There is a great interest in the possibility of repairing the nervous system by transplantation new cells that can replace those lost through damage in neurological disorders. Key functions such as the replacement of neural cells have been recently challenged by intrinsic bystander capacities of undifferentiated donor cells to restore these cells. A comprehensive knowledge how transplanted stem cells exert their therapeutic achievements is still lacking. Here we investigated the effects of HUCB-NSC infused into the damaged rat brain at 72 h post ischemia on endogenous neurogenesis. The goal of our studies was to examine the proliferation and migration of host progenitor cells, analyze the substantial matrix remodeling of tissue and the presence of neurotrophic factors in rat brain after focal ischemia followed by HUCB-NSC transplantation. Methods: 2×104 HUCB-NSC were transplanted into corpus callosum of naive or focally injured rat brain 3 days after ischemic insult. At 1, 3, 7 and 14 days rat brains were removed. Endogenous cell proliferation was determined by BrdU incorporation. Then immunocytochemical analysis of doublecortin (DCX) and PSA-NCAM (markers expressed by immature migratory neuroblasts), and in situ zymography of MMPs activity was performed. Additionally, total RNA was isolated from rat brain tissue and RTPCR was performed using sets of primers of each of human and rat neurotrophic factor genes. Results: OUA-induced brain lesion resulted in increase of proliferating (BrdU+) and migrating (DCX+ and PSA-NCAM+) cells in subventricular zone (SVZ) and subgranular zone (SGZ) regions in comparison to intact rats. This response has been potentiated by HUCB-NSC transplantation. At 7th day after HUCB-NSC infusion the intense migration of DCX+cells from SVZ towards ischemic boundary regions of the striatum was observed. Moreover, the activation of MMPs in cells was visible in SVZ. Double-labeling showed co-localization of DCX marker with MMPs activity. The presence of MMPs appeared to be associated with cell nuclei and cytoplasm but interestingly it was also seen outside the cell bodies and in the neuronal protrusions. In OUAinduced lesion rat brain tissue, the expression pattern of rat-origin neurotrophic factors mRNA was higher than in intact rats. HUCBNSC transplantation into focal brain ischemic tissue significantly increased mRNA expression of several rat-origin growth factors, such as GDNF, CNTF responsible for regulation of proliferation and maturation of stem cells as well as IGF-1, HGF and presaposin functioning as anti-apoptotic mediators. The significant increment was observed 7 days after HUCB-NSC infusion. Using Real Time PCR method we were able to detect the presence of mRNA of BDNF, GDNF, NT3, IGF-1, HGF, semaphorin and presaposin of human-origin factors in the rat brain recipients of HUCB-NSC grafts. Conclusions: Transplantation of HUCB-NSC triggers early expansion of endogenous progenitor pool increasing fraction of proliferating cells in SVZ and SGZ of brain ischemic rats. Proteolytic activity of MMPs in extracellular compartment suggests its ability to remodel extracellular matrix and facilitate migration of neuroblasts to the damaged brain areas. The mechanism promoting recovery from ischemic injury remains to be clarified, although it is likely that it might be due to HUCB-NSC graft-induced release of neurotrophic factors by the host cells as well as the presence of human neural stem cells derived factors. Supported by MMRC statutory fund.