Mesenchymal stem cell transplantation changes the gene expression profile of the neonatal ischemic brain

Abstract

Mesenchymal stem cell (MSC) treatment is an effective strategy to reduce brain damage after neonatal hypoxia-ischemia (HI) in mice. We recently showed that a single injection with MSC at either 3 or 10 days after HI (MSC-3 or MSC-10) increases neurogenesis. In case of two injections (MSC-3+10), the second MSC application does not increase neurogenesis, but promotes corticospinal tract remodeling. Here we investigated GFP(+)-MSC engraftment level in the brain using quantitative-PCR analysis. We show for the first time that in the neonatal ischemic brain survival of transplanted MSC is very limited. At 3 days after injection ∼22% of transplanted MSC were still detectable and 18 days after the last administration barely ∼1%. These findings indicate that engraftment of MSC is not likely the underlying mechanism of the efficient regenerative process. Therefore, we tested the hypothesis that the effects of MSC-treatment on regenerative processes are related to specific changes in the gene expression of growth factors and cytokines in the damaged area of the brain using PCR-array analysis. We compared the effect of one (MSC-10) or two (MSC-3+10) injections of 10(5) MSC on gene expression in the brain. Our data show that MSC-10 induced expression of genes regulating proliferation/survival. In response to MSC-3+10-treatment a pattern functionally categorized as growth stimulating genes was increased. Collectively, our data indicate that specific regulation of the endogenous growth factor milieu rather than replacement of damaged tissue by exogenous MSC mediates regeneration of the damaged neonatal brain by MSC-treatment.