Degeneration of the lumbar intervertebral discs is a leading cause of low back pain, a condition that affects a substantial proportion of the global population. The earliest degenerative changes typically manifest in the central nucleus pulposus (NP) region of the disc and are characterized by elevated local inflammation and a cell-mediated reduction in proteoglycan content and transition to a fibrotic extracellular matrix. The application of adult mesenchymal stem cells (MSCs) to arrest and reverse degenerative changes in the NP has received significant interest due to the availability and superior safety profile of these cells compared with other therapeutic cell types. Preclinically and clinically, however, the efficacy of MSC-based disc treatments is mixed, due in part to the limited ability of these cells to survive and function within the degenerate NP microenvironment. A potential strategy to improve the in vivo survival and anabolic performance of MSCs in the degenerate NP is preconditioning prior to implantation using a variety of biochemical and biophysical stimuli. In this review, we present an overview of existing techniques used for preconditioning MSCs to enhance their therapeutic performance in the degenerate NP. We outline respective advantages and challenges associated with each of these techniques and provide recommendations for their further refinement.
Impact Statement
The potential of mesenchymal stem cells (MSCs) for treating intervertebral disc degeneration is constrained by their limited ability to survive and function within the harsh in vivo microenvironment of the nucleus pulposus. This article provides a comprehensive review of in vitro preconditioning techniques designed to enhance the anabolic performance of MSCs after implantation into the degenerate nucleus pulposus.
FerreiraML, De LucaK, HaileLM, et al.Global, regional, and national burden of low back pain, 1990–2020, its attributable risk factors, and projections to 2050: A systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol, 2023; 5(6):e316–e329.
2.
ChangD, LuiA, MatsoyanA, et al.Comparative review of the socioeconomic burden of lower back pain in the United States and globally. Neurospine, 2024; 21(2):487–501; doi: 10.14245/ns.2448372.186
3.
FreemontAJ. The cellular pathobiology of the degenerate intervertebral disc and discogenic back pain. Rheumatology (Oxford), 2009; 48(1):5–10; doi: 10.1093/rheumatology/ken396
4.
SmithLJ, NerurkarNL, ChoiKS, et al.Degeneration and regeneration of the intervertebral disc: Lessons from development. Dis Model Mech, 2011; 4(1):31–41; doi: 10.1242/dmm.006403
5.
HumzahMD, SoamesRW. Human intervertebral disc: Structure and function. Anat Rec, 1988; 220(4):337–356; doi: 10.1002/ar.1092200402
6.
HunterCJ, MatyasJR, DuncanNA. Cytomorphology of notochordal and chondrocytic cells from the nucleus pulposus: A species comparison. J Anat, 2004; 205(5):357–362; doi: 10.1111/j.0021-8782.2004.00352.x
7.
CrumpKB, AlminnawiA, Bermudez-LekerikaP, et al.Cartilaginous endplates: A comprehensive review on a neglected structure in intervertebral disc research. JOR Spine, 2023; 6(4):e1294; doi: 10.1002/jsp2.1294
8.
VoNV, HartmanRA, PatilPR, et al.Molecular mechanisms of biological aging in intervertebral discs. J Orthop Res, 2016; 34(8):1289–1306; doi: 10.1002/jor.23195
9.
HoffeldK, LenzM, EgenolfP, et al.Patient-related risk factors and lifestyle factors for lumbar degenerative disc disease: A systematic review. Neurochirurgie, 2023; 69(5):101482; doi: 10.1016/j.neuchi.2023.101482
10.
UrbanJPG, FairbankJCT. Current perspectives on the role of biomechanical loading and genetics in development of disc degeneration and low back pain; a narrative review. J Biomech, 2020; 102:109573; doi: 10.1016/j.jbiomech.2019.109573
11.
LiS, DuJ, HuangY, et al.From hyperglycemia to intervertebral disc damage: Exploring diabetic-induced disc degeneration. Front Immunol, 2024; 15:1355503; doi: 10.3389/fimmu.2024.1355503
12.
Le MaitreCL, PockertA, ButtleDJ, et al.Matrix synthesis and degradation in human intervertebral disc degeneration. Biochem Soc Trans, 2007; 35(Pt 4):652–655; doi: 10.1042/BST0350652
13.
