Granulocyte-colony stimulating factor promotes brain repair following traumatic brain injury by recruitment of microglia and increasing neurotrophic factor expression

Article type: Research Article

Authors: Song, Shijie^{a; b} | Kong, Xiaoyuan^{a; c} | Acosta, Sandra^c | Sava, Vasyl^{a; b} | Borlongan, Cesar^c | Sanchez-Ramos, Juan^{a; b; *}

Affiliations: [a] James A Haley VAH Research Service, Tampa FL, USA | [b] Department of Neurology, University of South Florida, Tampa, FL, USA | [c] Department of Neurosurgery, University of South Florida, Tampa, FL, USA

Correspondence: [*] Corresponding author: Juan Sanchez-Ramos, PhD, MD, 13220 Laurel Drive, Tampa, FL 33612, USA. Tel.: +1 813 974 6022; Fax: +1 813 974 8032; E-mail: jsramos@health.usf.edu.

Abstract: Purpose: The overall objective was to elucidate cellular mechanisms by which G-CSF enhances recovery from traumatic brain injury in a hippocampal-dependent learning task. Methods: Chimeric mice were prepared by transplanting bone marrow cells that express green fluorescent protein (GFP+) from a transgenic “green” mice into C57BL/6 mice. Two months later, the animals sustained mild controlled cortical impact (CCI) to the right frontal-parietal cortex, followed by G-CSF (100 μg/kg) treatment for 3 consecutive days. The primary behavioral end-point was performance on the radial arm water maze (RAWM) assessed before and after CCI (days 7 and 14). Secondary endpoints included a), motor performance on a rotating cylinder (rotarod), b) measurement of microglial and astroglial response, c) hippocampal neurogenesis, and d) measures of neurotrophic factors (BDNF, GDNF) in brain homogenates. Results: G-CSF treatment resulted in significantly better performance on the rotorod at one week, and in the RAWM after one and two weeks. The cellular changes found 2 wks after CCI in the G-CSF group included increased numbers of hippocampal newborn neurons as well as astrocytosis and microgliosis in striatum and frontal cortex on both sides of brain. GFP+ cells that co-labeled with Iba1 (microglial marker) comprised a significant proportion of striatal microglia in G-CSF treated animals, indicating the capacity of G-CSF to increase microglial recruitment to the site of injury. Neurotrophic factors GDNF and BDNF, elaborated by activated microglia and astrocytes, were increased in G-CSF treated mice. Conclusions: G-CSF serves as a neurotrophic factor that increases hippocampal neurogenesis (or enhances survival of new-born neurons), and activates astrocytes and microglia. In turn, these activated glia release a plethora of cytokines and neurotrophic factors that contribute, in a poorly understood cascade, to the brain’s repair response. G-CSF also acts directly on bone marrow-derived cells to enhance recruitment of microglia to the site of CCI from circulating monocytes to the site of CCI.

Keywords: Granulocyte-colony stimulating factor, traumatic brain injury, neuro-inflammation, neurogenesis, doublecortin, astrocytosis, microgliosis, chimeric mice, green fluorescent protein

DOI: 10.3233/RNN-150607

Journal: Restorative Neurology and Neuroscience, vol. 34, no. 3, pp. 415-431, 2016