Endothelial progenitor cell transplantation improves long‐term stroke outcome in mice

Abstract

Endothelial progenitor cells (EPCs) have been implicated in playing an important role in vascular repair and revascularization in ischemic organs including brain tissue. However, the cause of EPC migration and the function of EPC playing following post-ischemia are unclear. Here, we reported EPC therapy in a mouse model of transient middle cerebral artery occlusion (tMCAO) to explore the roles of EPC following ischemic brain injury.Human EPCs were cultured, characterized, and confirmed with flow cytometry. Ex vivo expanded EPCs (1×10 6 ) were injected via jugular vein after 1 hour of tMCAO. Histological and behavioral analyses were performed from day 1 to 28 days after tMCAO.EPCs were detected in ischemic brain region 24 hours after MCAO. EPC transplantation significantly reduced ischemic infarct volume at 3 days following MCAO compared to the control (p<0.05). CXCR4 was expressed on majority of EPCs and SDF-1-induced EPC migration was blocked by AMD3100 in vitro. SDF-1 was up-regulated in ischemic brain and AMD3100 could reduce EPCs migration to the ischemic region in vivo, suggesting that SDF-1/CXCR4 was involved in EPC-mediated neuroprotection. Compared to the control, EPC therapy reduced mouse cortex atrophy 4 weeks after tMCAO, which was accompanied by improved neurobehavioral outcomes (p<0.05). In addition, EPC injection potently increased angiogenesis in the periinfarction area (p<0.05).We conclude that systemic delivery of EPC protect against cerebral ischemic injury, promote neurovascular repair, and improve long-term neurobehavioral outcomes. Our data suggests that SDF-1/CXCR4 plays a critical role in EPC-mediated neuroprotection.

Inhibition of CXCL12 Signaling Attenuates the Postischemic Immune Response and Improves Functional Recovery after Stroke

“…Indeed, neurogenesis and gliogenesis in the poststroke brain is markedly attenuated when animals are housed in an EE, 17 in accord with the findings of a decrease in growth-promoting cytokines and chemokines in brains of animals housed in enriched cages. Also, the action of EPCs is observed in immune-deficient nude mice 38 and therefore, the poststroke inflammatory response might have been critically attenuated contributing to the beneficial effects on recovery after MCAO, as observed in the present study. Hence, current data indicate that dependent on the spatiotemporal expression of CXCL12 and CXCR4, this chemokine pathway is involved in early neuroprotection but has adverse effects in the delayed inflammatory response after stroke.…”

“…37 After experimental stroke in mice, CXCL12 promotes angiogenesis and migration of neuronal and endothelial progenitor cells (EPCs) in the ischemic territory. 23,38 Endothelial progenitor cells are thought to secrete growth factors and other neuroprotectants that in concert mediate beneficial actions in the ischemic hemsiphere. 38 In that context, it can be envisaged that the CXCL12 pathway is important in homing of EPCs to the ischemic territory, and hence blockade of the CXCR4 by AMD3100 would be detrimental.…”

“…23,38 Endothelial progenitor cells are thought to secrete growth factors and other neuroprotectants that in concert mediate beneficial actions in the ischemic hemsiphere. 38 In that context, it can be envisaged that the CXCL12 pathway is important in homing of EPCs to the ischemic territory, and hence blockade of the CXCR4 by AMD3100 would be detrimental. It is, however, more likely that AMD3100 depresses the deletrious homing of inflammatory cells, while the importance of EPC in the context of our study may not be of prime significance for recovery.…”

hRpn13, a newly identified component of the 19S particle, regulates proliferation, differentiation, and function in the human osteoblast-like cell line MG63

“…Western blot was performed as described previously [8]. Anti-β-actin, anti-RANKL, anti-OPG, and anti-OCN antibodies were purchased from Cell Signaling (Danvers, MA, USA).…”

Hypoxia-controlled matrix metalloproteinase-9 hyperexpression promotes behavioral recovery after ischemia

“…Brain atrophy volume and behavioral outcome deter mination are commonly used to evaluate therapeutic effects in animal models of stroke [35] . In this study, we found that the HRE-MMP-9 group exhibited less brain atrophy than the CMV group at 3 weeks after ischemia (Fig.…”