title: Reconstitution of degenerated ovine lumbar discs by STRO-3-positive allogeneic mesenchymal precursor cells combined with pentosan polysulfate.
abstract: OBJECTIVE Disc degeneration and associated low-back pain are major causes of suffering and disability. The authors examined the potential of mesenchymal precursor cells (MPCs), when formulated with pentosan polysulfate (PPS), to ameliorate disc degeneration in an ovine model. METHODS Twenty-four sheep had annular incisions made at L2-3, L3-4, and L4-5 to induce degeneration. Twelve weeks after injury, the nucleus pulposus of a degenerated disc in each animal was injected with ProFreeze and PPS formulated with either a low dose (0.1 million MPCs) or a high dose (0.5 million MPCs) of cells. The 2 adjacent injured discs in each spine were either injected with PPS and ProFreeze (PPS control) or not injected (nil-injected control). The adjacent noninjured L1-2 and L5-6 discs served as noninjured control discs. Disc height indices (DHIs) were obtained at baseline, before injection, and at planned death. After necropsy, 24 weeks after injection, the spines were subjected to MRI and morphological, histological, and biochemical analyses. RESULTS Twelve weeks after the annular injury, all the injured discs exhibited a significant reduction in mean DHI (low-dose group 17.19%; high-dose group 18.01% [p < 0.01]). Twenty-four weeks after injections, the discs injected with the low-dose MPC+PPS formulation recovered disc height, and their mean DHI was significantly greater than the DHI of PPS- and nil-injected discs (p < 0.001). Although the mean Pfirrmann MRI disc degeneration score for the low-dose MPC+PPS-injected discs was lower than that for the nil- and PPS-injected discs, the differences were not significant. The disc morphology scores for the nil- and PPS-injected discs were significantly higher than the normal control disc scores (p < 0.005), whereas the low-dose MPC+PPS-injected disc scores were not significantly different from those of the normal controls. The mean glycosaminoglycan content of the nuclei pulposus of the low-dose MPC+PPS-injected discs was significantly higher than that of the PPS-injected controls (p < 0.05) but was not significantly different from the normal control disc glycosaminoglycan levels. Histopathology degeneration frequency scores for the low-dose MPC+PPS-injected discs were lower than those for the PPS- and Nil-injected discs. The corresponding high-dose MPC+PPS-injected discs failed to show significant improvements in any outcome measure relative to the controls. CONCLUSIONS Intradiscal injections of a formulation composed of 0.1 million MPCs combined with PPS resulted in positive effects in reducing the progression of disc degeneration in an ovine model, as assessed by improvements in DHI and morphological, biochemical, and histopathological scores.
authors.affiliation: The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria;
authors.forename: David
authors.initials: D
authors.lastname: Oehme
authors.affiliation: The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria;|Proteobioactives, Pty Ltd, Brookvale, New South Wales;|Mesoblast Ltd, Melbourne;
authors.forename: Peter
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria;|Mesoblast Ltd, Melbourne;
authors.forename: Tony
authors.initials: T
authors.lastname: Goldschlager
authors.affiliation: Mesoblast Ltd, Melbourne;
authors.forename: Silviu
authors.initials: S
authors.lastname: Itescu
authors.affiliation: Proteobioactives, Pty Ltd, Brookvale, New South Wales;
authors.forename: Susan
authors.initials: S
authors.lastname: Shimon
authors.affiliation: Proteobioactives, Pty Ltd, Brookvale, New South Wales;
authors.forename: Jiehua
authors.initials: J
authors.lastname: Wu
authors.affiliation: The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria;
authors.forename: Courtney
authors.initials: C
authors.lastname: McDonald
authors.affiliation: Diagnostic Imaging, Monash Health;
authors.forename: John M
authors.initials: JM
authors.lastname: Troupis
authors.affiliation: Department of Surgery, Monash University, Clayton; and.|Department of Neurosurgery, Alfred Hospital, Melbourne, Victoria, Australia.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Rosenfeld
authors.affiliation: The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria;
authors.forename: Graham
authors.initials: G
authors.lastname: Jenkin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007403:Intervertebral Disc / Q000187:drug effects / Q000473:pathology*; D055959:Intervertebral Disc Degeneration / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D012756:Sheep
chemical_list: D010426:Pentosan Sulfuric Polyester
keywords: AF = annulus fibrosus; DHI = disc height index; GAG = glycosaminoglycan; HA = hyaluronic acid; MPC = mesenchymal precursor cell; MSC = mesenchymal stem cell; NP = nucleus pulposus; PG = proteoglycan; PPS = pentosan polysulfate; cABC = chondroitinase ABC; degenerative; disc regeneration; mesenchymal precursor cell; pentosan polysulfate; sheep model