4Neurology Research, E&R Bldg, Rm 3056, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202.
5Eli-Lilly.

Tóm tắt

We tested the hypothesis that intravenous infusion of human bone marrow stromal cells (hMSCs) promotes vascular endothelial growth factor (VEGF) secretion, VEGF receptor 2 (VEGFR2) expression and angiogenesis in the ischemic boundary zone (IBZ) after stroke. hMSCs (1×10 6 ) were intravenously injected into rats 24 hours after middle cerebral artery occlusion (MCAo). Laser scanning confocal microscopy (LSCM), immunohistochemistry and ELISA were performed to assay angiogenesis and levels of human and rat VEGF in the host brain, respectively. In addition, capillary-like tube formation was measured using mouse brain-derived endothelial cells (MBDECs). Morphological and three dimensional image analyses revealed significant ( P <0.05) increases in numbers of enlarged and thin walled blood vessels and numbers of newly formed capillaries at the boundary of the ischemic lesion in rats (n=12) treated with hMSCs compared with numbers in rats (n=12) treated with PBS. ELISA measurements showed that treatment with hMSCs significantly ( P <0.05) raised endogenous rat VEGF levels in the IBZ from 10.5±1.7 ng/mL in the control group to 17.5±1.6 ng/mL in the hMSC-treated group. In addition, treatment with hMSCs increased endogenous VEGFR2 immunoreactivity. In vitro, when MBDECs were incubated with the supernatant obtained from cultured hMSCs, capillary-like tube formation was significantly ( P <0.01) induced. However, hMSC-induced capillary-like tube formation was significantly ( P <0.01) inhibited when the endothelial cells were incubated with the supernatant from hMSCs in the presence of a neutralizing anti-VEGFR2. These data suggest that treatment of stroke with hMSCs enhances angiogenesis in the host brain and hMSC-enhanced angiogenesis is mediated by increases in levels of endogenous rat VEGF and VEGFR2.

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Circulation Research

Tập 92 Số 6

692-699

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