Progenitor-like cells contributing to cellular heterogeneity in the nucleus pulposus are lost in intervertebral disc degeneration
Zhijia Tan,
Peikai Chen,
Xiaonan Dong,
Shuang Guo,
Victor Y.L. Leung,
Jason P.Y. Cheung,
Danny Chan,
Stephen M. Richardson,
Judith A. Hoyland,
Michael K.T. To,
Kathryn S.E. Cheah
Affiliations
Zhijia Tan
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Shenzhen Clinical Research Center for Rare Diseases, The University of Hong Kong – Shenzhen Hospital, Shenzhen, China; Department of Orthopaedics and Traumatology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Peikai Chen
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Shenzhen Clinical Research Center for Rare Diseases, The University of Hong Kong – Shenzhen Hospital, Shenzhen, China; Artificial Intelligence and Big Data Lab, The University of Hong Kong – Shenzhen Hospital, Shenzhen, China
Xiaonan Dong
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Shuang Guo
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Victor Y.L. Leung
Department of Orthopaedics and Traumatology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Jason P.Y. Cheung
Department of Orthopaedics and Traumatology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Danny Chan
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Stephen M. Richardson
Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester M13 9PT, UK
Judith A. Hoyland
Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester M13 9PT, UK
Michael K.T. To
Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Shenzhen Clinical Research Center for Rare Diseases, The University of Hong Kong – Shenzhen Hospital, Shenzhen, China; Department of Orthopaedics and Traumatology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Kathryn S.E. Cheah
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Corresponding author
Summary: The nucleus pulposus (NP) in the intervertebral disc (IVD) arises from embryonic notochord. Loss of notochordal-like cells in humans correlates with onset of IVD degeneration, suggesting that they are critical for healthy NP homeostasis and function. Comparative transcriptomic analyses identified expression of progenitor-associated genes (GREM1, KRT18, and TAGLN) in the young mouse and non-degenerated human NP, with TAGLN expression reducing with aging. Lineage tracing using Tagln-CreERt2 mice identified peripherally located proliferative NP (PeriNP) cells in developing and postnatal NP that provide a continuous supply of cells to the entire NP. PeriNP cells were diminished in aged mice and absent in puncture-induced degenerated discs. Single-cell transcriptomes of postnatal Tagln-CreERt2 IVD cells indicate enrichment for TGF-β signaling in Tagln descendant NP sub-populations. Notochord-specific removal of TGF-β/BMP mediator Smad4 results in loss of Tagln+ cells and abnormal NP morphologies. We propose Tagln+ PeriNP cells are potential progenitors crucial for NP homeostasis.
