title: 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.
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, United States of America.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Acosta
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, United States of America.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tajiri
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, United States of America.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Shinozuka
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, United States of America.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ishikawa
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, United States of America; Office of Research and Innovation, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Sanberg
authors.affiliation: James Haley Veterans Affairs Medical Center, Tampa, Florida, United States of America; Department of Neurology, University of South Florida, Tampa, Florida, United States of America; Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchez-Ramos
authors.affiliation: James Haley Veterans Affairs Medical Center, Tampa, Florida, United States of America; Department of Neurology, University of South Florida, Tampa, Florida, United States of America; Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Shijie
authors.initials: S
authors.lastname: Song
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, United States of America.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, United States of America.
authors.forename: Cesar V
authors.initials: CV
authors.lastname: Borlongan
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D002452:Cell Count; D064987:Cell- and Tissue-Based Therapy; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000166:cytology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects
chemical_list: D016179:Granulocyte Colony-Stimulating Factor