Low back pain (LBP) and neck pain currently form the primary causes of global disability [1], and prevalence is likely to increase with a generally aging population, further imposing concerns on the socioeconomic affordability of healthcare and social security expenses [2,3]. Both disorders are generally associated with the intervertebral discs (IVD) being subdued to progressive age- and non-age-related degeneration [4]. IVD constitute the fibrocartilage tissues between each two vertebrae, capable of distributing complex loads along the spine. The IVD is composed of a highly hydrophilic core, the nucleus pulposus (NP), which is laterally enclosed by multiple collagenous lamellae, cumulatively termed the annulus fibrosus (AF) (Figure 1A). The IVD is connected to each vertebra with a thin hyaline cartilage layer, the endplate, which forms the primary source of nutrient, waste, and gas exchange for the predominantly avascular discs [5]. The IVD derives its function through a careful interplay of the high osmotic pressure engendered by the proteoglycan-rich NP, which is constricted by a stiff AF, jointly enabling the IVD to absorb relatively large forces while retaining flexibility. Tissue-specific cells are responsible for maintaining and remodeling the region-distinct extracellular matrix (ECM) to maintain the IVD and its biomechanical features. Although the etiology and progression of IVD degeneration remain somewhat obscure, it is generally associated with a progressive decline in cell numbers and a cellular switch toward a more catabolic and senescent state [6,7] (Figure 1B). Consequently, deteriorating the quality and organization of the ECM, thereby compromising the discs biomechanical limits [8]. Jointly, these changes engender an inflammatory environment, promoting immunogenic cell migration and potentially inducing blood vessel and neuronal ingrowth into the disc, thereby conceivably sensitizing the discs or inflaming regional spinal nerves [5,9]. Moreover, the progressive decline of the biomechanical sturdiness of the disc may allow AF tissue to bulge or burst, compressing neuronal and vascular tissues along the spine. Alternatively, the loss of water retention in the NP leads to a decline in disc height and mechanical features that further stress other spinal tissues, e.g., facet joints and tendons, to thereby be involved in the pathogenesis.

Contemporary treatment strategies remain primarily palliative (Figure 2). Early-stage LBP is commonly treated with physiotherapy or the administration of analgesics [10]. Consequently, LBP has been indicated as the primary reason for non-cancer opioid prescription [11]. Nevertheless, high-quality evidence supporting the efficacy of these conservative therapies is severely lacking [10]. At later stages of LBP, surgical intervention may be employed. Generally, this involves either excision of protruding disc material in cases of disc herniation or complete removal of discs followed by arthroplasty or arthrodesis. Although these procedures are commonplace and rates are dramatically increasing [12,13], their efficacy remains largely controversial [14,15]. In addition, none of these interventions aim to resolve the degenerative cascade underlying the pathology, and furthermore, can trigger degenerative cascades in neighboring discs [16]. For treatment investigations, a slight reduction in the number of LBP patients, associated medical care, or back pain intensity can make a significant impact on socioeconomic costs, and translate to a large cohort of patients. These new strategies being explored focus on limiting, halting, and even reversing disc degeneration in an attempt to revitalize the disc’s composition and thus its biomechanical features, thereby resolving or preventing associated spinal disorders [17,18]. These include regenerative approaches, e.g., growth factor injection [19], gene therapy [20], tissue engineering [21,22], and biomaterial-applications [23], each being at different stages of development and presenting different levels of success in preclinical and/or clinical studies. Moreover, each strategy will likely be most effective at different stages of the degeneration cascade (Figure 2). One particular regenerative approach that has gained significant momentum in the recent decade is cell therapy [24,25]. Cell therapy involves the transplantation of additional cell populations into the IVD with the aim to either (i) directly impact IVD repair by repopulating the disc with de novo active cells to reestablish appropriate ECM production or (ii) indirectly induce IVD repair by stimulating or attracting regional cells to induce a more anabolic state, by for example tempering inflammation or to promote (re)initiation of IVD-ECM production by native cells (Figure 1C). The optimal strategy for restoring degenerative IVD in a clinic setting remains to be determined and is likely highly dependent on the degenerative state and disease indications. Multiple cell products and transplantation strategies have now been assessed in the clinical, showing promising results. Nevertheless, due to the accelerating speed of publication on this topic [24], new advancements in cellular therapy and new insights on potential limitations require continuous and careful review of progress in the field. Here we aim to assess the contemporary state and trends seen in the field of cell therapy in the clinic regarding safety and efficacy for cell-mediated therapy for the IVD. This review will discuss the main reported clinical trials, specifically focusing on the differences in cell products being examined. Moreover, we will supplement our review with our own experiences in cell-based therapeutics applied in a human condition.