Open AccessTransformation of resident notochord‐descendent nucleus pulposus cells in mouse injury‐induced fibrotic intervertebral discs
Author(s) -
Au Tiffany Y. K.,
Lam ToKam,
Peng Yan,
Wynn Sarah L.,
Cheung Kenneth M. C.,
Cheah Kathryn S. E.,
Leung Victor Y. L.
Publication year - 2020
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13254
Subject(s) - notochord , intervertebral disc , biology , cre recombinase , embryonic stem cell , microbiology and biotechnology , green fluorescent protein , pathology , genetically modified mouse , transgene , anatomy , gene , embryogenesis , medicine , genetics , embryo
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.