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| NPCy | NP-MSCs | BM-MSCs | ADSCs |
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| Hypoxia and low glucose concentration | NPCy survive by relying on anaerobic glycolysis [71]. Low O2 concentration increases the expression of HIF-1 and 2, which upregulate cell proliferation and matrix production [72]. | Low O2 concentration is associated with a higher viability and proliferative capacity of NP-MSCs compared to ADSCs [33, 34]. | Hypoxia increases BM-MSCs CFU, reduces cell senescence and maintains cell stemness [74–77]. | Low glucose slightly increases cell apoptosis and inhibits cell proliferation while enhancing aggrecan production [36, 73]. |
| Acidity | NPCy survival at low pH is mediated by ASICs [84–86], even if critically acidic pH has been associated with decreased cell viability and upregulation of metalloproteinases and proinflammatory cytokines [87–89]. | Low pH leads to reduced cell proliferation, enhanced apoptosis, and diminished expression of stemness-related and ECM genes [91]. However, overall performance was better than BM-MSCs and ADSCs [34]. | Acidic pH significantly decreases cell proliferation, aggrecan, and type I collagen production [90]. | Low pH promoted cell necrosis, reduced the proliferation rate, and diminished aggrecan production, while increasing type I collagen synthesis [36]. |
| Hyperosmolarity | NPCy respond to hyperosmolarity through TonEBP activation [92, 93], which increases ECM gene expression [96]. However, excessive hyperosmolarity results in upregulation of proinflammatory cytokines and cell apoptosis [97–100]. | Hyperosmolarity has been demonstrated to induce progenitor cell differentiation towards a mature NP phenotype [104]. | Hypertonic conditions reduced BM-MSC proliferation, anabolism, and chondrogenic differentiation [73]. | IVD-like hyperosmolarity significantly reduced ADSC viability and proliferative capacity and abated aggrecan and type I collagen synthesis [36]. |
| Mechanical loading | Physiological loadings promote cell anabolism while abnormal mechanical stimuli cause ECM breakdown and reduced cell viability [46, 105]. | Cyclic mechanical loading favours the differentiation of NP-MSCs towards mature NPCy [37], while static prolonged loading diminished cell viability, migration, differentiation, and stemness [110]. | Cyclic mechanical loading enhances BM-MSC chondrogenic differentiation and cell anabolism [26]. | ADCs may protect NPCy from apoptosis and promote the synthesis of ECM genes under prolonged loading [111]. |
| Inflammation | Proinflammatory cytokines induce NPCy apoptosis, senescence, and autophagy and upregulate the synthesis of metalloproteinases, thus resulting in ECM breakdown [51, 112]. | IL-1β may reduce aggrecan and SOX expression by NP-MSCs while improving their neurogenic differentiation, which may have a role in IVD neoinnervation [49]. | BM-MSCs may support resident cells by secreting anti-inflammatory cytokines, anticatabolic, and growth factors [79, 114]. | Under inflammatory conditions, ADSCs have been shown to increase proliferation, proinflammatory cytokine production, and osteogenic differentiation [125]. |
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