WuertzK, HaglundL. Inflammatory mediators in intervertebral disk degeneration and discogenic pain. Global Spine J, 2013; 3(3):175–184; doi: 10.1055/s-0033-1347299
14.
ZhaoCQ, WangLM, JiangLS, et al.The cell biology of intervertebral disc aging and degeneration. Ageing Res Rev, 2007; 6(3):247–261; doi: 10.1016/j.arr.2007.08.001
KarppinenJ, ShenFH, LukKD, et al.Management of degenerative disk disease and chronic low back pain. Orthop Clin North Am, 2011; 42(4):513–528, viii; doi: 10.1016/j.ocl.2011.07.009
17.
VergroesenPP, KingmaI, EmanuelKS, et al.Mechanics and biology in intervertebral disc degeneration: A vicious circle. Osteoarthritis Cartilage, 2015; 23(7):1057–1070; doi: 10.1016/j.joca.2015.03.028
18.
PradeepK, PalB. Biomechanical and clinical studies on lumbar spine fusion surgery: A review. Med Biol Eng Comput, 2023; 61(3):617–634; doi: 10.1007/s11517-022-02750-6
19.
ZiglerJE, BlumenthalSL, GuyerRD, et al.Progression of adjacent-level degeneration after lumbar total disc replacement: Results of a post-hoc analysis of patients with available radiographs from a prospective study with 5-year follow-up. Spine (Phila Pa 1976), 2018; 43(20):1395–1400; doi: 10.1097/BRS.0000000000002647
20.
TongW, LuZ, QinL, et al.Cell therapy for the degenerating intervertebral disc. Transl Res, 2017; 181:49–58; doi: 10.1016/j.trsl.2016.11.008
21.
BinchALA, FitzgeraldJC, GrowneyEA, et al.Cell-based strategies for IVD repair: Clinical progress and translational obstacles. Nat Rev Rheumatol, 2021; 17(3):158–175; doi: 10.1038/s41584-020-00568-w
22.
MochidaJ, SakaiD, NakamuraY, et al.Intervertebral disc repair with activated nucleus pulposus cell transplantation: A three-year, prospective clinical study of its safety. Eur Cell Mater, 2015; 29:202–212; discussion 212; doi: 10.22203/ecm.v029a15
23.
MeiselHJ, SiodlaV, GaneyT, et al.Clinical experience in cell-based therapeutics: Disc chondrocyte transplantation A treatment for degenerated or damaged intervertebral disc. Biomol Eng, 2007; 24(1):5–21; doi: 10.1016/j.bioeng.2006.07.002
24.
WilliamsRJ, TryfonidouMA, SnuggsJW, et al.Cell sources proposed for nucleus pulposus regeneration. JOR Spine, 2021; 4(4):e1175; doi: 10.1002/jsp2.1175
25.
SmithLJ, SilvermanL, SakaiD, et al.Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ORS spine section. JOR Spine, 2018; 1(4):e1036; doi: 10.1002/jsp2.1036
26.
XiaK, GongZ, ZhuJ, et al.Differentiation of pluripotent stem cells into nucleus pulposus progenitor cells for intervertebral disc regeneration. Curr Stem Cell Res Ther, 2019; 14(1):57–64; doi: 10.2174/1574888X13666180918095121
27.
LaaglandLT, Poramba LiyanageDWL, DespratR, et al.Disc-derived induced pluripotent stem cells and environmental cues for nucleus pulposus regeneration. Tissue Eng Part A, 2026; 32(1–2):54–67; doi: 10.1177/19373341251359106
28.
TangR, JingL, WillardVP, et al.Differentiation of human induced pluripotent stem cells into nucleus pulposus-like cells. Stem Cell Res Ther, 2018; 9(1):61; doi: 10.1186/s13287-018-0797-1
29.
Ortuno-CostelaMDC, CerradaV, Garcia-LopezM, et al.The challenge of bringing iPSCs to the patient. Int J Mol Sci, 2019; 20(24):6305; doi: 10.3390/ijms20246305
30.
VadalaG, AmbrosioL, RussoF, et al.Interaction between mesenchymal stem cells and intervertebral disc microenvironment: From cell therapy to tissue engineering. Stem Cells Int, 2019; 2019:2376172; doi: 10.1155/2019/2376172
31.
