TIE2-positive cells in the nucleus pulposus with a purpose: the who, what and why

Once thought to be solely involved in vasculogenesis, tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE2) has emerged as a crucial marker of progenitor-like cells in the avascular nucleus pulposus (NP), a tissue with notoriously limited regenerative capacity. Recent evidence suggests that TIE2 + NP cells play a pivotal role in disc tissue homeostasis, influencing extracellular matrix maintenance, cellular renewal, and tissue integrity. However, despite the reported regenerative potential of TIE2 + NP cells, their precise function remains enigmatic. This review consolidates in vivo, in vitro, and transcriptomic studies to validate the presence of TIE2 in the NP as a progenitor cell marker. We unravel the complexity of TIE2 + NP cells across species, highlighting key regulatory mechanisms and interspecies variations (including mice, rats, dogs, cows, sheep, pigs, and humans) that may influence their relevance as clinical- and regenerative therapeutic targets. Yet, methodological inconsistencies across studies continue to obscure our understanding of the precise role of TIE2 in NP cell biology. At present, clinical care is limited to managing pain conservatively or resorting to spinal surgery in severe cases. Thus, there exists an urgent need for innovative regenerative strategies to combat disc degeneration and its associated pain and disability. A range of emerging approaches, including biomaterials, gene therapy, and cell-based therapeutics, are under investigation. Within this context, TIE2 + NP cells are of particular interest as potential therapeutic vectors: as for example candidate cells for transplantation, as populations to be stimulated by biologic interventions, or as building blocks in tissue engineering strategies. As progenitor-like cells, they hold the theoretical potential to provide a sustained source of functional NP cells for disc maintenance and repair. By identifying existing knowledge gaps and proposing future research directions, this review aims to clarify their role and accelerate progress toward unlocking their full therapeutic potential.