Mesenchymal stem cells (MSCs) are considered as a source of cells for gene therapy and implantation. It is known that MSCs are non-committed pluripotent stem cells that are present in various tissues. They are available and easy to manipulate ^[1][5], but MSCs must be differentiated into chondrocyte-like cells before implantation in patients with intervertebral disc degeneration (IDD). Growth factors of the family of bone morphogenetic proteins are used to differentiate MSCs into chondrocytes ^[2][6]. In recent years, a differentiation factor from the cyclooxygenase (COX) family was studied as a more specific factor for the differentiation of MSCs, and members of the Brachyury transcription factor family are considered as MSCs adhesion factors ^[3][7]. The cultivation of MSCs with intervertebral disc (IVD) cells is used to induce a disk-like phenotype ^[4][8], and cultivation of MSCs under conditions of a three-dimensional system promotes the formation of a chondrocyte-like phenotype ^[5][9].

Increasingly, MSCs are being used in clinical trials for severe IDD and severe low back pain in humans. The mechanisms of action of MSCs are not fully understood. However, they are known to reduce the levels of pro-inflammatory cytokines in the pro-inflammatory/degenerative microenvironment of IVDs ^[6][10]. Preconditioning of MSCs with IL-1β increases the secretion of hIL-6, hIL-8, hMCP-1 (monocyte chemoattractant protein 1), and other pro-inflammatory biomarkers of IDD. On the other hand, MSCsec suppress the expression of genes encoding bIL-6, bIL-8, and metalloproteinase 1 (MMP-1). In contrast, MMP-3 and the tissue inhibitor of metalloproteinase 2 (TIMP-2) increase the expression of these genes. Increased aggrecan deposition was found in MSCsec-treated degenerating IVDs, although no differences were observed in other EMC components. Protein analysis of MSCsec-treated IVD supernatant revealed a significant increase in chemokine ligand 1 (CXCL-1), MCP-1, macrophage inflammatory protein 3 alfa (MIP-3α), IL-6, IL-8, and growth-related oncogenes alfa/beta/gamma (GRO-α/β/γ) and decreased interferon gamma (IFN-γ), IL-4, IL- 5, IL-10, and TNF-α. At the same time, MSCsec-treated IVD supernatants did not stimulate neo-angiogenesis and neurogenesis in vitro ^[7][11]. The immunomodulatory paracrine effect of MSCs in IDD (without a clear effect on extracellular matrix remodeling) was shown in the course of studies and suggests that the mechanism of action of MSCs depends on the cytokine feedback loop ^[8][12]. Delivery of MSCs to degenerating IVDs increases the population of Tie2-positive progenitors (differentiation clusters) and prevents apoptosis of NP and AF cells. Additionally, they may induce a proliferative response in NP and AF cells of degenerative IVDs ^[9][13]. Human umbilical cord-derived MSCs and chondroprogenitor derivatives may reduce back pain, inflammation, and promote cell regeneration in IVDs in a rat model of IDD ^[10][14]. Lithium chloride preconditioning (medium level) mechanically induced an increase in cellular reactive oxidative species (ROS) and ERK-1/2 (extracellular signal-regulated kinase 1/2) activation, which is closely associated with increased cell and ECM survival in IVDs. Treatment with preconditioned adipose-derived stem cells (ADSCs) showed a better therapeutic effect than control transplantation of ADSCs, with better preservation of NP cells and deposits of ECM in degenerative IVDs ^[11][15].

Degenerated IVDs can be populated with in vitro cultured cells. To prevent immune reactions, such cells must be autologous. The use of NP material selected at the time of microdiscectomy may be one of the approaches to obtaining cells for in vitro cultivation. However, the possibility of introducing autologous cultured cells or implants after surgery in IVDs is debatable ^[12][16]. The simplest approach to repair degenerating IVD using autologous cultured cells is the injection of cells grown ex vivo ^[13][17]. This approach allows achieving a significant therapeutic response in patients with IDD.

Another approach to using autologous cells for transplantation into a degenerating IVD is to culture the cells in a 3D culture system. A sufficient number of artificial three-dimensional matrices for culturing IVD cells was proposed ^[14][18]. At the same time, Gruber et al. ^[15][19] used autologous cells cultured in a conventional monolayer culture, which were then populated in a three-dimensional matrix in accordance with the cavity formed in the degenerating IVD. At 33 weeks, NF and AF cell structures were similar to that of healthy IVDs.

Cell therapy has some limitations in IDD therapy during in vitro studies, in vivo studies, and in many clinical studies ^[16][20]. Transplantation of MSCs may be an effective treatment for mild to moderate IDD. However, multifunctional tissue engineering treatment has advantages in severe IDD requiring structural support ^[17][18][19][21,22,23]. Tissue engineering (co-administration of growth factors, MSCs, and scaffold) is more important because of the positive results of using various types of functional polymers (alginate, chitosan, collagen, gelatin, hyaluronic acid, polyurethane, polyethylene glycol, and polyglycolic and polylactic acids). This high-tech method based on cells and scaffolds is considered as a more effective method for the treatment of severe IDD in humans ^[19][23].

Biomaterials for tissue engineering can be developed in the form of injections to mimic and preserve the structures of the IVD extracellular matrix, taking into account its degenerative changes at an early stage of the disease. Therapeutic small molecules or drugs can be incorporated into biomaterials to stop the pathological cascade that underlies the development of IDD. All of these biomaterials can be delivered to degenerating IVDs using percutaneous, minimally invasive procedures, in addition to existing treatments for early and mild disease ^[20][24]. Additionally, biomaterials can serve as an advanced cell delivery system in degenerating IVDs to support transplantation of MSCs, to repopulate native cells in IVDs with mild to severe degeneration associated with lower cellularity in IVD tissues.

A tissue engineering strategy based on precision biomaterials, taking into account the severity of the degenerative process in IVDs, is aimed at providing a regenerative effect in early, mild, and severe IDD. This is necessary to develop customized biomaterials and tissue engineering strategies to halt disease progression, stimulate NP and AF cell regeneration, and alleviate discogenic pain syndrome. Due to the advantages of an individual approach, many researchers are developing various tissue engineering methods to replace degenerating IVD in animal models ^[21][22][25,26].