StoyanovJV, Gantenbein-RitterB, BertoloA, et al.Role of hypoxia and growth and differentiation factor-5 on differentiation of human mesenchymal stem cells towards intervertebral nucleus pulposus-like cells. Eur Cell Mater, 2011; 21:533–547; doi: 10.22203/ecm.v021a40
32.
SmithLJ, GorthDJ, ShowalterBL, et al.In vitro characterization of a stem-cell-seeded triple-interpenetrating-network hydrogel for functional regeneration of the nucleus pulposus. Tissue Eng Part A, 2014; 20(13–14):1841–1849; doi: 10.1089/ten.TEA.2013.0516
33.
WanglerS, KamaliA, WappC, et al.Uncovering the secretome of mesenchymal stromal cells exposed to healthy, traumatic, and degenerative intervertebral discs: A proteomic analysis. Stem Cell Res Ther, 2021; 12(1):11–17.
34.
RichardsonSM, KalamegamG, PushparajPN, et al.Mesenchymal stem cells in regenerative medicine: Focus on articular cartilage and intervertebral disc regeneration. Methods, 2016; 99:69–80; doi: 10.1016/j.ymeth.2015.09.015
35.
HuangYC, LeungVY, LuWW, et al.The effects of microenvironment in mesenchymal stem cell-based regeneration of intervertebral disc. Spine J, 2013; 13(3):352–362; doi: 10.1016/j.spinee.2012.12.005
36.
WuertzK, GodburnK, Neidlinger-WilkeC, et al.Behavior of mesenchymal stem cells in the chemical microenvironment of the intervertebral disc. Spine (Phila Pa 1976), 2008; 33(17):1843–1849; doi: 10.1097/BRS.0b013e31817b8f53
37.
FarrellMJ, ShinJI, SmithLJ, et al.Functional consequences of glucose and oxygen deprivation on engineered mesenchymal stem cell-based cartilage constructs. Osteoarthritis Cartilage, 2015; 23(1):134–142; doi: 10.1016/j.joca.2014.09.012
38.
NaqviSM, BuckleyCT. Bone marrow stem cells in response to intervertebral disc-like matrix acidity and oxygen concentration: Implications for cell-based regenerative therapy. Spine (Phila Pa 1976), 2016; 41(9):743–750; doi: 10.1097/BRS.0000000000001314
39.
WehlingN, PalmerGD, PilapilC, et al.Interleukin-1beta and tumor necrosis factor alpha inhibit chondrogenesis by human mesenchymal stem cells through NF-kappaB-dependent pathways. Arthritis Rheum, 2009; 60(3):801–812; doi: 10.1002/art.24352
40.
WuertzK, GodburnK, IatridisJC. MSC response to pH levels found in degenerating intervertebral discs. Biochem Biophys Res Commun, 2009; 379(4):824–829; doi: 10.1016/j.bbrc.2008.12.145
41.
PittengerMF, MackayAM, BeckSC, et al.Multilineage potential of adult human mesenchymal stem cells. Science, 1999; 284(5411):143–147; doi: 10.1126/science.284.5411.143
42.
KimDH, MartinJT, GullbrandSE, et al.Fabrication, maturation, and implantation of composite tissue-engineered total discs formed from native and mesenchymal stem cell combinations. Acta Biomater, 2020; 114:53–62; doi: 10.1016/j.actbio.2020.05.039
43.
MwaleF, RoughleyP, AntoniouJ. Distinction between the extracellular matrix of the nucleus pulposus and hyaline cartilage: A requisite for tissue engineering of intervertebral disc. Eur Cell Mater, 2004; 8:58–63; discussion 63-4; doi: 10.22203/ecm.v008a06
44.
RisbudMV, GuttapalliA, StokesDG, et al.Nucleus pulposus cells express HIF-1 alpha under normoxic culture conditions: A metabolic adaptation to the intervertebral disc microenvironment. J Cell Biochem, 2006; 98(1):152–159; doi: 10.1002/jcb.20765
45.
ClarkeLE, McConnellJC, SherrattMJ, et al.Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition, and micromechanical properties of nucleus pulposus constructs. Arthritis Res Ther, 2014; 16(2):R67; doi: 10.1186/ar4505
46.
