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

Abstract

Abstract-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 (1ϫ10 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 (PϽ0.05) 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 (nϭ12) treated with hMSCs compared with numbers in rats (nϭ12) treated with PBS. ELISA measurements showed that treatment with hMSCs significantly (PϽ0.05) raised endogenous rat VEGF levels in the IBZ from 10.5Ϯ1.7 ng/mL in the control group to 17.5Ϯ1.6 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 (PϽ0.01) induced. However, hMSC-induced capillary-like tube formation was significantly (PϽ0.01) 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.

Neurorestorative treatment of stroke: Cell and pharmacological approaches

“…33,34 MSCs thus behave as small biochemical and molecular factories and catalysts, producing and inducing within parenchymal cells many cytokines and trophic factors that enhance angiogenesis and vascular stabilization in the ischemic boundary (which is where the majority of MSCs that survive in the brain are located). 35 In addition, neurogenesis in the SVZ and synaptogenesis are greatly amplified by MSC treatment. MSCs also induce other agents within injured brain, such as bone morphogenetic proteins BMP2 and BMP4 or connexin 43 expression in astrocytes.…”

Atorvastatin Induction of VEGF and BDNF Promotes Brain Plasticity after Stroke in Mice

“…Likewise, BDNF regulates neuronal survival, cell migration, and synaptic function (Aguado et al, 2003;Gorski et al, 2003). Statins increase VEGF in endothelial and osteoblast cells (Chen et al, 2003a;Maeda et al, 2003). Both VEGF and BDNF increase in ischemic brain with other neurorestorative treatments of stroke, such as with bone marrow stromal cells (Chen et al, 2002;Matsuno et al, 2004).…”

Primate Embryonic Stem Cell-Derived Neuronal Progenitors Transplanted into Ischemic Brain

“…However, present therapies are mainly for primary or secondary prevention. Therefore, cell replacement therapies, such as those involving embryonic stem cells (ES cells; Erdo et al, 2003), neural stem cells (Modo et al, 2002a, b;Nelson et al, 2002;Savitz et al, 2002;Watson et al, 2003), and bone marrow-derived stem cells (Beck et al, 2003;Chen et al, 2001Chen et al, , 2003Li et al, 2001Li et al, , 2002Zhao et al, 2003), have the possibility of offering a novel potential treatment for stroke damage (Bjorklund and Lindvall, 2000;Kondziolka et al, 2002).…”