Abstract
Notochord nucleus pulposus cells are characteristic of containing abundant and giant cytoplasmic vacuoles. This review explores the embryonic formation, biological function, and postnatal exhaustion of notochord vacuoles, aiming to characterize the signal network transforming the vacuolated nucleus pulposus cells into the vacuole-less chondrocytic cells. Embryonically, the cytoplasmic vacuoles within vertebrate notochord originate from an evolutionarily conserved vacuolation process during neurulation, which may continue to provide mechanical and signal support in constructing a mammalian intervertebral disc. For full vacuolation, a vacuolating specification from dorsal organizer cells, synchronized convergent extension, well-structured notochord sheath, and sufficient post-Golgi trafficking in notochord cells are required. Postnatally, age-related and species-specific exhaustion of vacuolated nucleus pulposus cells could be potentiated by Fas- and Fas ligand-induced apoptosis, intolerance to mechanical stress and nutrient deficiency, vacuole-mediated proliferation check, and gradual de-vacuolation within the avascular and compression-loaded intervertebral disc. These results suggest that the notochord vacuoles are active and versatile organelles for both embryonic notochord and postnatal nucleus pulposus, and may provide novel information on intervertebral disc degeneration to guide cell-based regeneration.
Highlights
According to systematic analysis for the Global Burden of Disease Study 2010, lower back pain (LBP) remains the leading cause of disability, affecting around 632 million people worldwide, followed by major depressive disorders [1]
A young and normal Intervertebral disc (IVD) is composed of three distinct components: the central gelatinous nucleus pulposus (NP), the outer fibrotic annulus fibrosus (AF), and the cartilaginous endplate (CEP) that anchors into the growth plate of the vertebral body 5, 8]
While a direct causeeffect relationship between the loss of notochordal NP cells (NNPCs) and IVDD has yet to be established, previous studies suggest that NNPCs are versatile and capable of: (1) generating offspring of chondrocyte-like NP cells (CNPCs) [14]; (2) attracting CEP chondrocytes into NP [15]; (3) secreting nutritional factors to rejuvenate neighboring disc cells [16, 17]; (4) stimulating chondrogenic differentiation of mesenchymal stem cells [18]; (5) inhibiting infiltration of neurons or endothelium into IVD [19, 20]; and (6) suppressing CNPC death within harsh disc niches [21]
Summary
According to systematic analysis for the Global Burden of Disease Study 2010, lower back pain (LBP) remains the leading cause of disability, affecting around 632 million people worldwide, followed by major depressive disorders [1]. Since intradiscal pressure is associated with the size and shape of IVD, the stability and force of muscle or ligament, as well as the integrity and functionality of zygapophyseal joints between vertebrae [84], it would not be surprising to find that NNPCs and their cytoplasmic vacuoles are exhausted inhomogeneously by diverse mechanical stresses among different animals and/or at different segments Another possibility concerns the avascular nature of IVD [5, 85], which likely fails to provide sufficient nutrients or energy to maintain high levels of post-Golgi trafficking and vesicle biogenesis. As the notochord cells in normoxic cultures (without hypoxia and compressive loading) lose vacuoles [14], there may be other unidentified factors exhausting the cytoplasmic vacuoles of NNPCs
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