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TNFR1-mediated senescence and lack of TNFR2-signaling limit human intervertebral disc cell repair in back pain conditions.
Gansau, Jennifer; Grossi, Elena; Rodriguez, Levon; Wang, Minghui; Laudier, Damien M; Chaudhary, Saad; Hecht, Andrew C; Fu, Wenyu; Sebra, Robert; Liu, Chuanju; Iatridis, James C.
Afiliação
  • Gansau J; Department of Orthopaedics, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
  • Grossi E; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
  • Rodriguez L; Department of Dermatology, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
  • Wang M; Department of Orthopaedics, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
  • Laudier DM; Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
  • Chaudhary S; Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
  • Hecht AC; Department of Orthopaedics, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
  • Fu W; Department of Orthopaedics, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
  • Sebra R; Department of Orthopaedics, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
  • Liu C; Department of Orthopaedics & Rehabilitation, Yale University School of Medicine; New Haven, CT 06510, USA.
  • Iatridis JC; Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai; New York, NY 10029, USA.
bioRxiv ; 2024 Jun 20.
Article em En | MEDLINE | ID: mdl-38948728
ABSTRACT
Poor intervertebral disc (IVD) healing causes IVD degeneration (IVDD) and progression to herniation and back pain. This study identified distinct roles of TNFα-receptors (TNFRs) in contributing to poor healing in painful IVDD. We first isolated IVDD tissue of back pain subjects and determined the complex pro-inflammatory mixture contained many chemokines for recruiting inflammatory cells. Single-cell RNA-sequencing of human IVDD tissues revealed these pro-inflammatory cytokines were dominantly expressed by a small macrophage-population. Human annulus fibrosus (hAF) cells treated with IVDD-conditioned media (CM) underwent senescence with greatly reduced metabolic rates and limited inflammatory responses. TNFR1 inhibition partially restored hAF cell metabolism sufficiently to enable a robust chemokine and cytokine response to CM. We showed that the pro-reparative TNFR2 was very limited on hIVD cell membranes so that TNFR2 inhibition with blocking antibodies or activation using Atsttrin had no effect on hAF cells with CM challenge. However, TNFR2 was expressed in high levels on macrophages identified in scRNA-seq analyses, suggesting their role in repair responses. Results therefore point to therapeutic strategies for painful IVDD involving immunomodulation of TNFR1 signaling in IVD cells to enhance metabolism and enable a more robust inflammatory response including recruitment or delivery of TNFR2 expressing immune cells to enhance IVD repair.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos