## 3 MSC Interaction with NP Cells  
Human MSCs are multipotent cells present in almost all tissues such as bone marrow, adipose tissue, skin, lung, synovial membrane, dental pulp, nasal olfactory mucosa, muscle, periosteum, corneal limbus, peripheral blood, endometrial and menstrual blood, uterine cervix, and in fetal/neonatal tissues [9]. Stem cell transplantation represents a promising approach to restore the homeostasis of the degenerated environment of IVD due to the ability of the stem cells to differentiate towards NP-like cells and their immunomodulatory and anti-catabolic effects [14]. In recent decades, several preclinical studies have evaluated the interaction between MSCs and NPCs in vitro [44; 45; 46]. [PERSON] et al. tested the systemic delivery of BM-MSCs in a rat IVD and reported a diminished hypoxic response, risk of herniation and synthesis of cytokines [45]. In an experimental study, [PERSON] et al. described the homing of MSCs as a potential strategy to prevent the onset of the degenerative cascade in IVDs. They have also evaluated the effect of human MSCs homing in bovine and human disc cells expressing Tie2 (also known as angiopoietin-1 receptor TEK tyrosine kinase). Tie2\({}^{+}\) cells represent a progenitor cell population with disogenic differentiation potential. The results showed a proliferative response and reduction in dead cells in both tissues [46]. Our group was one of the first to report the crosstalk mechanism between MSCs and NPCs. In a 3D culture system, where a short distance may improve communication among cells, a paracrine effect of MSCs on NPCs collected from a degenerative disc was demonstrated. Gene expression analysis on both cell types showed that MSCs exerted a trophic effect on NPCs while acquiring a chondrogenic phenotype due to the communication with NPCs [47]. In another similar in vitro study, we highlighted the significant increase in GAG content and proliferation of NPCs when co-cultured with MSCs [48]. In the last decade, intradiscal stem cell therapy for IDD has provoked increasing interest in the field. Since cell isolation and implantation procedures can be safely performed in a sterile environment and with low immunogenicity, both autologous and allogeneic transplants can be used [49]. In a pilot study by [PERSON] et al., 10 patients with chronic LBP were injected with autologous BM-MSCs for the treatment of lumbar disc degeneration. Three months after surgery, LBP and disability were significantly reduced. Despite the small number of patients, this study demonstrated that intradiscal BM-MSC transplantation was a safe procedure with a promising role in the treatment of IDD [50]. Similarly, a randomized controlled trial including 24 patients with lumbar IDD reported a significant reduction in pain in the lumbar region and reduced disability one year after BM-MSC allogeneic transplant, whereas the control group, who received a sham infiltration within the paravertebral musculature did not show any improvement [51]. Earlier research has proved that MSCs secrete bioactive molecules and trophic factors such as soluble proteins, nucleic acids, lipids and EVs, and highlights their anti-apoptotic, immunomodulatory, angiogenetic, anti-fibrotic functions and differentiation capacity, probably mediated by paracrine mechanisms [52; 53; 54]. The products released by MSCs in vitro and in vivo constitute their secretome [55]. In a bovine ex vivo model, [PERSON] et al. investigated the immunomodulatory paracrine effect of BM-MSCs in the proinflammatory IDD microenvironment. While MSCs viability was not influenced, cell migration increased, collagen type II and aggrecan levels remained stable while inflammatory cytokines IL-6, IL-8 and TNF-\(\alpha\) were downregulated by MSCs in IL-1\(\beta\)-stimulated IVDs [56]. Furthermore, MSCs have been shown to migrate from their niches to damaged sites in response to injury, immune or physicochemical signals.