Targeting endogenous stem cells: a novel regenerative strategy for intervertebral disc degeneration

Low back pain (LBP) is a leading cause of global disability, with around 40% of cases linked to intervertebral disc degeneration (IVDD). Current clinical treatments primarily address symptoms without reversing the degenerative process or restoring disc function. Although stem cell therapy has gained attention in regenerative medicine, the survival and functionality of exogenous stem cells are significantly hindered by the adverse microenvironment in degenerative discs. Recent discoveries of endogenous stem/progenitor cells within the disc present a promising alternative for regeneration and repair. These cells, located in the nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplate (CEP), demonstrate regional heterogeneity and multi-lineage differentiation potential. However, their function is closely regulated by the degenerative microenvironment, which includes hypoxia, oxidative stress, acidosis, inflammatory cytokines, and abnormal mechanical loading. This review provides a comprehensive overview of the niche characteristics of disc endogenous stem cells, the mechanisms by which the degenerative microenvironment influences their function, and recent advances in pharmacological and biomaterial-based strategies to modulate stem cell fate and foster tissue regeneration. The integration of biomimetic scaffolds, smart delivery systems, and multi-targeted regulatory strategies offers promise for the structural and functional reconstruction of the disc by targeting these endogenous cells. However, significant challenges persist, such as the complexity of the degenerative niche, depletion of reparative cell populations, and limitations in preclinical translation models. Achieving clinical application will require the convergence of single-cell multi-omics, spatiotemporally controlled release technologies, and the development of mechanically adaptive scaffolds to enable precise, endogenous repair-focused therapeutic strategies.