Abstract
Traumatic brain injury (TBI) is associated with neuro-inflammation, debilitating sensory-motor deficits, and learning and memory impairments. Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI. Here, we tested the potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model. Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function accompanied the combined therapy, which was either moderately or short-lived in the monotherapy conditions. These results suggest that combined treatment rather than monotherapy appears optimal for abrogating histophalogical and motor impairments in chronic TBI.
Highlights
Traumatic brain injury (TBI) produces debilitating conditions that affect millions worldwide [1]
Posthoc test analysis revealed a robust upregulation of activated microglia cells when comparing the total estimated volume of MHCII+ cells in the ipsilateral hemisphere of rats exposed to chronic TBI and treated with saline alone to their contralateral side across all gray and white matter areas analyzed (p,0.0001), except in the corpus callosum area (p.0.05)
Post hoc Bonferroni’s test revealed that monotherapy of human umbilical cord blood (hUCB) cells and the combined therapy of hUCB+granulocyte colony stimulating factor (G-Colony stimulating factors (CSF)) significantly decreased the TBI-associated upregulation of MHCII+ activated cells in the cortex, striatum, thalamus, subventricular zone (SVZ), and DG relative to rats exposed to chronic TBI treated with saline alone (p,0.05) (Fig. 1B, C)
Summary
Traumatic brain injury (TBI) produces debilitating conditions that affect millions worldwide [1]. In moderate to severe trauma, TBI survivors present with chronic disabilities associated with loss of primary cerebral parenchymal tissues, secondary cell death including apoptosis, and exacerbated neuroinflammation [9,10,11]. Preclinical studies have demonstrated that adult stem/progenitor cells transplantation is a promising therapeutic intervention for TBI [20,21]. TBI victims suffer from brain oxygen depletion, vasogenic edema, and secondary injury signals including reactive oxygen species, exacerbated activated MHCII+ cells, astrogliosis and pro-inflammatory cytokines such as, but not limited to, IL-1beta, TNF-alpha which can accumulate in the area of injury leading to decreased survival of transplanted adult stem cells [11,25,26]. The use of combined therapies stands as a promising technique to overcome molecular aberrations while enhancing the adult stem cells’ therapeutic potential in chronic TBI [27,28]
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