title: Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury.
abstract: Many therapeutic interventions for spinal cord injury (SCI) using neurotrophic factors have focused on reducing the area damaged by secondary, post-injury degeneration, to promote functional recovery. Hepatocyte growth factor (HGF), which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We previously reported that introducing exogenous HGF into the injured rodent spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, that study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF) intrathecally. Motor function was assessed using an original open field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. In vivo magnetic resonance imaging showed significant preservation of the intact spinal cord parenchyma. rhHGF-treatment did not give rise to an abnormal outgrowth of calcitonin gene related peptide positive fibers compared to the control group, indicating that this treatment did not induce or exacerbate allodynia. This is the first study to report the efficacy of rhHGF for treating SCI in non-human primates. In addition, this is the first presentation of a novel scale for assessing neurological motor performance in non-human primates after contusive cervical SCI.
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kitamura
authors.forename: Kanehiro
authors.initials: K
authors.lastname: Fujiyoshi
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Yamane
authors.forename: Fumika
authors.initials: F
authors.lastname: Toyota
authors.forename: Keigo
authors.initials: K
authors.lastname: Hikishima
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Nomura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Funakoshi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002144:Callithrix; D056324:Diffusion Tensor Imaging; D005385:Fingers / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007211:Indoles / Q000378:metabolism; D009038:Motion; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011712:Pyramidal Tracts / Q000187:drug effects / Q000503:physiopathology; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects*; D015203:Reproducibility of Results; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D013194:Staining and Labeling; D013997:Time Factors; D014953:Wrist / Q000503:physiopathology
chemical_list: C066855:HGF protein, human; D007211:Indoles; D011994:Recombinant Proteins; C018588:Luxol Fast Blue MBS; D017228:Hepatocyte Growth Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D015740:Calcitonin Gene-Related Peptide