Repairing the Brain by SCF+G-CSF Treatment at 6 Months Postexperimental Stroke

Now we just need to update and execute that stroke strategy and run human clinical trials on this. Followup which will never occur under current stroke leadership. It will fall thru the cracks like thousands of other studies.
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Mechanistic Determination of the Causal Link Between Neurovascular Regeneration and Motor Functional Recovery

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Lili Cui¹²

Lili Cui

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA2Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
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, Dandan Wang¹

Dandan Wang

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA
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, Sandra McGillis¹

Sandra McGillis

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA
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Michele Kyle¹

Michele Kyle

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA
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, Li-Ru Zhao¹²

Li-Ru Zhao

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA2Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
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First Published August 9, 2016 Research Article

https://doi.org/10.1177/1759091416655010

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Article Information

Volume: 8 issue: 4,

Article first published online: August 9, 2016; Issue published: June 1, 2016
Received: February 16, 2016; Accepted: April 19, 2016

https://doi.org/10.1177/1759091416655010

Lili Cui¹, ², Dandan Wang¹, Sandra McGillis¹, Michele Kyle¹, Li-Ru Zhao¹²

¹Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA

²Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Corresponding Author: Li-Ru Zhao, Department of Neurosurgery, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, New York, USA. Email: ZHAOL@upstate.edu

This article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).

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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.

Keywords brain repair, chronic stroke, G-CSF, hematopoietic growth factors, SCF, live brain imaging

Introduction

Stroke is a cerebrovascular disease in which brain tissue death (infarct) and neurological deficits occur from the sudden interruption of blood flow to a specific region of the brain. Stroke progresses through three phases: the acute, subacute, and chronic phase. The pathological profiles of the three phases appear to be quite different. Unlike in the acute and subacute phases, when massive neurons undergo primary and secondary damage (Parsons et al., 2000) in the chronic phase, a stroke patient’s neurological status becomes relatively stable and the surviving neurons establish new networks in an effort to take over the function of the dead neurons (Tombari et al., 2004; Carmichael, 2012; Cui et al., 2013; Zhao et al., 2013). The duration and pathological severity of the three phases vary between individuals and depend on the infarction size, infarct location, cerebrovascular collateral response, patient’s age, and medical comorbidities. Generally, the chronic phase begins 3 months after stroke onset (Hara et al., 1993; Parsons et al., 2000).
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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