Repairing the Brain by SCF+G-CSF Treatment at 6 Months Postexperimental Stroke
Abstract
Stroke, a leading cause of adult disability in the world, is a severe medical condition with limited treatment. Physical therapy, the only treatment available for stroke rehabilitation, appears to be effective within 6 months post-stroke. Here, we have mechanistically determined the efficacy of combined two hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF; SCF + G-CSF), in brain repair 6 months after cortical infarct induction in the transgenic mice carrying yellow fluorescent protein in Layer V pyramidal neurons (Thy1-YFP-H). Using a combination of live brain imaging, whole brain imaging, molecular manipulation, synaptic and vascular assessments, and motor function examination, we found that SCF + G-CSF promoted mushroom spine formation, enlarged postsynaptic membrane size, and increased postsynaptic density-95 accumulation and blood vessel density in the peri-infarct cavity cortex; and that SCF + G-CSF treatment improved motor functional recovery. The SCF + G-CSF-enhanced motor functional recovery was dependent on the synaptic and vascular regeneration in the peri-infarct cavity cortex. These data suggest that a stroke-damaged brain is repairable by SCF + G-CSF even 6 months after the lesion occurs. This study provides novel insights into the development of new restorative strategies for stroke recovery.
Introduction
Stroke is an enormous public health problem and the leading cause of persistent disability worldwide. Today, there is a large population of chronic stroke patients in the world suffering from stroke-induced disability. A recent study shows that in 2010, there were 102 million disability-adjusted life-years lost in the world (Feigin et al., 2014). In the United States alone, about 6.6 million stroke survivors are suffering from persistent disability (Mozaffarian et al., 2015). Targeting brain repair in chronic stroke is a highly important but much less investigated field in stroke research. Speech and physical therapies appear to be the only therapies available for chronic stroke patients. Since it would be unfeasible for stroke patients to spend every hour with physical therapists for physical performance, developing alternatives, such as a pharmaceutical approach, to help in restoring motor function for stroke survivors is needed. Importantly, the therapeutic window for traditional physical therapy appears to be limited within 6 months after stroke onset (Hendricks et al., 2002; Schaechter, 2004). Over 50% of chronic stroke patients, who are discharged from rehabilitation therapy at 6 months post-stroke, still show significant motor impairment (Gresham et al., 1975; Hendricks et al., 2002; Kelly-Hayes et al., 2003). Currently, therapies that can further improve functional restoration 6 months after stroke occurs have not yet been developed.
Recently, we have demonstrated the therapeutic efficacy of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) on brain repair and functional restoration in animal models of chronic stroke. SCF and G-CSF are well-characterized hematopoietic growth factors and play an essential role in controlling bone marrow stem cell growth, survival, and differentiation into blood cells (Welte et al., 1985; Zsebo et al., 1990). Increasing evidence, however, shows that SCF and G-CSF are also involved in neuronal plasticity, neuronal network formation, and neuronal function in learning and memory (Hirata et al., 1993; Motro et al., 1996; Katafuchi et al., 2000; Diederich et al., 2009; Su et al., 2013). Our earlier study revealed that systemic administration of combined SCF and G-CSF (SCF + G-CSF) 3.5 months after induction of cortical brain ischemia led to much greater functional improvement than SCF or G-CSF treatment alone (Zhao et al., 2007). However, it remains unanswered whether administration of SCF + G-CSF at a much-delayed time, 6 months after stroke, would be effective in brain repair.
Neurovascular network remodeling has been proposed to play an important role in stroke recovery (Moskowitz et al., 2010). Nuclear factor-κB (NF-κB), a transcription factor, is involved in synaptogenesis (Meffert et al., 2003; Memet, 2006; Boersma et al., 2011; Imielski et al., 2012) and angiogenesis (Stoltz et al., 1996). Our recent findings revealed that NF-κB mediates SCF + G-CSF-promoted neurite outgrowth in cultured primary cortical neurons (Su et al., 2013). The purpose of the present study was to determine whether administration of SCF + G-CSF at 6 months after experimental stroke would be effective in enhancing functional improvement and neurovascular network remodeling and whether NF-κB would be involved in the restorative process of SCF + G-CSF in such a delayed treatment.
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