Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Abstract

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing nucleus pulposus cells (NPCs), generated by the environmental stress in degenerating discs, that triggered the onset of discogenic LBP. Single-cell transcriptomic analysis of human tissues showed a strong correlation between this specific pain-triggering subtype and the pain conditions in human degenerated discs. Next, we recreated this pain-triggering subtype by applying known exogenous stressors to healthy NPCsin vitro. The recreated pain phenotype activated functional sensory neurons responsein vitroand induced local inflammatory responses, hyperalgesia, and mechanical sensitivity in a healthy rat IVDin vivo. Our findings provide strong evidence of a previously unknown pain-inducing mechanism mediated by NPCs in degenerating IVDs. This newly defined pathway will aid in the development of NPC-targeted therapeutic strategies for clinically unmet need to attenuate discogenic LBP.One Sentence SummaryDiscogenic low back pain can be initiated by a stress-induced subtype of nucleus pulposus cells present in human degenerating intervertebral discs

TNFR1-mediated senescence and lack of TNFR2-signaling limit human intervertebral disc cell repair in back pain conditions

“…Chronic inflammation from IVDD is a strong contributor to progressive degenerative conditions and pain. This is due to the known roles that pro-inflammatory cytokines play in increased matrix catabolism, neurovascular ingrowth into the IVD, and enhanced nociception (7)(8)(9)(10)(11)(12)(13)(14). Furthermore, infiltration of cytokine-releasing macrophages into the peripheral nervous system and damaged IVD has been observed, suggesting a correlation between immune cell infiltration and discogenic pain (15).…”