Research Papers:

Biologic canine and human intervertebral disc repair by notochordal cell-derived matrix: from bench towards bedside

Frances C. Bach, Anna R. Tellegen, Martijn Beukers, Alberto Miranda-Bedate, Michelle Teunissen, Willem A.M. de Jong, Stefan A.H. de Vries, Laura B. Creemers, Karin Benz, Björn P. Meij, Keita Ito and Marianna A. Tryfonidou _

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Oncotarget. 2018; 9:26507-26526. https://doi.org/10.18632/oncotarget.25476

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Frances C. Bach1, Anna R. Tellegen1, Martijn Beukers1, Alberto Miranda-Bedate1, Michelle Teunissen1, Willem A.M. de Jong1, Stefan A.H. de Vries2, Laura B. Creemers3, Karin Benz4, Björn P. Meij1, Keita Ito2,3 and Marianna A. Tryfonidou1

1Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584 CM, The Netherlands

2Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, MB 5600, The Netherlands

3Department of Orthopedics, University Medical Centre Utrecht, Utrecht, 3584 CX, The Netherlands

4TETEC AG, Reutlingen 72770, Germany

Correspondence to:

Marianna A. Tryfonidou, email: [email protected]

Keywords: intervertebral disc; regenerative medicine; notochordal cells; canine; human

Received: March 13, 2018     Accepted: April 28, 2018     Published: May 29, 2018


The socioeconomic burden of chronic back pain related to intervertebral disc (IVD) disease is high and current treatments are only symptomatic. Minimally invasive strategies that promote biological IVD repair should address this unmet need. Notochordal cells (NCs) are replaced by chondrocyte-like cells (CLCs) during IVD maturation and degeneration. The regenerative potential of NC-secreted substances on CLCs and mesenchymal stromal cells (MSCs) has already been demonstrated. However, identification of these substances remains elusive. Innovatively, this study exploits the regenerative NC potential by using healthy porcine NC-derived matrix (NCM) and employs the dog as a clinically relevant translational model. NCM increased the glycosaminoglycan and DNA content of human and canine CLC aggregates and facilitated chondrogenic differentiation of canine MSCs in vitro. Based on these results, NCM, MSCs and NCM+MSCs were injected in mildly (spontaneously) and moderately (induced) degenerated canine IVDs in vivo and, after six months of treatment, were analyzed. NCM injected in moderately (induced) degenerated canine IVDs exerted beneficial effects at the macroscopic and MRI level, induced collagen type II-rich extracellular matrix production, improved the disc height, and ameliorated local inflammation. MSCs exerted no (additive) effects. In conclusion, NCM induced in vivo regenerative effects on degenerated canine IVDs. NCM may, comparable to demineralized bone matrix in bone regeneration, serve as ‘instructive matrix’, by locally releasing growth factors and facilitating tissue repair. Therefore, intradiscal NCM injection could be a promising regenerative treatment for IVD disease, circumventing the cumbersome identification of bioactive NC-secreted substances.

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