Notochordal Cells in the Adult Intervertebral Disc: New Perspective on an Old Question

Abstract

The intervertebral disc is a soft tissue, positioned between each of the vertebrae, that accommodates applied biomechanical forces to the spine. The central compartment of the disc contains the nucleus pulposus (NP), which is enclosed by the annulus fibrosus and the endplate cartilage. The NP is derived from the notochord, a rodlike structure of mesodermal origin. Development of the notochord is tightly regulated by interactive transcription factors and target genes. Since a number of these molecules are unique, they have been used for cell lineage and fate mapping studies of tissues of the intervertebral disc. These studies have shown that in a number of species including human, NP tissue retains notochordal cells throughout life. In the adult NP, there are present both large and small notochordal cells, as well as a progenitor cell population which can differentiate along the mesengenic pathway. Since tissue renewal in the intervertebral disc is dependent on the ability of these cells to commit to the NP lineage and undergo terminal differentiation, studies have been performed to assess which signaling pathways may regulate these activities. The notch signaling pathway is active in the intervertebral disc and is responsive to hypoxia, probably through HIF-1α. From a disease viewpoint, it is hypothesized that an oxemic shift, possibly mediated by alterations in the vascular supply to the tissues of the disc, would be expected to lead to a failure in notochordal progenitor cell activation and a decrease in the number of differentiated cells. In turn, this would lead to decrements in function and enhancement of the effect of agents that are known to promote disc degeneration.

Molecular Basis of Intervertebral Disc Degeneration and Herniations: What Are the Important Translational Questions?

“…Notochordal cells play an important role in stimulating glycosaminoglycan and proteoglycan synthesis by NP cells and may also serve as progenitor cells to preserve and control the number of NP cells [74]. As a result of these anabolic effects, loss of notochordal cells from aging or disease states has magnified effects with eventual changes overall disc function and composition [75].…”

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

“…32 With aging and degeneration, NP tissue undergoes structural changes including gradual loss and degradation of proteoglycan-rich extracellular matrix, and ingrowth of neural and vascular structure along fissures in the outer annulus fibrosus. 1,33,36 Not surprisingly, changes in autophagy have also been associated with disc degeneration. Although the causative relationship between disc degeneration and autophagy is not yet clear, alterations in the level of autophagy have been observed in degenerated IVDs, IVDs of aged or diabetic rats [37][38][39] and NP cells derived from degenerative human discs.…”

CK8 phosphorylation induced by compressive loads underlies the downregulation of CK8 in human disc degeneration by activating protein kinase C

“…Studies show that CK8 expresses in notochord cells during the original development of NP as a marker to classify the origin of NP tissue. 24,25 In addition, CK8 exists in adult human NP cells and decreases with age or IDD. 7,8 However, the underlying mechanisms of the downregulation of CK8 are still unidentified.…”