Integrative single-cell transcriptomics and Mendelian randomization prioritize FN1 and DCN in intervertebral disc...

Area of Science:

• Biomedical Science
• Genetics
• Cell Biology

Background:

• Intervertebral disc degeneration (IDD) is a primary cause of low back pain.
• The cellular complexity and role of extracellular matrix (ECM) proteins in IDD are not fully understood.

Purpose of the Study:

• To investigate cellular heterogeneity in human intervertebral discs.
• To explore the association of circulating ECM proteins with IDD susceptibility.
• To identify potential molecular targets for IDD.

Main Methods:

• Integrated single-cell RNA sequencing data from healthy and degenerative human intervertebral discs.
• Performed Mendelian randomization (MR) using protein quantitative trait loci.
• Conducted functional assays in primary human nucleus pulposus cells.

Main Results:

• Single-cell analysis revealed disease-associated shifts in cell states and ECM organization, inflammatory signaling, and metabolic pathways.
• Network analyses highlighted fibronectin 1 (FN1), decorin (DCN), CCN2, EGFR, and COL1A1 as potential ECM candidates.
• MR analysis indicated non-significant association for FN1, while DCN showed nominal significance. siRNA-mediated knockdown of FN1 or DCN affected matrix and inflammatory markers in a TNF-alpha model.

Conclusions:

• The study prioritizes specific ECM candidates and cell states for further mechanistic investigation in intervertebral disc degeneration.
• Identified FN1 and DCN as potential targets for future IDD research.
• Highlights the complexity of IDD pathogenesis involving cellular heterogeneity and ECM components.