Decoding stem cell preconditioning as a novel strategy for improving its therapeutic efficacy in intervertebral disc regeneration.

Intervertebral disc degeneration (IDD) is one of the major contributors to chronic low back pain, imposing a significant global socioeconomic burden. IDD is primarily driven by the degeneration of nucleus pulposus cells (NPCs) within the intervertebral disc (IVD), mainly due to oxidative stress, which leads to excessive reactive oxygen species (ROS) accumulation. ROS activate inflammatory and catabolic signaling pathways, resulting in degradation of the extracellular matrix (ECM) and progressive disc failure. Current treatments scarcely address the underlying biological mechanisms and fail to restore disc integrity. Mesenchymal stem cell (MSC)-based intervention has emerged as promising solution for disc regeneration due to its potential to mitigate inflammation and promote matrix synthesis. However, the avascular and proinflammatory environment of the degenerated disc limits cell-based interventions, as transplanted cells exhibit poor survival and engraftment after transplantation. To overcome these limitations, preconditioning strategies have been developed both to enhance direct MSC survival/engraftment and to optimize cell-free therapies utilizing preconditioned MSC secretome/extracellular vesicles. Preconditioning MSCs using various stimuli can improve their therapeutic performance by releasing factors that can support cell viability, reduce apoptosis, and increase cells' resilience to oxidative stress. Despite these promising findings, there remains a lack of comprehensive understanding regarding their role in IDD treatment. This review examines current MSC-based therapies, the mechanisms behind various preconditioning strategies, and the translational challenges that remain unexplained. Ultimately, preconditioned MSC-derived products offer a novel and potentially more effective approach for intervertebral disc regeneration.