Intervertebral disc progenitor cells: roles in regeneration and disease

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.

1. Introduction

Low back pain (LBP) is one of the main causes of disability worldwide, which led to an enormous burden on society and the economy [1]. With the increase in the population and the aging of society, the incidence of LBP and its related medical expenses have increased rapidly, resulting in a huge social and economic burden. IVD degeneration is the primary cause of LBP and approximately 40% of LBP is related to IVD degeneration [2, 3]. The pathological factors of IVD degeneration are complicated, and they include genetic factors [3], age [4], trauma effects [5], and other causes. In a macroscopic view, the pathological process of degeneration leads to morphological changes in IVD, including a decline in the water content of the nucleus pulposus (NP), tears of the annulus fibrosis (AF), and ossification of the cartilage endplate (CEP), which ultimately result in disc bulging and a reduction in the intervertebral space height [6]. In a microscopic view, IVD degeneration leads to degradation of the extracellular matrix (ECM), decreasing cell numbers, reduced viability, and altered cell phenotypes in situ [7]. The pathological mechanisms of IVD degeneration include inflammation [8], a decline of progenitor cells [9], CEP calcification [10], etc. Regenerative medicine based on biological therapy for IVD regeneration has shown great clinical potential for the treatment of IVD degeneration [11, 12]. It is expected that these technologies will be used to synthesize native ECM via stimulating endogenous cells or transplanting exogenous cells. Studies have shown that cell therapy may be effective in repairing IVD. S. Haufe and A. Mork were the first to clinically study stem cell transplantation for ameliorating IVD degeneration [13]. They injected hematopoietic stem cells into the IVDs of 10 patients but found no improvement in symptoms one year after the operation. Thereafter, L. Orozco et al. transplanted autologous bone marrow mesenchymal stem cells (BM-MSCs) and adipose-derived mesenchymal stem cells (AD-MSCs) into the IVDs of patients with LBP. After the operation, the pain was rapidly relieved, and MRI scans showed an increase in water content in the NP [14]. Notably, a kind of mesoderm-derived progenitors in the IVD has been deciphered and named as IVD progenitor cells (IVD-PCs) or IVD mesenchymal stem cells (IVD-MSCs). Because their stemness has not been fully clarified, it could be more precise to be classified as IVD-PCs. IVD-PCs have exhibited great value as a cell source for cell transplantation because they show superior biosafety and functional controllability owing to feasibly being isolated from autologous IVDs [11, 12]. However, studies about the identification of IVD-PCs and the regulation of cell fate are still in their infancy. Key requirements for their clinical application include precise identification of IVD-PCs, characterization of their cell functions, and clarification of the cell fate determinants. Therefore, we reviewed recent progress on the identification of IVD-PCs and the microenvironmental regulatory cues on IVD-PCs fate and provide potential clues for future investigations of IVD-PCs.