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

Abstract

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.

The Immune Privilege of the Intervertebral Disc: Implications for Intervertebral Disc Degeneration Treatment

“…In another study, Wiet et al found that healthy AF conditioned medium obtained from AF cultures could inhibit mast cell activation by downregulating its expression of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, interleukin (IL)-1β and chemokine (C-C motif) ligand 2 (CCL2/MCP-1), and inhibit mast cell induced angiogenesis [26]. In addition, numerous studies have reported the protective effect of notochordal cells in IVD and its suppressive impact on inflammation [27,28]. Cornejo et al and Kwon et al found soluble factors from notochordal cells inhibit endothelial cell invasion and vessel formation by suppressing VEGF signaling [29,30].…”

Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ORS spine section

“…Like pain, the ability to assess these parameters directly or indirectly is dependent on the type of model system. With respect to structure, the most clinically relevant outcome measure is stabilization or restoration of disc height as demonstrated through imaging (MRI, plain radiographs or computed tomography), and is possible for in vivo models as well as in vitro whole‐disc organ culture models . Importantly, these non‐invasive imaging metrics can be applied longitudinally and thus used to confirm both acute regenerative effects and sustained, long term efficacy.…”

“…With respect to structure, the most clinically relevant outcome measure is stabilization or restoration of disc height as demonstrated through imaging (MRI, plain radiographs or computed tomography), and is possible for in vivo models as well as in vitro whole-disc organ culture models. 93,138,139 Importantly, these non-invasive imaging metrics can be applied longitudinally and thus used to confirm both acute regenerative effects and sustained, long term efficacy. With respect to biomechanical properties, in vitro model systems that incorporate three-dimensional constructs or whole-disc organ culture facilitate direct assessment of mechanical function.…”

Notochordal cell matrix: An inhibitor of neurite and blood vessel growth?

“…By using NCM, the NCCM incubation period, in which bioactive factors may be subject to degradation and inflammatory factors may be produced as a result of free swelling conditions is omitted. NCM induced stronger proteoglycan production and proliferation of bovine NPCs compared to NCCM, and induced a regenerative and anti‐inflammatory effect in a canine in vivo model underscoring its potential in biological IVD repair. Furthermore, NCM is directly harvested from the healthy IVD, hence it is also rich in GAGs.…”