Dysregulation of YAP by the Hippo pathway is involved in intervertebral disc degeneration, cell contact inhibition, and cell senescence

Abstract

The Hippo pathway plays important roles in wound healing, tissue repair and regeneration, and in the treatment of degenerative diseases, by regulating cell proliferation and apoptosis in mammals. Intervertebral disc degeneration (IDD) is one of the major causes of low back pain, a widespread issue associated with a heavy economic burden. However, the mechanism underlying how the Hippo pathway regulates IDD is not well understood. Here, we demonstrate that the Hippo pathway is involved in natural IDD. Activation and dephosphorylation of yes-associated protein (YAP) were observed in younger rat discs, and decreased gradually with age. Surprisingly, Hippo pathway suppression was accompanied by overexpression of YAP, caused by acute disc injury, suggesting a limited ability for self-repair in IDD. We also demonstrated that YAP is inhibited by cell-to-cell contact via the Hippo pathway in vitro. Phosphorylation by large tumor suppressor kinases 1/2 (LATS1/2) led to cytoplasmic translocation and inactivation of YAP. YAP dephosphorylation was mainly localized in the nucleus and regulated by the Hippo pathway, whereas YAP dephosphorylation occurred in the cytoplasm and was associated with nucleus pulposus cell (NPC) senescence. Moreover, NPCs were transfected with shYAP and it accelerates the premature senescence of cells by interfered Hippo pathway through YAP. Therefore, our results indicate that the Hippo pathway plays an important role in maintaining the homeostasis of intervertebral discs and controlling NPC proliferation.

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

“…Based on these findings, it is possible that by maintaining a high level of cellcell junctional proteins the crowded cytoplasmic vacuoles may activate the Hippo pathways to slow down the proliferation of NNPC. In rat CNPC, the offspring of vacuolated NNPC, YAP was found to localize primarily in the nucleus in low-density cultures; however, in highdensity cultures, YAP demonstrated cytoplasmic accumulation in the less proliferative cells, supporting that cell-cell contact and Hippo-YAP regulation are also involved in the control of NP cell proliferation [Zhang et al, 2017].…”

“…In support of this notion, as rat IVD matures the cartilaginous matrix accumulates while the ratio of NNPC gradually decreases [Wang et al, , 2016Zhang et al, 2017Zhang et al, , 2018. Besides, compared to large and vacuolated NNPC, smaller nonvacuolated CNPC express higher levels of type I collagen, biglycan, and tissue inhibitor of metalloproteinases (MMP)-1 [Chen et al, 2006].…”

AMOT130 linking F‐actin to YAP is involved in intervertebral disc degeneration

“…Forty male SD rats were randomly divided into 4w group, 14w group, P4w group and 50w group on average. IDD was analysed by X‐ray, MRI and haematoxylin and eosin (HE) staining, as described previously …”

“…The IVD is an alymphatic and avascular tissue consisting of 3 distinct compartments: the gel‐like nucleus pulposus (NP), cartilaginous endplates present on the superior and inferior surfaces, and the annulus fibrosus (AF), which can be further categorized into outer (OAF) and inner (IAF) layers . The AF, in particular the OAF, withstands both tensional and strain forces, while the NP resists compressive loads applied to the spine.…”

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

“…We recently demonstrated that fibrotic regions of lung tissue from IPF patients show both regional depletion of AT2 cells and the presence of epithelial cells with abnormal activation of multiple pathways, including p53 and TGFb signaling (20). In other organs, such changes in cell phenotype promote cellular senescence (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Thus, age-dependent senescence of AT2 cells, accompanied by loss of stem/progenitor cell function, could contribute to progressive lung fibrosis.…”