Large Cytoplasmic Vacuoles within Notochordal Nucleus Pulposus Cells: A Possible Regulator of Intracellular Pressure That Shapes the Cytoskeleton and Controls Proliferation
Abstract:Degeneration of the intervertebral disc, which is closely associated with the loss of vacuolated notochordal nucleus pulposus cells (NNPC), remains a major cause of lower-back pain and motor deficiency. Being the most defining characteristic of NNPC, large cytoplasmic vacuoles not only modulate the cytoskeleton and shape cell morphology but they also respond to the disc microenvironment and regulate the biological behavior of vacuolated cells as a potent reporter of the histocytological changes that occur at t… Show more
“…2 ). This observation is of interest because AHA staining within vacuolar structures appeared modest at best, which may support the hypothesis that vacuoles play a more important role in regulation of intracellular pressure than in molecular transport [ 65 – 67 ]. However, further assessments need to be conducted to better understand these findings and their implications.…”
“…2 ). This observation is of interest because AHA staining within vacuolar structures appeared modest at best, which may support the hypothesis that vacuoles play a more important role in regulation of intracellular pressure than in molecular transport [ 65 – 67 ]. However, further assessments need to be conducted to better understand these findings and their implications.…”
“…The NC vacuoles are presumably mechanoprotected by the caveolae, flask-shaped structures of the plasma membrane that express caveolins ( Nixon et al, 2007 ; Sinha et al, 2011 ; Bach et al, 2016a ) and by the ECM of the notochordal sheath, rich in collagens, proteoglycans (mostly chondroitin sulfate and heparan sulfate), laminins, and fibronectins ( Yasuoka, 2020 ). Since the vacuoles play an important biomechanical role in the developing embryo, they might also have a biomechanical role in the postnatal IVD by maintaining intracellular pressure to resist mechanical loading ( Hong et al, 2018 ). Since NC vacuoles are important organelles in the embryonic notochord and postnatal NP, they might also be involved in the NC-mediated regenerative effects.…”
Section: Discussionmentioning
confidence: 99%
“…In addition to the cargo content, also the self-renewal ability of the NCs is a topic of debate. There is evidence that the presence of large intracytoplamic vacuoles is a limiting factor for cell proliferation ( Joo Han Kim et al, 2009 ; Hong et al, 2018 ), which is important to consider when aiming for NC-based regenerative therapies. Taken together, studying the NC vacuoles may provide novel information, possibly enabling guidance for NC-based IVD regeneration.…”
Chronic low back pain is the number one cause of years lived with disability. In about 40% of patients, chronic lower back pain is related to intervertebral disc (IVD) degeneration. The standard-of-care focuses on symptomatic relief, while surgery is the last resort. Emerging therapeutic strategies target the underlying cause of IVD degeneration and increasingly focus on the relatively overlooked notochordal cells (NCs). NCs are derived from the notochord and once the notochord regresses they remain in the core of the developing IVD, the nucleus pulposus. The large vacuolated NCs rapidly decline after birth and are replaced by the smaller nucleus pulposus cells with maturation, ageing, and degeneration. Here, we provide an update on the journey of NCs and discuss the cell markers and tools that can be used to study their fate and regenerative capacity. We review the therapeutic potential of NCs for the treatment of IVD-related lower back pain and outline important future directions in this area. Promising studies indicate that NCs and their secretome exerts regenerative effects, via increased proliferation, extracellular matrix production, and anti-inflammatory effects. Reports on NC-like cells derived from embryonic- or induced pluripotent-stem cells claim to have successfully generated NC-like cells but did not compare them with native NCs for phenotypic markers or in terms of their regenerative capacity. Altogether, this is an emerging and active field of research with exciting possibilities. NC-based studies demonstrate that cues from developmental biology can pave the path for future clinical therapies focused on regenerating the diseased IVD.
“…The ion pump on the vacuole membrane generates a hypotonic solution in the vacuole, which can be released into the cytoplasm to dilute under osmotic pressure changes. This not only balances the osmotic pressure across the cell membrane, 70 but also regulates cell volume and tension during rapid osmotic pressure changes, protecting NCs from damage caused by swelling and rupture 71 . Therefore, the increase in vacuoles within NCs may indirectly indicate an elevation of pressure within the NCs.…”
Section: Biological Characteristics Of Ncsmentioning
Intervertebral disc degeneration (IDD) is a prevalent musculoskeletal degenerative disorder worldwide, and ~40% of chronic low back pain cases are associated with IDD. Although the pathogenesis of IDD remains unclear, the reduction in nucleus pulposus cells (NPCs) and degradation of the extracellular matrix (ECM) are critical factors contributing to IDD. Notochordal cells (NCs), derived from the notochord, which rapidly degrades after birth and is eventually replaced by NPCs, play a crucial role in maintaining ECM homeostasis and preventing NPCs apoptosis. Current treatments for IDD only provide symptomatic relief, while lacking the ability to inhibit or reverse its progression. However, NCs and their secretions possess anti‐inflammatory properties and promote NPCs proliferation, leading to ECM formation. Therefore, in recent years, NCs therapy targeting the underlying cause of IDD has emerged as a novel treatment strategy. This article provides a comprehensive review of the latest research progress on NCs for IDD, covering their biological characteristics, specific markers, possible mechanisms involved in IDD and therapeutic effects. It also highlights significant future directions in this field to facilitate further exploration of the pathogenesis of IDD and the development of new therapies based on NCs strategies.
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