With the growth of the global population and accelerated aging, low back pain (LBP) has become common public health problem worldwide (Cieza et al., 2021). Currently, the prevalence of LBP is 9.4% worldwide and is the leading cause of disability and loss of productivity (Geurts et al., 2018; Wu et al., 2020; Knezevic et al., 2021). Annually, the direct cost of treating LBP is approximately US$ 30 billion and the indirect socio-economic losses account for approximately US$ 100 billion in the United States (Binch et al., 2021). Although the causative factors of LBP are complex and varied, intervertebral disc degeneration (IDD) is considered to be the most common cause of LBP(Maher et al., 2017). IDD can be caused by cellular senescence, genetics, mechanical loading, obesity and even smoking (Adams and Roughley, 2006; Xin et al., 2022).

At present, the treatment of IDD mainly includes conservative treatment and surgical treatment. Although these treatments can provide good relief to patients, they do not slow or reverse the reduction of extracellular matrix (ECM) and nucleus pulposus cells (NPCs), do not repair the patient’s disc tissue, and have unsatisfactory long-term outcomes. In contrast, regenerative therapies based on restoring the physiological structure and biomechanical function of the intervertebral disc (IVD) have gained widespread interest in recent years. Among them, the current research related to mesenchymal stem cells (MSCs) for IDD is the most extensive. MSCs are pluripotent stem cells with the ability to differentiate into a tri-spectrum of osteoblasts, chondrocytes and adipocytes (Pittenger et al., 1999). Positivity for surface markers CD73, CD105 and CD90 is a distinctive feature (Dominici et al., 2006). MSCs are used as the first choice for regenerating IVD because of their abundant source and easy availability, extremely low immunogenicity, strong ability to induce differentiation, and to proliferate in a low-oxygen, low-sugar environment (Miao et al., 2006).

In the past, bone marrow mesenchymal stem cells (BMMSCs) were considered to be the gold standard of regenerative therapy. However, recent studies have found that umbilical cord mesenchymal stem cells (UCMSCs) are superior to BMMSCs in terms of cell source and differentiation potential. The IVD is the largest avascular tissue in the body (Molladavoodi et al., 2020). The survival of UCMSCs injected into the intervertebral disc is limited by the complex anatomy and harsh microenvironment within the disc (Sun et al., 2020). In recent years, with the continuous development of biomaterials with good biocompatibility as well as mechanical properties, tissue engineering techniques by implanting pretreated MSCs into biomaterial scaffolds have compensated for the shortcomings of MSCs for the treatment of IDD. However, there is still controversy regarding the selection of the most suitable cell type as well as the biological material. In this paper, we explored the effectiveness and feasibility of UCMSCs and their tissue engineering for regenerating IVD, and we hope that this study will help researchers to explore more systematically the prospects of UCMSCs in regenerating IVD.

IVD is the largest avascular tissue in the body and consists of fibrocartilage tissue, which is one of the most important structures of the spine. Anatomically, IVD consists of three main components: the central highly hydrated gelatinous nucleus pulposus (NP), fibrous rings (AF) consisting of thin sheets of collagen fibers around the NP, and cartilage end plate (CEP) is a transparent cartilage structure that connects adjacent vertebrae (Smith et al., 2011; Molladavoodi et al., 2020). The above structure distributes the axial load from the spinal cone and increases the mobility of the spine. NP is rich in proteoglycans and type II collagen, and it is highly hydrated, such that physiologic osmotic pressures readily dissipate any mechanical forces transmitted through the spine (Frith et al., 2013). AF is a laminar structure consisting mainly of type I collagen in a highly oriented manner, with approximately 15–25 layers. The closer the AF is to NP, the higher content of type II collagen and water (Torre et al., 2019; Kamali et al., 2021). CEP consists of hyaline cartilage that lies between the soft tissue of the IVD and the bony structures of the vertebral body. CEP is essential to maintain the mechanical integrity of the IVD and the exchange of nutrients (Zhang X. B. et al., 2021). Essential substances such as glucose and oxygen permeate into the NP mainly through the CEP to maintain IVD activity (Frost et al., 2019). ECM is present in the extracellular environment of all tissues. The main components of the ECM within the IVD include: collagens, proteoglycan, and non-collagenous proteins. The intensity of normal IVD is primarily affected by the components of ECM (Roughley et al., 2006; Liang et al., 2022).

