Research reportThe contribution of stem cell factor and granulocyte colony-stimulating factor in reducing neurodegeneration and promoting neurostructure network reorganization after traumatic brain injury
Introduction
As a growing clinical problem around the world, traumatic brain injury (TBI) remains the leading cause of death and disability in young adults (Maas et al., 2008). The pathological period of post-TBI is divided into 3 phases: an acute phase, a subacute phase, and a chronic phase. The precise duration of the 3 clinical phases is different for individuals because many factors may affect the pathological time course such as their ages and TBI severity. Generally, the acute phase is the first 7 days after TBI, the subacute phase is between 7 days and 3 weeks after TBI, and the chronic phase may begin 3 to 5 weeks after TBI (Edlow et al., 2016, Ge et al., 2018, Missault et al., 2018, Witcher et al., 2018). In severe cases, the chronic phase begins at 3 months post-TBI and continues years after TBI or can even last throughout an individual’s lifespan (Barnes, 1999, Giacino, 2016). To date, the majority of pre-clinical studies have focused on pharmaceutical interventions in neuroprotection in the acute phase of TBI, such as complement inhibition (Rich et al., 2016), immunomodulation (Yen et al., 2018), angiotensin II receptor blockage (Villapol et al., 2015), and cerebral infusion of insulin-like growth factor-1 (Carlson and Saatman, 2018). However, little work has been done in exploring pharmaceutical approaches in post-acute phases of TBI.
The process of the secondary brain injury is progressive, and secondary neuron loss happens in both the ipsilateral and contralateral hemispheres. A recent study has revealed a long-term and progressive neuropathology in bilateral hemispheres up to one year after a single severe brain injury in a mouse model of controlled cortical impact (CCI) (Pischiutta et al., 2018). Moreover, progressive neurodegeneration after CCI-TBI has been found in both the ipsilateral and contralateral hemispheres (Hall et al., 2005, Hall et al., 2008). Widespread neurodegeneration after TBI has been thought to be the results of secondary brain injury and lead to cognitive impairments (Cruz-Haces et al., 2017). In addition to widespread neurodegeneration, reduced functional connectivity in both hemispheres has also been observed in TBI patients (Alhourani et al., 2016). TBI-induced loss of dendrites and axons is also related with cognitive impairments (Rubovitch et al., 2017, Sen et al., 2017). The pharmaceutical intervention for inhibiting widespread neurodegeneration and enhancing neural network reorganization may restrict TBI-induced progressive neuropathology and improve functional outcomes after TBI.
Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are the key hematopoietic growth factors to regulate bone marrow stem cell proliferation, differentiation and mobilization (Greenbaum and Link, 2011, McNiece and Briddell, 1995, Welte et al., 1985, Zsebo et al., 1990). Accumulating evidence shows that SCF and G-CSF also play a role in neuroprotection and neuronal plasticity. Many studies have demonstrated that administration of SCF (Zhao et al., 2007c), G-CSF (Schneider et al., 2005, Sehara et al., 2007, Shyu et al., 2004, Six et al., 2003, Solaroglu et al., 2006, Zhao et al., 2007c), or SCF + G-CSF (Kawada et al., 2006, Toth et al., 2008, Zhao et al., 2007c) leads to reduction in infarction size and amelioration of neurological deficits in experimental stroke. In addition to neuroprotection, SCF has been shown to promote neurite outgrowth (Hirata et al., 1993, Zhao et al., 2007a), and lack of SCF impairs spatial and learning memory (Katafuchi et al., 2000). G-CSF deficient mice also show cognitive problems, impairments in long-term potentiation, and reductions in dendrites in the hippocampus (Diederich et al., 2009). SCF and G-CSF have been demonstrated to cross the blood–brain barrier in intact animals (Zhao et al., 2007b). SCF and G-CSF combined treatment (SCF + G-CSF) has shown synergistic effects in enhancing neurite outgrowth (Su et al., 2013) and neural network reorganization in chronic stroke (Zhao et al., 2007a). We have also demonstrated that SCF + G-CSF treatment in the chronic phase of experimental stroke synergistically improves functional recovery (Zhao et al., 2007a). SCF + G-CSF-improved functional recovery in the chronic phase of experimental stroke is dependent on the SCF + G-CSF-enhanced neurostructural network remodeling (Cui et al., 2015, Cui et al., 2016). Our previous study has demonstrated therapeutic efficacy of SCF + G-CSF in the earlier subacute phase of severe CCI-TBI (Toshkezi et al., 2018a). However, it remains unexplored whether this pharmaceutical approach is effective at the late stage of TBI. The knowledge concerning reparative efficacy of SCF + G-CSF treatment in post-acute TBI remains incomplete.
The aim of the present study is to determine and validate the efficacy of SCF + G-CSF treatment in post-acute TBI on brain repair and functional recovery.
Section snippets
SCF + G-CSF treatment does not improve TBI-impaired cognitive and motor functions 2 weeks after treatment
To ensure that TBI mice presented equal pathological conditions in the treated and non-treated groups before the SCF + G-CSF treatment initiation, we examined cognitive and motor functional deficits one week before treatment by a brief of water maze test and Rota-Rod test (3d test), respectively (Fig. 1). SCF + G-CSF or an equal volume of vehicle solution was subcutaneously injected for 7 consecutive days starting on day 21 post-TBI (Fig. 1). The latency to find the platform was longer in all
Discussion
In the present study, we have demonstrated that the combination treatment of SCF and G-CSF at 3 weeks post-TBI ameliorates severe TBI-induced long-term impairments in spatial learning, reduces neurodegeneration, and enhances neurostructural network reorganization.
SCF + G-CSF treatment improves spatial learning 6 weeks, but not 2 weeks, after treatment in a severe CCI-TBI model. This observation suggests that SCF + G-CSF requires a prolonged period (6 weeks) to repair the brain damaged by severe
Experimental procedure
The animal experiments followed ethical guidelines of the Animal Research, Reporting In Vivo Experiments (ARRIVE). All procedures in this study were approved by the Institutional Animal Care and Use Committee and performed in accordance with the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health.
CRediT authorship contribution statement
JCH contributed to data curation, data analysis, data validation, and writing original draft of manuscript. TR conducted TBI and behavioral tests. XCQ performed brain lesion volume assessment. FH assisted in data analysis. MK performed brain sectioning and histochemical staining. LC contributed to funding acquisition, manuscript review and editing. LRZ contributed to conceptualization, funding acquisition, project administration and supervision, and final revision of the manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This study was supported by Merit Review Award (I01RX002125) from the United States Department of Veterans Affairs Rehabilitation Research & Development Service.
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