Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury

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.

Temporal and Spatial Changes in the Pattern of Iba1 and CD68 Staining in the Rat Brain Following Severe Traumatic Brain Injury

“…In human patients, damage to white matter tracts can be seen on scans years after a moderate or severe TBI [14] [31] [32]. Furthermore, reports from both humans and animal models indicate that white matter injury (WMI) progresses temporally [32].…”

“…Activated microglia can be detected in the thalamus for up to 1-year post-TBI [3] [14]. Although unremarkable at 48 hours post-TBI, the laterodorsal thalamic nuclei displayed an interesting response pattern at subsequent time points (Figure 9).…”

“…Activation of microglia has been linked to neuropathologies, including chronic pain, amyotrophic lateral sclerosis (ALS) and Alzheimer's disease [6] [11] [12]. Paradoxically, activation of microglia has been linked to both neuroprotection [3] [13] and neurotoxic events [14] [15].…”

G-CSF as an Adjunctive Therapy with Umbilical Cord Blood Cell Transplantation for Traumatic Brain Injury

“…In a recent study, we showed that a combination therapy with hUCB + G-CSF produced functional improvement to a greater extent than that exerted by monotherapy with hUCB or G-CSF (2). Notably, beneficial effects of combination therapy were more longer lasting than those exerted by hUCB transplantation or G-CSF administration alone.…”

“…These results indicate that complementary brain repair processes distinctly or mutually afforded by these two therapies could have mediated improved functional recovery exerted by combination treatment of 451 G-CSF AS AN ADJUNCTIVE THERAPY FOR TRAUMATIC BRAIN INJURY hUCB + G-CSF. Regenerative mechanisms such as those accomplished by G-CSF-mobilized endogenous stem cells, the growth factors secreted by hUCB grafts, as well as the potential graft-host integration that facilitates reconstruction of synaptic circuitry (125), may have altogether caused more profound functional improvement in TBI rats subjected to a combination therapy than in rats that underwent hUCB or G-CSF monotherapy (2,23).…”