Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury

PLoS One. 2011;6(11):e27706. doi: 10.1371/journal.pone.0027706. Epub 2011 Nov 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Callithrix
  • Diffusion Tensor Imaging
  • Fingers / physiopathology
  • Hepatocyte Growth Factor / pharmacology
  • Hepatocyte Growth Factor / therapeutic use*
  • Humans
  • Indoles / metabolism
  • Motion
  • Motor Activity / drug effects
  • Motor Neurons / drug effects
  • Myelin Sheath / metabolism
  • Myelin Sheath / pathology
  • Organ Size / drug effects
  • Pyramidal Tracts / drug effects
  • Pyramidal Tracts / physiopathology
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Recovery of Function / drug effects*
  • Reproducibility of Results
  • Spinal Cord / enzymology
  • Spinal Cord / pathology
  • Spinal Cord Injuries / drug therapy*
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / physiopathology*
  • Staining and Labeling
  • Time Factors
  • Wrist / physiopathology

Substances

  • HGF protein, human
  • Indoles
  • Recombinant Proteins
  • Luxol Fast Blue MBS
  • Hepatocyte Growth Factor
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcitonin Gene-Related Peptide