Grafted Neural Progenitor Cells Persist in the Injured Site and Differentiate Neuronally in a Rodent Model of Cardiac Arrest-Induced Global Brain Ischemia.

Hypoxic-ischemic brain injury is the leading cause of disability and death after successful resuscitation from cardiac arrest, and, to date, no specific treatment option is available to prevent subsequent neurofunctional impairments. The hippocampal cornu ammonis segment 1 (CA1) is one of the brain areas most affected by hypoxia, and its degeneration is correlated with memory deficits in patients and corresponding animal models. The aim of this work was to evaluate the feasibility of neural progenitor cell (NPC) transplantation into the hippocampus in a refined rodent cardiac arrest model. Adult rats were subjected to 12 min of potassium-induced cardiac arrest and followed up to 6 weeks. Histological analysis showed extensive neuronal cell death specifically in the hippocampal CA1 segment, without any spontaneous regeneration. Neurofunctional assessment revealed transient memory deficits in ischemic animals compared to controls, detectable after 4 weeks, but not after 6 weeks. Using stereotactic surgery, embryonic NPCs were transplanted in a subset of animals 1 week after cardiac arrest and their survival, migration, and differentiation were assessed histologically. Transplanted cells showed a higher persistence in the CA1 segment of animals after ischemia. Glia in the damaged CA1 segment expressed the chemotactic factor stromal cell-derived factor 1 (SDF-1), while transplanted NPCs expressed its receptor CXC chemokine receptor 4 (CXCR4), suggesting that the SDF-1/CXCR4 pathway, known to be involved in the migration of neural stem cells toward injured brain regions, directs the observed retention of cells in the damaged area. Using immunostaining, we could demonstrate that transplanted cells differentiated into mature neurons. In conclusion, our data document the survival, persistence in the injured area, and neuronal differentiation of transplanted NPCs, and thus their potential to support brain regeneration after hypoxic-ischemic injury. This may represent an option worth further investigation to improve the outcome of patients after cardiac arrest.