Vasculogenesis in Experimental Stroke After Human Cerebral Endothelial Cell Transplantation

Abstract

Background and Purpose Despite the reported functional recovery in transplanted stroke models and patients, the mechanism of action underlying stem cell therapy remains not well understood. Here, we examined the role of stem cell-mediated vascular repair in stroke. Methods Adult rats were exposed to transient occlusion of the middle cerebral artery and 3 hours later randomly stereotaxically transplantated with 100K, 200K, or 400K human cerebral endothelial cell 6 viable cells or vehicle. Animals underwent neurological examination and motor test up to day 7 after transplantation then euthanized for immunostaining against neuronal, vascular, and specific human antigens. A parallel in vitro study cocultured rat primary neuronal cells with human cerebral endothelial cell 6 under oxygen-glucose deprivation and treated with vascular endothelial growth factor (VEGF) and anti-VEGF. Results Stroke animals that received vehicle infusion displayed typical occlusion of the middle cerebral artery-induced behavioral impairments that were dose-dependently reduced in transplanted stroke animals at days 3 and 7 after transplantation and accompanied by increased expression of host neuronal and vascular markers adjacent to the transplanted cells. Some transplanted cells showed a microvascular phenotype and juxtaposed to the host vasculature. Infarct volume in transplanted stroke animals was significantly smaller than vehicle-infused stroke animals. Moreover, rat neurons cocultured with human cerebral endothelial cell 6 or treated with VEGF exhibited significantly less oxygen-glucose deprivation-induced cell death that was blocked by anti-VEGF treatment. Conclusions We found attenuation of behavioral and histological deficits coupled with robust vasculogenesis and neurogenesis in endothelial cell-transplanted stroke animals, suggesting that targeting vascular repair sets in motion a regenerative process in experimental stroke possibly via the VEGF pathway.

Candesartan Induces a Prolonged Proangiogenic Effect and Augments Endothelium-Mediated Neuroprotection after Oxygen and Glucose Deprivation: Role of Vascular Endothelial Growth Factors A and B

“…The failure of direct neuroprotection in stroke therapy has promoted a more holistic approach to treatment, taking into consideration the communication between different brain cell types and especially considering endothelial cells as a "neuroprotective organ" (Guo et al, 2008). In agreement, a recent study demonstrated the involvement of VEGF-A in endothelium-mediated neuroprotection after stroke (Ishikawa et al, 2013). In summary, our findings provide new insights on the benefits of candesartan and show that these benefits are mediated through orchestrated actions of multiple players, including endothelial VEGF-A and VEGF-B.…”

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

“…94 A recent study showed that endothelial cells transplanted into the brain promote vasculogenesis and enhance neurogenesis further providing support for this concept. 95 This neuroplasticity is important for meaningful functional recovery, but may be diminished by aging and other comorbidities. 93 There is emerging evidence that neuroplasticity and recovery after brain injury involve areas remote from the injury itself.…”

An update on stem cell therapy for neurological disorders: cell death pathways as therapeutic targets

“…The study revealed death of RCMs through the conference of cell death signals from the ischemic brain to the heart. With the results gained from this study [14], Ghanekar and her colleagues address these findings and their clinical implications in this review paper. Considering the insular cortex is responsible for controlling heart rhythm, they assert that stroke in this region could result in arrhythmias or even sudden death.…”

“…Considering the insular cortex is responsible for controlling heart rhythm, they assert that stroke in this region could result in arrhythmias or even sudden death. The in vitro study also identified autophagy-related cell death signals could be responsible for cardiac failure following stroke [14], indicating that while stroke may initiate in one area, the damage can spread to the rest of the brain and possibly the heart. The presence of elevated levels of brain natriuretic peptide (BNP) and N-terminal-pro-brain natriuretic peptide (NT-proBNP) following ischemic stroke suggests the role of the kidney in stroke pathology.…”

“…Accumulating evidence advances the importance of determining the direct cell death pathway between ischemic stroke and cardiac failure in order to further the development of innovative treatments that address both diseases [14,15]. Ghanekar and her collaborators first highlight the shared risk factors of both diseases, including hypertension and diabetes, as well as asserting that after a stroke, high levels of cardiac enzymes exist in the body, indicating the presence of stressed or dying cardiac cells.…”