Large Cytoplasmic Vacuoles within Notochordal Nucleus Pulposus Cells: A Possible Regulator of Intracellular Pressure That Shapes the Cytoskeleton and Controls Proliferation

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 the beginning of disc aging and degeneration. Here we hypothesize a model in which large cytoplasmic vacuoles primarily function to maintain a reasonable intracellular pressure (Pv) that facilitates NNPC in resisting the extracellular mechanical loading (Pe), part of which is absorbed by the extracellular matrix (Pm), forming the equation Pe = Pm + Pv. By mimicking a situation of contact-induced growth inhibition, the crowded cytoplasmic vacuoles slow down the proliferation of NNPC and restrain the generation of nonvacuolated chondrocytic nucleus pulposus cells (CNPC), whereas increased mechanical loading (↑Pe) alters cytoskeletons and breaches cytoplasmic vacuoles, which in turn weakens the vacuoles-mediated proliferation check, increases the generation of CNPC that accumulates fibrocartilaginous matrix, and rebalances the increased loading with elevated Pm (↑Pm) and lowered Pv (↓Pv), equating to ↑Pe = ↑Pm + ↓Pv. By depicting the biological function and the disappearance of the cytoplasmic vacuoles, our model highlights a mechanical exhaustion of the notochordal cell resources, which might help to elucidate the histocytological changes that initiate disc aging and degeneration.