Transplantation of human umbilical cord blood (hucb) cells in a model of hypoxic-ischemic brain injury led to the amelioration of lesion-impaired neurological and motor functions. However, the mechanisms by which transplanted cells mediate functional recovery after brain injury are largely unknown. In this study, the effects of hucb cell transplantation were investigated in this experimental paradigm at the cellular and molecular level. As the pathological cascade in hypoxic-ischemic brain injury includes inflammation, reduced blood flow, and neuronal cell death, we analyzed the effects of peripherally administered hucb cells on these detrimental processes, investigating the expression of characteristic marker proteins. Application of hucb cells after perinatal hypoxic-ischemic brain injury correlated with an increased expression of the proteins Tie-2 and occludin, which are associated with angiogenesis. Lesion-induced apoptosis, determined by expression of cleaved caspase-3, decreased, whereas the number of vital neurons, identified by counting of NeuN-positive cells, increased. In addition, we observed an increase in the expression of neurotrophic and pro-angiogenic growth factors, namely BDNF and VEGF, in the lesioned brain upon hucb cell transplantation. The release of neurotrophic factors mediated by transplanted hucb cells might cause a lower number of neurons to undergo apoptosis and result in a higher number of living neurons. In parallel, the increase of VEGF might cause growth of blood vessels. Thus, hucb transplantation might contribute to functional recovery after brain injury mediated by systemic or local effects.

Previous studies have shown that transplanted human umbilical cord blood (hUCB)-derived mononuclear cells exert therapeutic effects in various animal models of CNS impairments, including those of perinatal hypoxic-ischemic brain injury. However, the mechanisms of how transplanted cells exert their beneficial effects on the damaged tissue are still unclear. As detection of hUCB cells at the lesion site coincides with the therapeutic effects observed in our model, we investigated the role of the chemokine stromal derived factor (SDF)-1 (CXCL12) as a possible candidate for chemotaxis-mediated 'homing' of transplanted hUCB cells to a hypoxic-ischemic lesion in the perinatal rat brain. Following the hypoxic-ischemic insult expression of SDF-1 significantly increased in lesioned brain hemispheres and was mainly associated with astrocytes. Transplanted hUCB cells expressing the SDF-1 receptor CXCR4 migrated to the lesion site within one day. Inhibition of SDF-1 by application of neutralizing antibodies in vivo resulted in a significantly reduced number of hUCB cells at the lesioned area. The increase in glial SDF-1 expression shortly after induction of the lesion and hUCB cells expressing the corresponding receptor makes SDF-1 a potential chemotactic factor for hUCB cell migration. The reduction of hUCB cells present at the lesion site upon functional inhibition of SDF-1 strengthens the view that the SDF-1/CXCR4 axis is of major importance for cell 'homing'.

Cell yield is affected by certain donor characteristics. hUCB- and WJ-derived MSCs may serve distinct therapeutic niches.

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