A Porcine Model of Intervertebral Disc Injury Recapitulates Human Discogenic Pain Via Notochordal Cell Loss and Pain-Inducing Nucleus Pulposus Cell Emergence.

Background: Lower back pain (LBP) is one of the most common causes of disability, with up to 40% of LBP cases attributed to intervertebral disc (IVD) degeneration. While small animal models are widely used to study IVD degeneration and LBP, the small size of their IVDs limits translational and biological relevance. Large animal models more accurately emulate human disease; however, methods of measuring LBP are not well established. The porcine model has been questioned for LBP research, due to notochordal cells (NCs) persistence through life, unlike humans. Here, we developed a comprehensive porcine model with quantitative measures of discogenic pain via biobehavioral testing (BBT), MRI, and multi-omics tissue analyses of the IVD and DRGs. Methods: Utilizing a previously established porcine annular injury model of IVD degeneration, pigs underwent longitudinal MRI and biobehavioral testing to monitor degenerative changes in the IVD and pain development. At the study endpoint, IVD and dorsal root ganglia (DRG) tissues were collected for multi-omic analysis. Results: MRI demonstrated the progression of IVD degeneration beginning at 4 weeks post-injury. BBTs showed the development of significant pain responses as early as week 2 post-injury, supported by transcriptomics of injury-matched DRGs. Single-cell transcriptomics, trajectory, and cell-cell communication analyses suggest that, with injury, NCs are differentiating to nucleus pulposus cells (NPCs). Furthermore, NPCs showed upregulation of cellular stress, neural outgrowth, and inflammation pathways, consistent with pain-inducing distress signals found in human samples. Conclusions: This study establishes novel MRI and BBT-based methods for quantifying LBP in pigs and supports its translational relevance to human discogenic LBP. The identification of LBP-associated clusters mirrors our previous findings in humans. Moreover, the shift of NC to NPC phenotype further supports that the porcine model is relevant to human pathology, as the injury induced accelerated aging and loss of NCs with IVD degeneration and discogenic pain.