PLoS One. 2013 Jun 4;8(6):e64684.

Reestablishing neuronal networks in the aged brain by stem cell factor and granulocyte-colony stimulating factor in a mouse model of chronic stroke.

Lili Cui, Sasidhar R. Murikinati, Dongliang Wang, Xiangjian Zhang, Wei-Ming Duan, Li-Ru Zhao*

PLoS One. 2013 Jun 4;8(6):e64684.

 

*Corresponding author:

Li-Ru Zhao, MD., PhD

Director for Stroke Research and Brain Repair

Department of Neurosurgery

State University of New York Upstate Medical University

4110 IHP

750 E. Adams Street

Syracuse, NY 13210

E-mail: ZHAOL@upstate.edu

Telephone: +1 315 464 8470

Fax: +1 315 464 5505

 

Abstract

Stroke has a high incidence in the elderly. Stroke enters the chronic phase 3 months after initial stroke onset. Currently, there is no pharmaceutical treatment available for chronic stroke. We have demonstrated the therapeutic effects of the combination of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF) on chronic stroke. However, it remains unclear how SCF+G-CSF repairs the brain in chronic stroke. In this study, we determined the effects of SCF+G-CSF on neuronal network remodeling in the aged brain of chronic stroke. Cortical brain ischemia was produced in 16-18 month-old transgenic mice expressing yellow fluorescent protein in layer V pyramidal neurons. SCF+G-CSF was subcutaneously injected for 7 days beginning at 3.5 months post-ischemia. Using both live brain imaging and immunohistochemistry, we observed that SCF+G-CSF increased the mushroom-type spines on the apical dendrites of layer V pyramidal neurons adjacent to the infarct cavities 2 and 6 weeks after treatment. SCF+G-CSF also augmented dendritic branches and post-synaptic density protein 95 puncta in the peri-infarct cortex 6 weeks after treatment. These data suggest that SCF+G-CSF treatment in chronic stroke remodels neural circuits in the aged brain. This study provides evidence to support the development of a new therapeutic strategy for chronic stroke.

PMID: 23750212

 

Supplement

Stroke is a cerebrovascular disorder with a high incidence in elderly people over age 65. Stroke has remained the leading cause of disability in adults worldwide, although numerous efforts have been made for several decades to prevent brain damage in the early phase and to facilitate functional recovery in the late phase of this devastating neurological disorder. Chronic stroke is the phase of recovery after stroke onset, and the status of stroke patients is relatively stable in the phase of chronic stroke. Enhancing brain repair and improving functional outcome would be the therapeutic strategy for treatment of chronic stroke. Currently, chronic stroke treatment is limited to the physical therapy, yet the pharmaceutical approach for brain repair in chronic stroke has not been developed. Our earlier study has demonstrated that the combination of two essential hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF) induces stable and long-term functional improvement when administered in the chronic phase of experimental stroke. However, the mechanism underlying the SCF+G-CSF-induced functional improvement in chronic stroke remains largely unknown.

Brain has the capability to be remodeled in both the physiological and pathological conditions throughout the life span. A large body of evidence has shown that brain plasticity is critically involved in brain repair during chronic stroke. In the present study, using both live brain imaging and immunohistochemistry approaches, we have determined the effects of SCF+G-CSF on neuronal network remodeling in aged animals under the condition of chronic stroke. Male transgenic mice expressing yellow fluorescent protein (YFP) only in the layer V pyramidal neurons (Thy1-YFPH) were subjected to cerebral cortical ischemia (cortical model of stroke) at age of 16-18 months (equal to 62-69 years old human). The live brain imaging was performed with a multiphoton microscope through a thinned-skull window before treatment (week 0), again 2 and 6 weeks after treatment, and 3 sites per brain adjacent to the infarct cavities were selected for live brain imaging (Fig. 1 A, B and E). Before treatment (week 0), both mushroom-type and thin-type spines were reduced, and uncertain-type spines were increased in the brains of all stroke mice, suggesting that synaptic networks in the lesion side brain undergo degeneration due to neuron loss in the infarct zone (Figs. 1 and 2). However, after SCF+G-CSF treatment, the mushroom-type spines were significantly increased at week 2 and 6 post-treatment, and the uncertain-type spines were significantly reduced 6 weeks after treatment, suggesting that SCF+G-CSF treatment in chronic stroke re-establishes synaptic networks in the cortex outside the infarct cavities. Immunohistochemistry data further confirmed that the densities of dendrites and post-synapses in the cortex adjacent to the infarct cavities were significantly increased 6 weeks after SCF+G-CSF treatment.

Figure 1

Rewiring neuronal networks in the peri-infarct cortex has been shown to play an important role in functional recovery after stroke. Our findings reveal that SCF+G-CSF treatment in chronic stroke enhances neuronal network remodeling in the peri-infarct cortex of aged brain. These data suggest that an aged brain in the chronic phase of stroke is repairable by hematopoietic growth factors, SCF and G-CSF. This study provides new insights into the contribution of hematopoietic growth factors in brain repair and brain plasticity.

Figure 2

 

Acknowledgements: This study was supported by The National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS), R01 NS060911 to L.R.Z

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