title: A comparison of the behavioral and anatomical outcomes in sub-acute and chronic spinal cord injury models following treatment with human mesenchymal precursor cell transplantation and recombinant decorin.
abstract: This study assessed the potential of highly purified (Stro-1(+)) human mesenchymal precursor cells (hMPCs) in combination with the anti-scarring protein decorin to repair the injured spinal cord (SC). Donor hMPCs isolated from spinal cord injury (SCI) patients were transplanted into athymic rats as a suspension graft, alone or after previous treatment with, core (decorin(core)) and proteoglycan (decorin(pro)) isoforms of purified human recombinant decorin. Decorin was delivered via mini-osmotic pumps for 14 days following sub-acute (7 day) or chronic (1 month) SCI. hMPCs were delivered to the spinal cord at 3 weeks or 6 weeks after the initial injury at T9 level. Behavioral and anatomical analysis in this study showed statistically significant improvement in functional recovery, tissue sparing and cyst volume reduction following hMPC therapy. The combination of decorin infusion followed by hMPC therapy did not improve these measured outcomes over the use of cell therapy alone, in either sub-acute or chronic SCI regimes. However, decorin infusion did improve tissue sparing, reduce spinal tissue cavitation and increase transplanted cell survivability as compared to controls. Immunohistochemical analysis of spinal cord sections revealed differences in glial, neuronal and extracellular matrix molecule expression within each experimental group. hMPC transplanted spinal cords showed the increased presence of serotonergic (5-HT) and sensory (CGRP) axonal growth within and surrounding transplanted hMPCs for up to 2 months; however, no evidence of hMPC transdifferentiation into neuronal or glial phenotypes. The number of hMPCs was dramatically reduced overall, and no transplanted cells were detected at 8 weeks post-injection using lentiviral GFP labeling and human nuclear antigen antibody labeling. The presence of recombinant decorin in the cell transplantation regimes delayed in part the loss of donor cells, with small numbers remaining at 2 months after transplantation. In vitro co-culture experiments with embryonic dorsal root ganglion explants revealed the growth promoting properties of hMPCs. Decorin did not increase axonal outgrowth from that achieved by hMPCs. We provide evidence for the first time that (Stro-1(+)) hMPCs provide: i) an advantageous source of allografts for stem cell transplantation for sub-acute and chronic spinal cord therapy, and (ii) a positive host microenvironment that promotes tissue sparing/repair that subsequently improves behavioral outcomes after SCI. This was not measurably improved by recombinant decorin treatment, but does provide important information for the future development and potential use of decorin in contusive SCI therapy.
authors.affiliation: Eileen Bond Spinal Cord Research Center, School of Anatomy, Physiology & Human Biology, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Hodgetts
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Simmons
authors.forename: Giles W
authors.initials: GW
authors.lastname: Plant
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D003131:Combined Modality Therapy; D058575:Decorin / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D011994:Recombinant Proteins / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000503:physiopathology / Q000601:surgery / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D058575:Decorin; D011994:Recombinant Proteins
keywords: Cellular therapy; Chronic; Contusion; Decorin; Mesenchymal precursors; Proteoglycan; Spinal cord; Sub-acute; Transplantation