Transformation of resident notochord‐descendent nucleus pulposus cells in mouse injury‐induced fibrotic intervertebral discs

• Published in: Aging cell 2020-11, Vol.19 (11), p.e13254-n/a
• Main Authors: Au, Tiffany Y. K., Lam, To‐Kam, Peng, Yan, Wynn, Sarah L., Cheung, Kenneth M. C., Cheah, Kathryn S. E., Leung, Victor Y. L.
• Format: Article
• Language: English
• Subjects: Aging; Analysis; Backache; Collagen (type I); Cre recombinase; Degeneration; Degenerative disc disease; disc degeneration; Embryos; fibroblast; Fibroblasts; fibrosis; Fluorescence; Genetic engineering; Genetic transformation; Genotype & phenotype; Green fluorescent protein; Hybridization; Intervertebral discs; Low back pain; Notochord; Nucleus pulposus; Proteins; Proteoglycans; Short Take; Short Takes; Transgenic mice
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13254

Intervertebral disc degeneration (IDD), a major cause of low back pain, occurs with ageing. The core of the intervertebral disc, the nucleus pulposus (NP), embedded in a proteoglycan‐rich and gelatinous matrix, is derived from the embryonic notochord. With IDD, the NP becomes fibrous, containing fewer cells, which are fibroblastic and of unknown origin. Here, we used a lineage tracing strategy to investigate the origin of cells in the NP in injury‐induced mouse IDD. We established a Foxa2 notochord‐specific enhancer‐driven Cre transgenic mouse model (Foxa2mNE‐Cre) that acts only in the embryonic to foetal period up to E14.5, to genetically label notochord cells with enhanced green fluorescent protein (EGFP). When this mouse is crossed to one carrying a Cre recombinase reporter, Z/EG, EGFP‐labelled NP cells are present even at 2 years of age, consistent with their notochordal origin. We induced tail IDD in Foxa2mNE‐Cre; Z/EG mice by annulus puncture and observed the degenerative changes for 12 weeks. Soon after puncture, EGFP‐labelled NP cells showed strong Col2a1+ expression unlike uninjured control NP. Later, accompanying fibrotic changes, EGFP‐positive NP cells expressed fibroblastic and myofibroblastic markers such as Col1a1, ASMA, FAPA and FSP‐1. The number of EGFP+ cells co‐expressing the fibroblastic markers increased with time after puncture. Our findings suggest resident NP cells initially upregulate Col2a1+ and later transform into fibroblast‐like cells during injury‐mediated disc degeneration and remodelling. This important discovery concerning the cellular origin of fibrotic pathology in injury‐induced IDD has implications for management in disease and ageing. Resident notochord descendant cells may transform into collagen II expressing cells and fibroblast‐like cells in induced mouse intervertebral disc degeneration featuring disc fibrosis. This work implicates a trans‐differentiation potential of nucleus pulposus cells in response to injurious or inflammatory stress, providing insights into the cellular origin of disc related pathology.