Abstract
Intervertebral disc (IVD) degenerative disease is a prevalent and debilitating spinal disease. Current treatments only focus on symptomatic relief but fail to halt disease progression or restore the native biomechanical function of the spine. Regenerative medicine strategies, particularly those harnessing endogenous progenitor cells, offer a promising avenue for achieving biological repair and functional homeostasis. The identification of intervertebral disc progenitor cells (IVD-PCs) has unveiled a potential cellular reservoir for self-repair, given their demonstrated stemness attributes, including clonogenicity and multipotent differentiation. However, the clinical translation of IVD-PCs is significantly hampered by an incomplete understanding of their inherent heterogeneity, hierarchical organization, and, most critically, the dynamic interplay with their unique microenvironment, which dictates their fate decisions. This review synthesizes recent advances in deciphering the molecular signatures and functional plasticity of IVD-PCs. We place a particular emphasis on how key physicochemical, mechanical, and cellular cues within the IVD niche orchestrate progenitor cell behavior-ranging from maintenance and activation to aberrant differentiation-during both homeostasis and degeneration. Furthermore, we propose forward-looking insights to bridge critical knowledge gaps, aiming to propel the development of novel progenitor cell-based therapeutics for IVD degeneration.