Intervertebral disc cells from human back pain subjects exhibit TNFR1-mediated senescence and lack TNFR2-modulated repair capacity

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Intervertebral disc (IVD) degeneration (IVDD) progresses to herniation and back pain due to the poor IVD healing capacities. However, factors contributing to inferior IVD repair remain to be elucidated. Here we identify distinct roles of TNFα-receptors (TNFRs) in IVD cell responses to back pain conditions as key factors in poor IVD healing responses. IVDD tissue of back pain subjects with herniation secreted a complex array of pro-inflammatory cytokines and chemokines (including IL-6, IL-10, CCL2 and CCL5) collected as IVDD conditioned media (IVDD-CM). Single-cell RNA-sequencing (scRNA-seq) of human IVDD tissues revealed these cytokines were dominantly expressed by a small macrophage-population with surprisingly low expression by native IVD cells. Human annulus fibrosus (hAF) cells from surgical tissue had reduced metabolic rates and underwent senescence in IVDD-CM, whereas Basal media restored mitotic potential. Inhibiting the TNFR1 pathway in hAF cells under IVDD-CM challenge enhanced proliferation and induced pro-inflammatory responses with extensive cytokines and chemokines produced. Surprisingly, modulating the pro-reparative TNFR2 using blocking antibodies or using Atsttrin as TNFR2 activator had no effect on hAF cell transcriptome. We discovered TNFR2 was lacking on hIVD cell membranes using immunostaining and scRNA-seq on human autopsy samples and back pain tissue. The absence of TNFR2 on hIVD cells is a new finding revealing these cells are inherently limited in their repair response to inflammatory challenges. Results point to a TNFR-specific strategy for IVD repair involving TNFR1 inhibition to restore IVD cell metabolism and express chemokines to recruit TNFR2-expressing cells capable of a more robust repair response.

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