Defects in intervertebral disc and spine during development, degeneration, and pain: New research directions for disc regeneration and therapy

Abstract

Intervertebral discs are cartilaginous joints present between vertebrae. The centers of the intervertebral discs consist of a gelatinous nucleus pulposus derived from the embryonic notochord. With age or injury, intervertebral discs may degenerate, causing neurological symptoms including back pain, which affects millions of people worldwide. Back pain is a multifactorial disorder, and disc degeneration is one of the primary contributing factors. Recent studies in mice have identified the key molecules involved in the formation of intervertebral discs. Several of these key molecules including sonic hedgehog and Brachyury are not only expressed by notochord during development, but are also expressed by neonatal mouse nucleus pulposus cells, and are crucial for postnatal disc maintenance. These findings suggest that intrinsic signals in each disc may maintain the nucleus pulposus microenvironment. However, since expression of these developmental signals declines with age and degeneration, disc degeneration may be related to the loss of these intrinsic signals. In addition, findings from mouse and other mammalian models have identified similarities between the patterning capabilities of the embryonic notochord and young nucleus pulposus cells, suggesting that mouse is a suitable model system to understand disc development and aging. Future research aimed at understanding the upstream regulators of these developmental signals and the modes by which they regulate disc growth and maintenance will likely provide mechanistic insights into disc growth and aging. Further, such findings will likely provide insights relevant to the development of effective therapies for treatment of back pain and reversing the disc degenerative process. This article is categorized under: Birth Defects > Organ Anomalies Vertebrate Organogenesis > Musculoskeletal and Vascular Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Aging.

Keywords: Brachyury; Shh; disc degeneration; lower back pain; regeneration.

Figure 1.

Back pain is a multifactorial disorder. Degeneration of the disc and defects in the spine are significant contributors to back pain.

Figure 2.

Hematoxylin and eosin stained mid-coronal section of a two-week-old mouse lumbar spine. The center of the disc has gelatinous nucleus pulposus (NP) cells, surrounded by annulus fibrosus (AF) and located between cartilaginous endplate (EP). EP is adjacent to the growth plate (GP) of the vertebra. Spinal nerves are on the lateral side of the disc.

Figure 3.

Embryonic origin of the disc. a. Mid-coronal section, b. Transverse section- through a four-month-old Shh^Cre; R26^mTmG mouse lumbar intervertebral disc. The nucleus pulposus (np) is a homogenous population of descendants of Shh-expressing cells. Panels c and d show intervertebral disc from Scx^Cre; R26R neonatal mouse where the annulus fibrosus (pointed by arrows) stained positive for X-gal staining. c. Frontal section through a lumbar. d Transverse section through a thoracic intervertebral disc. The asterisk in c shows nucleus pulposus cells. np- nucleus pulposus, vb- vertebral body, nt- neural tube, ivd- intervertebral disc. Panels c and d are adapted from Sugimoto et al., 2013 Genesis, DOI: (10.1002/dvg.22372), with permission from Wiley.

Figure 4.

Similarities between embryonic notochord (a) and postnatal nucleus pulposus (b). Both notochord and nucleus pulposus act as signaling center, and both express SHH which is crucial for maintenance and patterning of themselves and the surrounding structure. The young and healthy disc is vascularized, and blood vessels (red lines) are restricted at the growth plate (GP) in the vertebrae. FP- floor plate, NT- Neural tube, NP- nucleus pulposus, AF- annulus fibrosus, EP- endplate.

Figure 5.

Morphological changes in the mouse disc with normal aging. With aging, the expression of developmental signals and their targets like extracellular matrix (ECM) are reduced. Fewer nucleus pulposus cells that appear phenotypically different from the young nucleus pulposus cells are seen. Arrows point to smaller, “chondrocyte-like cells” encased within lacunae. The surrounding annulus fibrosus, which is regulated by signals from nucleus pulposus, also becomes thinner and disorganized with aging. NP- nucleus pulposus, AF- annulus fibrosus, EP- endplate. Adapted from Winkler et al., 2014, https://doi.org/10.1371/journal.pone.0098444.g004, with permission from PlosOne.

Figure 6.

Potential strategies for regeneration of the disc and cure for back pain. NP- nucleus pulposus, MSCs- Mesenchymal Stem Cells, iPSCs- induced pluripotent stem cells.