Human embryonic neural stem cell transplantation increases subventricular zone cell proliferation and promotes peri‐infarct angiogenesis after focal cerebral ischemia

Abstract

Neurogenesis and angiogenesis are two important processes that may contribute to the repair of brain injury after stroke. This study was designed to investigate whether transplantation of human embryonic neural stem cells (NSCs) into cortical peri-infarction 24h after ischemia effects cell proliferation in the subventricular zone (SVZ) and angiogenesis in the peri-infarct zone. NSCs were prepared from embryonic human brains at 8 weeks gestation. Focal cerebral ischemia was induced by permanent occlusion of the middle cerebral artery of adult rats. Animals were randomly divided into two groups (n=30, each) at 24h after ischemia: NSC-grafted and medium-grafted groups. Toluidine blue staining and 5'-bromo-2'-deoxyuridine (BrdU) or von Willebrand factor (vWF) immunohistochemistry were performed at 7, 14 and 28 days after transplantation. NSC transplantation increased the number of BrdU-positive cells in the ischemic ipsilateral SVZ compared with the medium control at 7 days (P<0.01). This difference in SVZ cell proliferation persisted at 14 days (P<0.01), but was not significant at 28 days (P>0.05). In addition, angiogenesis, as indicated by BrdU and vWF staining in cortical peri-infarct regions, was augmented by 46% and 65% in NSC-grafted rats versus medium-grafted rats at 7 and 14 days, respectively (P<0.05). However, this increase became non-significant at 28 days (P>0.05). Our results indicate that NSC transplantation enhances endogenous cell proliferation in the SVZ and promotes angiogenesis in the peri-infarct zone, even if it is performed in the acute phase of ischemic injury.

Role of neural precursor cells in promoting repair following stroke

“…These results prompt further study of HIF, especially given HIF's role in inducing the expression of various previously discussed factors, including VEGF, EPO, and HB-EGF. Transplanted NPCs have also been shown to promote endogenous NPC proliferation in the SVZ [150,151] , angiogenesis [151] , and to release various trophic factors to promote axonal and dendritic plasticity [152] . The latter study found that the predominantly released factor was VEGF, which may explain the proliferative and angiogenic effects.…”

Neural Stem Cells: Exogenous and Endogenous Promising Therapies for Stroke

“…In addition, this transplanted NSCs managed to survive, migrate, differentiate, and also induce improvement in neurological functions (Zhang et al, 2009a(Zhang et al, , 2009bZhang et al, 2010). Grafted NSCs enhanced the number of BrdU-positive cells in ischemic ipsilateral SVZ at 7 days after transplantation, an effect that persisted to at least 14 days post-transplantation.…”

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

“…Early research also included undifferentiated pluripotent stem cells, however, their use has become limited due to the risk of teratoma and tumor formation (Kawai et al, 2010;Yamashita et al, 2011). Transplanted cells have been demonstrated to promote stroke recovery in animal models through a variety of mechanisms: stimulating both endogenous NPCs and endothelial progenitor cells to migrate to ischemic sites (Bliss et al, 2010;Lindvall and Kokaia, 2011;Dailey et al, 2013), stimulating the proliferation of neuroblasts in the SVZ (Chen et al, 2003;Jin et al, 2011a;Zhang et al, 2011), promoting angiogenesis in the peri-infarct zone (Horie et al, 2011;Zhang et al, 2011;Oki et al, 2012), and decreasing infarct size (Chen et al, 2010a;Gomi et al, 2012;Oki et al, 2012). In addition to the effects on endogenous tissue, transplanted cells can integrate into the existing neural circuitry, reestablishing connections with host cells ; however, it remains unclear if these new connections contribute directly to recovery.…”