The specific mechanism leading to IDD is still unclear, and the prevailing view is that cell senescence, inadequate nutritional supply, repeated mechanical stress, obesity, trauma, genetics, and even smoking can lead to the development of IDD (Adams and Roughley, 2006; Gübitz et al., 2018; Okada et al., 2019; Zhang et al., 2019). Among them, genetic factors are the main cause of IDD, approximately 50%–70% of the variability in disc degeneration is caused by an individual’s genetic inheritance (Battié et al., 1995; Buckwalter, 1995; Battié et al., 2008). In the early stages of IDD, there is an altered NPCs phenotype and a decrease in cell numbers, as well as an upregulation of the expression of enzymes such as MMP that mediate the degradation of ECM. This results in the inhibition of proteoglycans, glycosaminoglycans, aggrecan and type II collagen production, and an increase in type I collagen production. Ultimately, this leads to a weakening of IVD hydration and a reduction in height. The axial pressure from the spine is dispersed through the NP to the adjacent AF, which leads to altered biomechanical function of the AF as well as structural damage (Freemont, 2009; Morris et al., 2021; Ohnishi et al., 2022). The rupture of AF provides a suitable microenvironment for the growth of sensory neurons and blood vessels, prompting their growth into the IVD and accelerating the development of pain (Yee et al., 2016). As IDD progresses further, high levels of inflammatory cytokines are produced by AF cells, NPCs, and immune cells. These inflammatory factors, such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α, further aggravate IDD by exacerbating the inflammatory response, inhibiting IVD cell proliferation and differentiation, accelerating cellular senescence and apoptosis, and promoting ECM degradation (Rogers et al., 2017; Song et al., 2017; Wang et al., 2020). Calcification of CEP exacerbates metabolic disturbances within the IVD by affecting the exchange of substances (Wang et al., 2018). In addition, the above-mentioned series of pathological changes promote the production of reactive oxygen species (ROS) within the IVD and form a positive feedback loop, accelerating apoptosis within the disc (Feng et al., 2017).

Currently, the traditional treatment modalities for IDD include conservative treatment and surgery, and it is critical to choose the appropriate treatment for patients with different degrees of degeneration and clinical manifestations. For patients with early IDD, pharmacotherapy has a clear role in controlling pain and improving patient function and quality of life (van Middelkoop et al., 2011). However, the long-term use of drugs may lead to serious side effects as well as potential drug addiction and dependence, which makes the clinical use of drug therapy controversial (Hale et al., 2005; Wong et al., 2017). In addition, non-pharmacological treatments such as bed rest, brace immobilization, acupuncture, massage, electromagnetic or electrothermal therapy are also very effective in relieving acute attacks of LBP, and they are often combined with pharmacological treatments and surgery (Wegner et al., 2013; Glazov et al., 2014).

For patients with advanced IDD and those who have failed conservative treatment, surgery becomes the best option. Common surgical procedures include spinal decompression, spinal fusion and total disc replacement. Currently, spinal fusion is the most widely used in clinical practice and is considered the gold standard for the surgical treatment of IDD (Lee et al., 2016). Spinal fusion improves the stability of the spine and reduces patient pain by joining and fusing adjacent vertebrae (Phillips et al., 2013). It has been shown that when the vertebrae are fused, intervertebral motion between adjacent vertebrae is reduced, increasing the load on the surrounding tissues and adjacent IVD, which may further contribute to the development of IDD in adjacent segments (Kumar et al., 2001). For total disc replacement, prolonged wear of IVD prostheses prepared from metal and polymeric materials can lead to an immune inflammatory response and bone loss and are usually used only in the presence of single-segment IDD and in the absence of small joint disease. (Fritzell et al., 2001; Veruva et al., 2017; Werner et al., 2018). Surgical treatment can provide good relief to patients, but the high incidence of postoperative IVD stenosis and recurrence has become a major problem for physicians and patients (Scoville and Corkill, 1973; Hashimoto et al., 2019). Consequently, further explorations about more effective IDD treatment approaches are of great significance.

In recent years, researchers have begun to investigate regenerative therapies aimed at regulating anabolic and catabolic metabolism within the IVD and restoring ECM and NPCs. These methods mainly include direct injection of growth factors, cell transplantation, gene therapy and tissue engineering.

In cell therapy, researchers transplant cells with differentiation potential into the IVD to help restore the number of cells in the disc, promote ECM synthesis, and immune regulation. For discs with different degrees of development and degeneration, the selection of the appropriate cell type and source is critical for successful cell transplantation and disc regeneration. Common cell types include MSCs, intervertebral disc-derived stem cells (IVDSCs), and pluripotent stem cells (PSCs) (Hwang et al., 2009). These cells are related in terms of embryonic origin and genealogy. Among them, MSCs lack low expression of the major histocompatibility complex II and co-stimulatory factors CD80, CD86 and CD40, which leads to their low immunogenicity (Fouillard et al., 2007; Jacobs et al., 2013). In addition, MSCs have the advantages of a wide source, high proliferative capacity, multispectral differentiation potential and low tumorigenicity (Tsaryk et al., 2017).This seems to offer a promising alternative to regenerative therapy. However, the microenvironment of IVD is characterized by hypoxia, nutrient deficiency, acidity, hyperosmolarity, and mechanical loading. Its internal microenvironment further deteriorates during IVD denaturation with mechanical overload and accumulation of inflammatory cytokines and proteases (Lyu et al., 2019; Ryu et al., 2020; Vasanthan et al., 2020; Guerrero et al., 2021). This causes the survival of cells injected into the disc to be a primary issue. Some studies have reported that leakage during MSCs injection therapy can further aggravate IDD (Vadalà et al., 2012). In addition, the potential ethical issues of cell therapy, how to obtain sufficient numbers of MSCs for clinical treatment and the associated rejection reactions are still issues that we need to address urgently.

