Progenitor-like cells contributing to cellular heterogeneity in the nucleus pulposus are lost in intervertebral disc degeneration

Abstract

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-Cre^ERt2 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-Cre^ERt2 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.

Keywords: CP: Developmental biology; SMAD4; TAGLN; TGF-β/BMP signaling; disc degeneration; nucleus pulposus; progenitors.