ArticleStem cell research & therapy2026
TGF-β/SMAD signaling maintains nucleus pulposus stem cell quiescence to protect against oxidative injury in intervertebral disc degeneration.
Article in Stem cell research & therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundIntervertebral disc degeneration (IVDD) is characterized by progressive nucleus pulposus cell loss and extracellular matrix degradation, in which persistent oxidative stress plays a critical pathogenic role. Transplantation of nucleus pulposus-derived stem cells (NPSCs) is a promising therapeutic strategy, yet the hostile oxidative microenvironment severely compromises cell survival. Although cellular quiescence has been suggested to enhance stress tolerance, its regulatory mechanisms and relevance in NPSCs remain largely unexplored.
methodsOxidative stress was evaluated in human degenerated disc tissues, a rat needle-puncture degeneration model, and tert-butyl hydroperoxide-treated NPSCs in vitro. Proliferating and quiescent NPSCs were compared for reactive oxygen species (ROS) levels, apoptosis, viability, and transcriptomic profiles. Pathway enrichment analyses were performed to identify critical signaling mechanisms. Recombinant transforming growth factor-beta 3 (rhTGF-β3) was used to activate the pathway, while small interfering RNA targeting the transforming growth factor-beta receptor type 2 (Tgfbr2) and the pharmacological inhibitor SB431542 were applied for pathway suppression. Functional assays, organ culture, and in vivo transplantation were conducted to assess cell survival and regenerative effects.
resultsElevated oxidative stress was consistently observed across clinical, animal, and cellular models of disc degeneration. Quiescent NPSCs demonstrated enhanced resistance to oxidative injury, with reduced ROS accumulation, decreased apoptosis, and improved survival. Transcriptomic analyses revealed suppression of metabolic and P53-mediated apoptotic pathways, alongside marked activation of TGF-β/SMAD signaling. Activation of this pathway induced quiescence, reduced ROS levels, inhibited mitochondrial apoptotic signaling, and protected NPSCs from oxidative injury, whereas pathway inhibition abolished these protective effects. In both organ culture and in vivo transplantation models, quiescent and TGF-β-activated NPSCs exhibited superior survival and significantly improved disc structural preservation compared with proliferating or pathway-blocked cells.
conclusionActivation of the TGF-β/SMAD pathway induces NPSC quiescence and enhances oxidative stress tolerance by suppressing P53-dependent mitochondrial apoptosis. Pharmacological induction of quiescence represents a potential strategy to improve stem cell-based therapies for intervertebral disc degeneration.
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