Direct injection of growth factors into the IVD has also been used as a new treatment modality. Growth factors commonly used in injectable therapy include bone morphogenetic protein (BMP)-7, BMP-2, transforming growth factor-β (TGF-β), insulin like growth factor (IGF), epidermal growth factor (EGF) and differentiation factor (GDF)-5 etc., (Knezevic et al., 2017; Cecerska-Heryć et al., 2022). However, growth factors have a short half-life and often require multiple injections for treatment, which makes the risk of injection-related injury as well as infection significantly higher. Growth factors are peptides that target cells. However, for patients with advanced IDD, only a small number of cells are present within the IVD, which makes growth factor therapy for IDD difficult to implement clinically. Gene therapy mainly involves the transfer of target genes into IVD cells via viral or non-viral vectors, which are amplified in vitro and then subsequently injected into the IVD. These IVD cells with the target gene will be retained in the IVD for a long time, promoting IVD regeneration and improving the patient’s symptoms. (Sampara et al., 2018). However, this gene therapy is difficult to mitigate the complications associated with viruses used for gene transfection and non-viral vectors, and the clinical application of this method is still limited to medically life-threatening diseases (Han, 2020; Takeoka et al., 2020). Moreover, most of the relevant studies at this stage are still in the experimental stage and still need a lot of investment in research.

MSCs were first discovered and isolated in the bone marrow of rats (Friedenstein et al., 1966), and more and more organs and tissues have been reported to provide a stable source of MSCs, including bone marrow, adipose tissue, umbilical cord, pulp, placenta, skin, tonsils etc., (Zuk et al., 2001; Lai et al., 2014; Ryu et al., 2014; Yan et al., 2014; Miceli et al., 2021). MSCs from different sources have certain similarities in morphology, differentiation potential and immunophenotype, but there are still differences in population numbers, growth rates, colony frequencies, success rates of isolation, immunosuppressive ability and gene expression profiles (Thirumala et al., 2013).

Currently, conventional treatment modalities for IDD provide good relief of symptoms in IDD patients, but their long-term outcomes are hardly satisfactory. A series of regenerative therapies have received much attention for their effectiveness in delaying or even reversing IDD. The higher proliferative differentiation potential, higher in vitro expansion rate and stability, lower immunogenicity and risk of infection make UCMSCs promising as an ideal choice for the treatment of IDD. In vitro and in vivo experiments have demonstrated that UCMSCs can differentiate into NPCs, promote ECM synthesis and regulate inflammatory responses within the IVD. However, the regenerative capacity of UCMSCs has reached opposite conclusions in some trials, and relevant clinical trials are scarce.The survival of UCMSCs under the harsh IVD microenvironment and pressure load is the main factor limiting their regenerative capacity. As the field of biomaterials continues to evolve, a new way of thinking is provided by the fact that UCMSCs have been shown to better perform their regenerative role by being attached to a variety of biomaterial scaffolds with excellent properties.

UCMSCs, as stem cells that have only recently entered the public eye, have been little studied, and existing experiments are similarly deficient. The main reason for this situation is the immaturity of UCMSCs in terms of extraction, storage and in vitro amplification. In recent years, cell banks for UCMSCs have been established in several countries with the aim of achieving access to large numbers of UCMSCs and helping heir clinical application. However, the number of established cell banks is currently much lower than expected. With the development and widespread use of 3D printing technology in the field of tissue engineering, 3D printed scaffolds may become a major trend. These scaffolds can be artificially adjusted to better meet the needs of UCMSCs survival and better repair the IVD. In addition, exosomes with lipid bilayers obtained by paracrine action of MSCs have been shown to promote tissue repair and regeneration. Because of their unique cell-free properties, they are significantly superior to MSCs in overcoming the microenvironment within IVD, immune rejection risk, tumorigenicity and ethical risk, which provides new ideas for further studies of UCMSCs. In the future, there are still many issues that need to be addressed for UCMSCs in regenerative treatment of IDD. More trials are needed to validate their effectiveness and safety in order to reduce the burden of IDD patients.