VadalaG, StuderRK, SowaG, et al.Coculture of bone marrow mesenchymal stem cells and nucleus pulposus cells modulate gene expression profile without cell fusion. Spine (Phila Pa 1976), 2008; 33(8):870–876; doi: 10.1097/BRS.0b013e31816b4619
NaqviSM, BuckleyCT. Extracellular matrix production by nucleus pulposus and bone marrow stem cells in response to altered oxygen and glucose microenvironments. J Anat, 2015; 227(6):757–766; doi: 10.1111/joa.12305
49.
ZhangJ, ZhangW, SunT, et al.The influence of intervertebral disc microenvironment on the biological behavior of engrafted mesenchymal stem cells. Stem Cells Int, 2022; 2022:8671482; doi: 10.1155/2022/8671482
50.
UrbanJP, SmithS, FairbankJC. Nutrition of the intervertebral disc. Spine (Phila Pa 1976), 2004; 29(23):2700–2709; doi: 10.1097/01.brs.0000146499.97948.52
51.
SmithLJ, ElliottDM. Formation of lamellar cross bridges in the annulus fibrosus of the intervertebral disc is a consequence of vascular regression. Matrix Biol, 2011; 30(4):267–274; doi: 10.1016/j.matbio.2011.03.009
52.
NerlichAG, SchaafR, WalchliB, et al.Temporo-spatial distribution of blood vessels in human lumbar intervertebral discs. Eur Spine J, 2007; 16(4):547–555; doi: 10.1007/s00586-006-0213-x
53.
NachemsonA, LewinT, MaroudasA, et al.In vitro diffusion of dye through the end-plates and the annulus fibrosus of human lumbar inter-vertebral discs. Acta Orthop Scand, 1970; 41(6):589–607; doi: 10.3109/17453677008991550
54.
HolmS, MaroudasA, UrbanJP, et al.Nutrition of the intervertebral disc: Solute transport and metabolism. Connect Tissue Res, 1981; 8(2):101–119; doi: 10.3109/03008208109152130
55.
TroneMAR, StoverJD, AlmarzaA, et al.pH: A major player in degenerative intervertebral disks. JOR Spine, 2024; 7(4):e70025; doi: 10.1002/jsp2.70025
56.
WangY, ChengH, WangT, et al.Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment. Cell Prolif, 2023; 56(9):e13448; doi: 10.1111/cpr.13448
57.
RisbudMV, ShapiroIM. Role of cytokines in intervertebral disc degeneration: Pain and disc content. Nat Rev Rheumatol, 2014; 10(1):44–56.
58.
HudsonKD, BonassarLJ. Hypoxic expansion of human mesenchymal stem cells enhances three-dimensional maturation of tissue-engineered intervertebral discs. Tissue Eng Part A, 2017; 23(7–8):293–300; doi: 10.1089/ten.TEA.2016.0270
59.
WangW, WangY, DengG, et al.Transplantation of hypoxic-preconditioned bone mesenchymal stem cells retards intervertebral disc degeneration via enhancing implanted cell survival and migration in rats. Stem Cells Int, 2018; 2018:7564159; doi: 10.1155/2018/7564159
60.
ChiangER, MaHL, WangJP, et al.Use of allogeneic hypoxic mesenchymal stem cells for treating disc degeneration in rabbits. J Orthop Res, 2019; 37(6):1440–1450; doi: 10.1002/jor.24342
61.
ElabdC, CentenoCJ, SchultzJR, et al.Intra-discal injection of autologous, hypoxic cultured bone marrow-derived mesenchymal stem cells in five patients with chronic lower back pain: A long-term safety and feasibility study. J Transl Med, 2016; 14(1):253; doi: 10.1186/s12967-016-1015-5
62.
PeckSH, BendigoJR, TobiasJW, et al.Hypoxic preconditioning enhances bone marrow-derived mesenchymal stem cell survival in a low oxygen and nutrient-limited 3d microenvironment. Cartilage, 2021; 12(4):512–525; doi: 10.1177/1947603519841675
63.
PeroglioM, EglinD, BennekerLM, et al.Thermoreversible hyaluronan-based hydrogel supports in vitro and ex vivo disc-like differentiation of human mesenchymal stem cells. Spine J, 2013; 13(11):1627–1639.
64.
GansauJ, BuckleyC. Priming as a strategy to overcome detrimental PH effects on cells for intervertebral disc regeneration. Eur Cell Mater, 2021; 41:153–169.
