Table 2.

Different responses of NPCy, NP-MSCs, BM-MSCs, and ADSCs to the degenerative microenvironment.

	NPCy	NP-MSCs	BM-MSCs	ADSCs
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].

NPCy = nucleopulpocytes; NP-MSCs = nucleus pulposus-derived mesenchymal stem cells; BM-MSCs = bone marrow-derived mesenchymal stem cells; ADSCs = adipose tissue-derived mesenchymal stem cells; HIF = hypoxia-inducible factor; CFU = colony-forming units; ASIC = acid-sensing ion channels; ECM = extracellular matrix; TonEBP = tonicity enhancer-binding protein; NP = nucleus pulposus; IVD = intervertebral disc; IL = interleukin.