Ab1398 stromal Cells in Modic Type 1 Change Bone Marrow Promote Neurite Outgrowth

Abstract

BackgroundVertebral bone marrow lesions known as Modic type 1 changes (MC1) are a major contributor to unspecific lower back pain. Pain may relate to the higher innervation of MC1 endplates. Blocking neo-innervation in MC1 could be a promising treatment approach for MC1. Bone marrow stromal cells (BMSC) can produce neurotrophic factors and are dysregulated in MC1.ObjectivesThe aim of the study was to identify if BMSC in MC1 support neo-innervation through release of neurotrophic factors.MethodsThe RNA sequencing data set (ENA PRJEB39993) of MC1 BMSC vs. intra-patient control vertebral BMSC (n=3 MC1 + 3 intra-patient control) was used to investigate enriched gene sets. From additional patients, BMSC were isolated from vertebral bone marrow aspirates (n=4 MC1 + 4 intra-patient control) and were co-cultured with the neuroblastoma cell line SH-SY5Y for 8 days. Neurite outgrowth from SH-SY5Y was quantified as a measure for neurotrophic activity using microscopy. Thirty neurotrophic cytokines were analyzed in the supernatant of the co-culture using C-Series Human Neuro Discovery Array C2.ResultsGene set enrichment analysis of MC1 vs. intra-patient control BMSC identified gene sets associated with BDNF signaling such as “BDNF TRKB signaling” (normalized enrichment score (NES) = 1.71, p<0.001) and “mBDNF and proBDNF regulation of GABA neurotransmission” (NES = 1.61, p<0.001) amongst the top enriched gene sets.SH-SY5Y cells co-cultured with MC1 BMSC compared to intra-patient control showed significantly increased neurite outgrowth after 4 days (p = 0.045), 6 days (p = 0.027), and 8 days (p = 0.031). (Fig. 1a).Cytokine array analysis revealed significantly more mature brain-derived neurotrophic factor (mBDNF) (p = 0.021) and ciliary neurotrophic factor (CNTF) (p = 0.030) in supernatant of MC1 vs. control BMSC (Fig. 1b).ConclusionNeurotrophic activity of MC1 BMSC is increased. This might be mediated by BDNF and CNTF. Therefore, BDNF and CNTF may represent interesting novel treatment approaches for MC1 that directly target pain mechanisms.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsTamara Mengis: None declared, Irina Heggli: None declared, Nick Herger: None declared, Borbala Aradi-Vegh: None declared, Florian Brunner: None declared, Mazda Farshad: None declared, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant Siences, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Pfizer, Prometheus, Redxpharna, Roivant, Sanofi and Topadur, Grant/research support from: BI, Kymera, Mitsubishi Tanabe, Stefan Dudli: None declared.