Human Umbilical Vein Endothelial Cells Protect Against Hypoxic-Ischemic Damage in Neonatal Brain via Stromal Cell-derived Factor 1/C-X-C Chemokine Receptor Type 4
Background and Purpose—Agents that protect against neurovascular damage provide a powerful neuroprotective strategy. Human umbilical vein endothelial cells (HUVECs) may be used to treat neonates with hypoxic-ischemia (HI) because of its autologous capability. We hypothesized that peripherally injected HUVECs entered the brain after HI, protected against neurovascular damage, and provided protection via stromal cell–derived factor 1/C-X-C chemokine receptor type 4 pathway in neonatal brain.
Methods—Postpartum day 7 rat pups received intraperitoneal injections of low-passage HUVEC-P4, high-passage HUVEC-P8, or conditioned medium before and immediately after HI. HUVECs were transfected with adenovirus-green fluorescent protein for cell tracing. Oxygen–glucose deprivation was established by coculturing HUVEC-P4 with mouse neuroblastoma neuronal cells (Neuro-2a) and with mouse immortalized cerebral vascular endothelial cells (b.End3).
Results—HUVEC-P4–treated group had more blood levels of green fluorescent protein–positive cells than HUVEC-P8–treated group 3 hours postinjection. Intraperitoneally injected HUVEC-P4, but not HUVEC-P8, entered the cortex after HI and positioned closed to the neurons and microvessels. Compared with the condition medium–treated group, the HUVEC-P4–treated but not the HUVEC-P8–treated group showed significantly less neuronal apoptosis and blood–brain barrier damage and more preservation of microvessels in the cortex 24 hours after HI. On postpartum day 14, the HUVEC-P4–treated group showed significant neuroprotection compared with the condition medium–treated group. Stromal cell–derived factor 1 was upregulated in the ipsilateral cortex 3 hours after HI, and inhibiting the stromal cell–derived factor 1/C-X-C chemokine receptor type 4 reduced the protective effect of HUVEC-P4. In vitro transwell coculturing of HUVEC-P4 also significantly protected against oxygen–glucose deprivation cell death in neurons and endothelial cells.
Conclusions—Cell therapy using HUVECs may provide a powerful therapeutic strategy in treating neonates with HI.
- Received October 15, 2012.
- Accepted December 19, 2012.
- © 2013 American Heart Association, Inc.