65.
MalonzoC, ChanSC, KabiriA, et al.A papain‐induced disc degeneration model for the assessment of thermo‐reversible hydrogel–cells therapeutic approach. J Tissue Eng Regen Med, 2015; 9(12):E167–E176.
66.
HingertD, Barreto HenrikssonH, BrisbyH. Human mesenchymal stem cells pretreated with interleukin-1β and stimulated with bone morphogenetic growth factor-3 enhance chondrogenesis. Tissue Eng Part A, 2018; 24(9–10):775–785.
67.
FerreiraJ, TeixeiraG, NetoE, et al.IL-1β-pre-conditioned mesenchymal stem/stromal cells’ secretome modulates the inflammatory response and aggrecan deposition in intervertebral disc. Eur Cell Mater, 2021; 41:431–453.
68.
ZengY, FengS, LiuW, et al.Preconditioning of mesenchymal stromal cells toward nucleus pulposus-like cells by microcryogels-based 3D cell culture and syringe-based pressure loading system. J Biomed Mater Res B Appl Biomater, 2017; 105(3):507–520; doi: 10.1002/jbm.b.33509
69.
HuangX, ChenD, LiangC, et al.Swelling-mediated mechanical stimulation regulates differentiation of adipose-derived mesenchymal stem cells for intervertebral disc repair using injectable UCST microgels. Adv Healthc Mater, 2023; 12(3):e2201925; doi: 10.1002/adhm.202201925
70.
ZhangYY, HuZL, QiYH, et al.Pretreatment of nucleus pulposus mesenchymal stem cells with appropriate concentration of H(2)O(2) enhances their ability to treat intervertebral disc degeneration. Stem Cell Res Ther, 2022; 13(1):340; doi: 10.1186/s13287-022-03031-7
71.
ZhuZ, XingH, TangR, et al.The preconditioning of lithium promotes mesenchymal stem cell-based therapy for the degenerated intervertebral disc via upregulating cellular ROS. Stem Cell Res Ther, 2021; 12(1):239; doi: 10.1186/s13287-021-02306-9
72.
ChenQ, YangQ, PanC, et al.Quiescence preconditioned nucleus pulposus stem cells alleviate intervertebral disc degeneration by enhancing cell survival via adaptive metabolism pattern in rats. Front Bioeng Biotechnol, 2023; 11:1073238; doi: 10.3389/fbioe.2023.1073238
73.
BartelsEM, FairbankJC, WinloveCP, et al.Oxygen and lactate concentrations measured in vivo in the intervertebral discs of patients with scoliosis and back pain. Spine (Phila Pa 1976), 1998; 23(1):1–7; discussion 8; doi: 10.1097/00007632-199801010-00001
74.
EjeskarA, HolmS. Oxygen tension measurements in the intervertebral disc. A methodological and experimental study. Ups J Med Sci, 1979; 84(1):83–93; doi: 10.3109/03009737909179143
75.
StairmandJW, HolmS, UrbanJP. Factors influencing oxygen concentration gradients in the intervertebral disc. A theoretical analysis. Spine (Phila Pa 1976), 1991; 16(4):444–449; doi: 10.1097/00007632-199104000-00010
76.
FujitaN, ChibaK, ShapiroIM, et al.HIF-1alpha and HIF-2alpha degradation is differentially regulated in nucleus pulposus cells of the intervertebral disc. J Bone Miner Res, 2012; 27(2):401–412; doi: 10.1002/jbmr.538
77.
RisbudMV, SchipaniE, ShapiroIM. Hypoxic regulation of nucleus pulposus cell survival: From niche to notch. Am J Pathol, 2010; 176(4):1577–1583; doi: 10.2353/ajpath.2010.090734
78.
SilagiES, SchipaniE, ShapiroIM, et al.The role of HIF proteins in maintaining the metabolic health of the intervertebral disc. Nat Rev Rheumatol, 2021; 17(7):426–439; doi: 10.1038/s41584-021-00621-2
79.
AgrawalA, GuttapalliA, NarayanS, et al.Normoxic stabilization of HIF-1alpha drives glycolytic metabolism and regulates aggrecan gene expression in nucleus pulposus cells of the rat intervertebral disk. Am J Physiol Cell Physiol, 2007; 293(2):C621–C31; doi: 10.1152/ajpcell.00538.2006
80.
