Transplantation of Flk-1+ human bone marrow-derived mesenchymal stem cells promotes angiogenesis and neurogenesis after cerebral ischemia in rats

Abstract

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) is a potential therapy for cerebral ischemia. Although BMSCs-induced angiogenesis is considered important for neurological functional recovery, the neurorestorative mechanisms are not fully understood. We examined whether BMSCs-induced angiogenesis enhances cerebral tissue perfusion and creates a suitable microenvironment within the ischemic brain, which in turn accelerates endogenous neurogenesis and leads to improved functional recovery. Adult female rats subjected to 2 h middle cerebral artery occlusion (MCAO) were transplanted with a subpopulation of human BMSCs from male donors (Flk-1+ hBMSCs) or saline into the ipsilateral brain parenchymal at 3 days after MCAO. Flk-1+ hBMSCs-treated rats exhibited significant behavioral recovery, beginning at 2 weeks after cerebral ischemia compared with controls. Moreover, rats treated with Flk-1+ hBMSCs showed increased glucose metabolic activity and reduced infarct volume. Flk-1+ hBMSCs treatment significantly increased the expression of vascular endothelial growth factor and brain-derived neurotrophic factor, promoted angiogenesis, and facilitated cerebral blood flow in the ischemic boundary zone. Further, Flk-1+ hBMSCs treatment enhanced proliferation of neural stem/progenitor cells (NSPCs) in the subventricular zone and subgranular zone of the hippocampus. Finally, more NSPCs migrated toward the ischemic lesion and differentiated to mature neurons or glial cells with less apoptosis in Flk-1+ hBMSCs-treated rats. These data indicate that angiogenesis induced by Flk-1+ hBMSCs promotes endogenous neurogenesis, which may cause functional recovery after cerebral ischemia.

Erythropoietin Pretreatment of Transplanted Endothelial Colony-Forming Cells Enhances Recovery in a Cerebral Ischemia Model by Increasing Their Homing Ability: A SPECT/CT Study

“…Clinical follow-up of apoptotic regions has already been correlated with neurologic outcome in patients (32). On day 3 after MCAO, we observed in ECFC PBS and ECFC EPO a huge decrease in apoptosis activation, matching previous ex vivo reports using bone-marrow-derived endothelial progenitor cells (33), C-X-C chemokine receptor type 4-primed endothelial progenitor cells (34), and vascular endothelial growth factor R2 1 mesenchymal stem cell transplantation in MCAO rodent models (35). Moreover, we showed a direct correlation between the number of homing transplanted cells and the attenuation of apoptosis.…”

Opportunities and Challenges: Stem Cell‐Based Therapy for the Treatment of Ischemic Stroke

“…We and other studies demonstrated MSCs treatment increased VEGF expression and angiogenesis in ischemic rats brain [158,159]. In addition, in vitro studies showed that VEGF increased in the conditioned medium of MSCs [160].…”

The Rise of Cell Therapy Trials for Stroke: Review of Published and Registered Studies

“…In summary, MSCs, bone marrow MNCs (BM-MNCs), and UCB-MNCs can improve neurological function in several models of stroke, through a combination of effects, such as neuroprotection, immunomodulation, and stimulation of neural plasticity [54][55][56][57][58][59][60][61][62][63][64], but these effects are not necessarily due to the presence of the cells at the injury site. In addition, MSC and HSPC transplantation can also induce angiogenesis and neurogenesis in the ischemic brain [65,66], two processes that are tightly linked by several regulatory mechanisms [67]. These mechanisms of action seem to rely on the secretion of neurotrophic factors and immunomodulatory molecules by the transplanted cells [68,69], an effect that can be further modulated by the host microenvironment.…”