Intracerebral transplantation of erythropoietin-producing fibroblasts facilitates neurogenesis and functional recovery in an ischemic stroke model.

ABSTRACT

INTRODUCTION: Erythropoietin (EPO) can enhance neurogenesis and fibroblasts can secrete growth factors; together, they may benefit ischemic stroke. We transplanted EPO-producing fibroblasts into the rodent infarcted brain to test their effect on neurogenesis and functional recovery. METHODS: A total of 106 cells of EPO-producing NIH/3T3 fibroblasts (EPO/EGFP/3T3) or enhanced green fluorescence protein (EGFP)-expressing fibroblasts (EGFP/3T3) were stereotaxically injected into the infarcted striatum of adult rats that received transient middle cerebral artery occlusion (MCAO) surgery 1 day poststroke. On day 14 after MCAO, the animals were euthanized for the evaluation of neurogenesis via immunohistochemistry and of the expression of growth factors using enzyme-linked immunosorbent assay. The infarct volume was analyzed using magnetic resonance imaging and the neurological behavior was assessed using the neurological severity scoring performed within 14 days after MCAO. RESULTS: The MCAO rats with EPO/EGFP/3T3 treatment showed high EPO expression in the infarcted brain for at least 1 week. The concentration of brain-derived neurotrophic factor was higher in both hemispheres of MCAO rats with either EGFP/3T3 or EPO/EGFP/3T3 treatment at 14 days poststroke compared with untreated MCAO rats. The number of Ki-67-, nestin-, or doublecortin-immunoreactive cells in bilateral subventricular zones was higher in EPO/EGFP/3T3-treated MCAO rats than it was in untreated MCAO control animals, indicating the enhancement of neurogenesis after EPO/EGFP/3T3 treatment. Notably, post-MCAO EPO/EGFP/3T3 treatment significantly reduced infarct size and improved functional recovery. CONCLUSION: The intracerebral transplantation of EPO-producing fibroblasts benefited an ischemic stroke model probably via the enhancement of neurogenesis.