Abstract
IntroductionErythropoietin (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.MethodsA 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.ResultsThe 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.ConclusionThe intracerebral transplantation of EPO‐producing fibroblasts benefited an ischemic stroke model probably via the enhancement of neurogenesis.
Highlights
Erythropoietin (EPO) can enhance neurogenesis and fibroblasts can secrete growth factors; together, they may benefit ischemic stroke
The EPO concentration in bilateral striata was not different between the three groups on day 14 post‐ middle cerebral artery occlusion (MCAO). These results showed that the post‐MCAO transplantation of fibroblasts (EGFP/3T3 or EPO/enhanced green fluorescence protein (EGFP)/3T3 cells) in‐ creased the concentration of brain‐derived neurotrophic factor (BDNF) in bilateral striata of MCAO rats
The glial fibrillary acidic protein (GFAP)‐immunoreactive area in bilateral sub‐ ventricular zone (SVZ) was sim‐ ilar among the three groups. These findings indicate that both EPO/ EGFP/3T3 and EGFP/3T3 treatments enhanced cell proliferation in the bilateral SVZs of MCAO rats
Summary
Stroke is one of the leading causes of mortality and physical/men‐ tal disability worldwide (Benjamin et al, 2017). Poststroke neuroprotective therapy has been investigated for decades, no treatment has shown obvious benefi‐ cial effects in clinical trials (Charidimou et al, 2017). Preclinical studies have demonstrated that systemic EPO treatment facilitated stroke recovery in experimental stroke models (Gonzalez et al, 2013; Nguyen, Cherry, Scott, Ryou, & Mallet, 2014; Siren et al, 2001; Wang, Zhang, Wang, Zhang, & Chopp, 2004), clinical trials using sys‐ temic EPO administration did not consistently show effectiveness and safety in stroke patients (Yao et al, 2017). In this study, we attempted to use a fibroblast cell line as a carrier and transplant EPO‐producing fibroblasts directly into the infarcted brain of a rodent model of ischemic stroke. The aim of this study was to investigate the ther‐ apeutic effect of the intracerebral transplantation of EPO‐pro‐ ducing fibroblasts on endogenous neurogenesis and poststroke functional recovery
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