MerceronC, MangiaviniL, RoblingA, et al.Loss of HIF-1alpha in the notochord results in cell death and complete disappearance of the nucleus pulposus. PLoS One, 2014; 9(10):e110768; doi: 10.1371/journal.pone.0110768
81.
HarrisonJS, RameshwarP, ChangV, et al.Oxygen saturation in the bone marrow of healthy volunteers. Blood, 2002; 99(1):394; doi: 10.1182/blood.v99.1.394
82.
PasaricaM, SeredaOR, RedmanLM, et al.Reduced adipose tissue oxygenation in human obesity: Evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes, 2009; 58(3):718–725; doi: 10.2337/db08-1098
83.
SamalJRK, RangasamiVK, SamantaS, et al.Discrepancies on the role of oxygen gradient and culture condition on mesenchymal stem cell fate. Adv Healthc Mater, 2021; 10(6):e2002058; doi: 10.1002/adhm.202002058
84.
AdesidaAB, Mulet-SierraA, JomhaNM. Hypoxia mediated isolation and expansion enhances the chondrogenic capacity of bone marrow mesenchymal stromal cells. Stem Cell Res Ther, 2012; 3(2):9; doi: 10.1186/scrt100
85.
MullerJ, BenzK, AhlersM, et al.Hypoxic conditions during expansion culture prime human mesenchymal stromal precursor cells for chondrogenic differentiation in three-dimensional cultures. Cell Transplant, 2011; 20(10):1589–1602; doi: 10.3727/096368910X564094
86.
ChoiJR, Pingguan-MurphyB, Wan AbasWA, et al.Impact of low oxygen tension on stemness, proliferation and differentiation potential of human adipose-derived stem cells. Biochem Biophys Res Commun, 2014; 448(2):218–224; doi: 10.1016/j.bbrc.2014.04.096
87.
RajagopalK, ArjunanP, MarepallyS, et al.Controlled differentiation of mesenchymal stem cells into hyaline cartilage in miR-140-activated collagen hydrogel. Cartilage, 2021; 13(2_suppl):571S–581S.
88.
SomozaRA, WelterJF, CorreaD, et al.Chondrogenic differentiation of mesenchymal stem cells: Challenges and unfulfilled expectations. Tissue Eng Part B Rev, 2014; 20(6):596–608.
89.
NovaisEJ, NarayananR, CansecoJA, et al.A new perspective on intervertebral disc calcification—from bench to bedside. Bone Res, 2024; 12(1):3.
90.
MasudaK, OegemaTRJr, AnHS. Growth factors and treatment of intervertebral disc degeneration. Spine (Phila Pa 1976), 2004; 29(23):2757–2769.
91.
Le MaitreCL, HoylandJA, FreemontAJ. Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1β and TNFα expression profile. Arthritis Res Ther, 2007; 9(4):R77–R11.
92.
FerreiraJR, TeixeiraGQ, SantosSG, et al.Mesenchymal stromal cell secretome: Influencing therapeutic potential by cellular pre-conditioning. Front Immunol, 2018; 9:2837.
93.
TilottaV, VadalàG, AmbrosioL, et al.Mesenchymal stem cell-derived secretome enhances nucleus pulposus cell metabolism and modulates extracellular matrix gene expression in vitro. Front Bioeng Biotechnol, 2023; 11:1152207.
94.
ChanSC, FergusonSJ, Gantenbein-RitterB. The effects of dynamic loading on the intervertebral disc. Eur Spine J, 2011; 20(11):1796–1812; doi: 10.1007/s00586-011-1827-1
95.
WilkeHJ, NeefP, CaimiM, et al.New in vivo measurements of pressures in the intervertebral disc in daily life. Spine (Phila Pa 1976), 1999; 24(8):755–762; doi: 10.1097/00007632-199904150-00005
96.
AdamsMA, McNallyDS, DolanP. ‘Stress’ distributions inside intervertebral discs. The effects of age and degeneration. J Bone Joint Surg Br, 1996; 78(6):965–972; doi: 10.1302/0301-620x78b6.1287
97.
FearingBV, HernandezPA, SettonLA, et al.Mechanotransduction and cell biomechanics of the intervertebral disc. JOR Spine, 2018; 1(3):e1026; doi: 10.1002/jsp2.1026
98.
