Transplantation of mesenchymal stem cells in a canine disc degeneration model

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan.
Journal of Orthopaedic Research (Impact Factor: 2.99). 05/2008; 26(5):589-600. DOI: 10.1002/jor.20584
Source: PubMed


Transplantation of mesenchymal stem cells (MSCs) is effective in decelerating disc degeneration in small animals; much remains unknown about this new therapy in larger animals or humans. Fas-ligand (FasL), which is only found in tissues with isolated immune privilege, is expressed in IVDs, particularly in the nucleus pulposus (NP). Maintaining the FasL level is important for IVD function. This study evaluated whether MSC transplantation has an effect on the suppression of disc degeneration and preservation of immune privilege in a canine model of disc degeneration. Mature beagles were separated into a normal control group (NC), a MSC group, and the disc degeneration (nucleotomy-only) group. In the MSC group, 4 weeks after nucleotomy, MSCs were transplanted into the degeneration-induced discs. The animals were followed for 12 weeks after the initial operation. Subsequently, radiological, histological, biochemical, immunohistochemical, and RT-PCR analyses were performed. MSC transplantation effectively led to the regeneration of degenerated discs. FACS and RT-PCR analyses of MSCs before transplantation demonstrated that the MSCs expressed FasL at the genetic level, not at the protein level. GFP-positive MSCs detected in the NP region 8 weeks after transplantation expressed FasL protein. The results of this study suggest that MSC transplantation may contribute to the maintenance of IVD immune privilege by the differentiation of transplanted MSCs into cells expressing FasL.

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    • "However, the harvest of NP cells from normal discs could induce degeneration in the donor disc [4], whereas cells derived from degenerative discs show an altered phenotype, increased senescence [5] and decreased expression of matrix components [2]. As NP cells possess a chondrocyte-like phenotype [6], bone marrow mesenchymal stem cells (BMSCs), which are capable of differentiating into a chondrocyte-like phenotype when appropriately stimulated [7], [8], have shown promise as a suitable cell source to be widely used for IVD regeneration [9]–[11]. "
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    ABSTRACT: The effect of Sox9 on the differentiation of bone marrow mesenchymal stem cells (BMSCs) to nucleus pulposus (NP)-like (chondrocyte-like) cells in vitro has been demonstrated. The objective of this study is to investigate the efficacy and feasibility of Sox9-transduced BMSCs to repair the degenerated intervertebral disc in a rabbit model. Fifty skeletally mature New Zealand white rabbits were used. In the treatment groups, NP tissue was aspirated from the L2-L3, L3-L4, and L4-L5 discs in accordance with a previously validated rabbit model of intervertebral disc degeneration and then treated with thermogelling chitosan (C/Gp), GFP-transduced autologous BMSCs with C/Gp or Sox9-transduced autologous BMSCs with C/Gp. The role of Sox9 in the chondrogenic differentiation of BMSCs embedded in C/Gp gels in vitro and the repair effect of Sox9-transduced BMSCs on degenerated discs were evaluated by real-time PCR, conventional and quantitative MRI, macroscopic appearance, histology and immunohistochemistry. Sox9 could induce the chondrogenic differentiation of BMSCs in C/Gp gels and BMSCs could survive in vivo for at least 12 weeks. A higher T2-weighted signal intensity and T2 value, better preserved NP structure and greater amount of extracellular matrix were observed in discs treated with Sox9-transduced BMSCs compared with those without transduction. Sox9 gene transfer could significantly enhance the repair effect of BMSCs on the degenerated discs.
    PLoS ONE 04/2014; 9(4):e93570. DOI:10.1371/journal.pone.0093570 · 3.23 Impact Factor
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    • "Only two recent studies have investigated degeneration of the intervertebral disc in both chondrodystrophic and non-chondrodystrophic dogs by studying the biomolecular signalling profiles associated with notochordal cell maintenance in the nucleus pulposus and replacement of these cells by chondrocyte-like cells (Smolders et al. 2012, 2013). To investigate the future usefulness of MSCs transplantation in humans, its effect has therefore been studied in dogs (Hiyama et al. 2008). Dogs in the latter study underwent a nucleotomy followed by injection of BM-MSCs and showed significant improvement compared with the nucleotomy-only group. "
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    ABSTRACT: Interest in mesenchymal stem cells (MSCs) both for regenerative and reparative therapies in dogs is emerging, as the current treatment options for several conditions often do not result either in the desired clinical outcome or in the patients' return to normal function. In addition, canine MSCs have been evaluated in some experimental and preclinical studies on efficacy and safety testing of novel treatments for humans, since the dog is considered to be a superior model for humans than rodents. Although these MSCs can be derived from several sources, clinical use has favoured bone marrow and adipose tissue because of their relative ease of stem cell recovery and the minimal donor-site morbidity. Before any type of stem cell can be applied clinically, its unequivocal characterization by a set of specific functional or phenotypic markers is crucial. However, no uniform characterization criteria are available for canine MSCs so far. Moreover, although multi-lineage potential of canine MSCs has been demonstrated in a limited number of studies, research on the differentiation potential of MSCs towards tenocytes is still lacking in canine medicine. In contrast, this latter subject has been explored already in human as well as in equine medicine, demonstrating the need for a specific 'niche', i.e. factors with a positive influence on the MSC differentiation. Since most of these factors are still unknown regarding canine MSC, critical basic knowledge is urgently required to motivate and correctly translate the potential therapeutic applications of these stem cells in both dog and man.
    01/2014; 33(4). DOI:10.1080/01652176.2013.873963
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    • "Insertion of autologous and allogeneic CLCs in the NP has been shown to retard IVD degeneration in various species without inducing any appreciable host-versus-graft response [21,28,29]. This is in line with the notion that the IVD is immune privileged due to its avascularity [30] and the expression of Fas ligand (FasL), which induces apoptosis of invading Fas-bearing T-cells [24,31]. "
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    ABSTRACT: Pain due to spontaneous intervertebral disc (IVD) disease is common in dogs. In chondrodystrophic (CD) dogs, IVD disease typically develops in the cervical or thoracolumbar spine at about 3-7 years of age, whereas in non-chondrodystrophic (NCD) dogs, it usually develops in the caudal cervical or lumbosacral spine at about 6-8 years of age. IVD degeneration is characterized by changes in the biochemical composition and mechanical integrity of the IVD. In the degenerated IVD, the content of glycosaminoglycan (GAG, a proteoglycan side chain) decreases and that of denatured collagen increases. Dehydration leads to tearing of the annulus fibrosus (AF) and/or disc herniation, which is clinically characterized by pain and/or neurological signs. Current treatments (physiotherapy, anti-inflammatory/analgesic medication, surgery) for IVD disease may resolve neurological deficits and reduce pain (although in many cases insufficient), but do not lead to repair of the degenerated disc. For this reason, there is interest in new regenerative therapies that can repair the degenerated disc matrix, resulting in restoration of the biomechanical function of the IVD. CD dogs are considered a suitable animal model for human IVD degeneration because of their spontaneous IVD degeneration, and therefore studies investigating cell-, growth factor-, and/or gene therapy-based regenerative therapies with this model provide information relevant to both human and canine patients. The aim of this article is to review potential regenerative treatment strategies for canine IVD degeneration, with specific emphasis on cell-based strategies.
    BMC Veterinary Research 01/2014; 10(1):3. DOI:10.1186/1746-6148-10-3 · 1.78 Impact Factor
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