Importance of Injury in Stem Cell Neurorepair

Milano, Italy -

In various pathological conditions injured tissue attracts endogenous stem cells through release of various factors. This is known, for example, in the area of myocardial infarction where circulating levels of stem cells increase in the peripheral blood of patients after heart attacks. Theoretically, the idea is that the ischemia and tissue damage release systemic factors which mobilize stem cells.

The concept of microenvironment in stem cell activity was recently addressed (Capone et al. Neurosphere-derived cells exert a neuroprotective action by changing the ischemic microenvironment. PLoS ONE. 2007 Apr 18;2:e373).

The paper used neurosphere derived cells (B6 mouse derived) as a source of stem cells and administered these cells intracerebroventricularly into syngeneic mice that were given a 30 minute middle cerebral artery occlusion.

The interesting thing is that the authors injured the cells either 4 hours after induction of ischemia or 7 days.

Mice injected at 4 hours had a marked improvement in behavioural functions as opposed to mice injected 7 days after ischemia induction. Injection of fibroblast control cells did not improve behavioral functions.

Stem cell viability was much longer in the group that recieved stem cells 4 hours after ischemia as opposed to 7 days. Interestingly, expression of neuroprotective cytokines was also found only in mice recieving the cells 4 hours but not 7 days after ischemia.

These data appear to suggest that timing of stem cell administration is critical, as well as the importance of the local microenvironmental conditions.




NC were infused intracerebroventricularly 4 h or 7 d after 30 min middle cerebral artery occlusion. In ischemic mice receiving cells at 4 h, impairment of open field performance was significantly improved and neuronal loss significantly reduced 7-14 d after ischemia compared to controls and to ischemic mice receiving cells at 7 d. Infusion of murine foetal fibroblast in the same experimental conditions was not effective. Assessment of infused cell distribution revealed that they migrated from the ventricle to the parenchyma, progressively decreased in number but they were observable up to 14 d. In mice receiving NC at 7 d and in sham-operated mice, few cells could be observed only at 24 h, indicating that the survival of these cells in brain tissue relates to the ischemic environment. The mRNA expression of trophic factors such as Insulin Growth Factor-1, Vascular Endothelial Growth Factor-A, Transforming Growth Factor-beta1, Brain Derived Neurotrophic Factor and Stromal Derived Factor-1alpha, as well as microglia/macrophage activation, increased 24 h after NC infusion in ischemic mice treated at 4 h compared to sham-operated and to mice receiving cells at 7 d. CONCLUSIONS/SIGNIFICANCE: NC reduce functional impairment and neuronal damage after ischemia/reperfusion injury. Several lines of evidence indicate that the reciprocal interaction between NC and the ischemic environment is crucial for NC protective actions. Based on these results we propose that a bystander control of the ischemic environment may be the mechanism used by NC to rapidly restore acutely injured brain function.