Induction of neuro-protective/regenerative genes in stem cells infiltrating post-ischemic brain tissue

Ischemic strokes were induced in C57BL/6 mice by middle cerebral artery occlusion for 1 h, followed by reperfusion. BMSC were isolated from H-2 Kb-tsA58 (immortomouse？) mice, and were administered (i.v.) 24 h after reperfusion. At the peak of therapeutic improvement (14 days after the ischemic insult), infarcted brain tissue was isolated, and the BMSC were isolated by culturing at 33°C. Microarray analysis and RT-PCR were performed to compare differential gene expression between na？ve and infiltrating BMSC populations.Z-scoring revealed dramatic differences in the expression of extracellular genes between na？ve and infiltrating BMSC. Pair-wise analysis detected 80 extracellular factor genes that were up-regulated (≥ 2 fold, P < 0.05, Benjamini-Hochberg correction) between na？ve and infiltrated BMSC. Although several anticipated neuroregenerative, nerve guidance and angiogenic factor (e.g., bFGF, bone morphogenetic protein, angiopoietins, neural growth factor) genes exhibited an increased expression, a remarkable induction of genes for nerve guidance survival (e.g., cytokine receptor-like factor 1, glypican 1, Dickkopf homolog 2, osteopontin) was also noted.BMSC infiltrating the post-ischemic brain exhibit persistent epigenetic changes in gene expression for numerous extracellular genes, compared to their na？ve counterparts. These genes are relevant to the neuroprotection, regeneration and angiogenesis previously described following stem cell therapy in animal models of ischemic stroke.In various animal models of central nervous system (CNS) injury, bone marrow stromal cells (BMSC) have been reported to be effective in limiting tissue damage[1-4]. The therapeutic effects of stem cells have been attributed to their ability to release of a mixture of neurotrophins, growth factors, and other substances that induce restorative processes in post-ischemic brain tissue[1,5-8]. Although some studies have focused on the role of one or more potential neuroprotective factors th