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

Nucleus pulposus (NP) cells of the intervertebral disc (IVD) provide protection against mechanical load and arise from the embryonic notochord. After birth large vacuolated notochordal-like cells (NCLs) and smaller chondrocyte-like cells (CLCs) populate the NP. In humans, loss of NCLs is thought to correlate with the age-onset of intervertebral disc disease (IDD). In the mouse, which is more resistant to IDD, NCLs persist and may protect against IDD. We identified genes associated with progenitors such as T, TAGLN and KRT18 that are expressed in mouse and human non-degenerated NP but diminished in human degenerated NP. Lineage tracing using Tagln-CreERt2 mice identified proliferative NP cells located in the periphery of the developing and postnatal NP (PeriNP) that provide a continuous supply of cells to the entire NP. PeriNP cells were diminished in aged NP and absent in puncture-induced degenerated discs. Single-cell transcriptomes of postnatal Day10 and 8-week Tagln-CreERt2 IVD cells indicate enrichment for TGF-β signaling in the NP Tagln descendant sub-populations. Notochord specific removal of TGF-β/BMP mediator Smad4 by Foxa2mNE-Cre results in loss of Tagln+ cells and abnormal disc morphology, resembling IDD. Tagln+ PeriNP cells are implicated as potential progenitors crucial for NP development and maintenance, and their loss is relevant to IDD.