LotzJC, ChinJR. Intervertebral disc cell death is dependent on the magnitude and duration of spinal loading. Spine (Phila Pa 1976), 2000; 25(12):1477–1483; doi: 10.1097/00007632-200006150-00005
99.
KoreckiCL, KuoCK, TuanRS, et al.Intervertebral disc cell response to dynamic compression is age and frequency dependent. J Orthop Res, 2009; 27(6):800–806; doi: 10.1002/jor.20814
100.
BianL, ZhaiDY, ZhangEC, et al.Dynamic compressive loading enhances cartilage matrix synthesis and distribution and suppresses hypertrophy in hMSC-laden hyaluronic acid hydrogels. Tissue Eng Part A, 2012; 18(7–8):715–724; doi: 10.1089/ten.TEA.2011.0455
101.
WangD, ChenY, CaoS, et al.Cyclic mechanical stretch ameliorates the degeneration of nucleus pulposus cells through promoting the ITGA2/PI3K/AKT signaling pathway. Oxid Med Cell Longev, 2021; 2021:6699326; doi: 10.1155/2021/6699326
102.
CaoG, YangS, CaoJ, et al.The role of oxidative stress in intervertebral disc degeneration. Oxid Med Cell Longev, 2022; 2022:2166817; doi: 10.1155/2022/2166817
103.
GuoL, DuJ, YuanDF, et al.Optimal H(2)O(2) preconditioning to improve bone marrow mesenchymal stem cells’ engraftment in wound healing. Stem Cell Res Ther, 2020; 11(1):434; doi: 10.1186/s13287-020-01910-5
104.
LiaoN, ShiY, WangY, et al.Antioxidant preconditioning improves therapeutic outcomes of adipose tissue-derived mesenchymal stem cells through enhancing intrahepatic engraftment efficiency in a mouse liver fibrosis model. Stem Cell Res Ther, 2020; 11(1):237; doi: 10.1186/s13287-020-01763-y
105.
ZhangJ, ChenGH, WangYW, et al.Hydrogen peroxide preconditioning enhances the therapeutic efficacy of Wharton’s Jelly mesenchymal stem cells after myocardial infarction. Chin Med J (Engl), 2012; 125(19):3472–3478.
106.
ZhuZ, YinJ, GuanJ, et al.Lithium stimulates human bone marrow derived mesenchymal stem cell proliferation through GSK-3beta-dependent beta-catenin/Wnt pathway activation. FEBS J, 2014; 281(23):5371–5389; doi: 10.1111/febs.13081
107.
KazemiH, Noori-ZadehA, DarabiS, et al.Lithium prevents cell apoptosis through autophagy induction. Bratisl Lek Listy, 2018; 119(4):234–239; doi: 10.4149/BLL_2018_044
108.
WangJW, ZhuL, ShiPZ, et al.1,25(OH)(2)D(3) mitigates oxidative stress-induced damage to nucleus pulposus-derived mesenchymal stem cells through PI3K/Akt pathway. Oxid Med Cell Longev, 2022; 2022:1427110; doi: 10.1155/2022/1427110
109.
ShiPZ, WangJW, WangPC, et al.Urolithin a alleviates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells through SIRT1/PGC-1alpha pathway. World J Stem Cells, 2021; 13(12):1928–1946; doi: 10.4252/wjsc.v13.i12.1928
110.
NanLP, WangF, RanD, et al.Naringin alleviates H(2)O(2)-induced apoptosis via the PI3K/Akt pathway in rat nucleus pulposus-derived mesenchymal stem cells. Connect Tissue Res, 2020; 61(6):554–567; doi: 10.1080/03008207.2019.1631299
111.
ZehraU, TryfonidouM, IatridisJC, et al.Mechanisms and clinical implications of intervertebral disc calcification. Nat Rev Rheumatol, 2022; 18(6):352–362; doi: 10.1038/s41584-022-00783-7
112.
MoyaA, LarochetteN, PaquetJ, et al.Quiescence preconditioned human multipotent stromal cells adopt a metabolic profile favorable for enhanced survival under ischemia. Stem Cells, 2017; 35(1):181–196; doi: 10.1002/stem.2493
113.
LoiblM, Wuertz-KozakK, VadalaG, et al.Controversies in regenerative medicine: Should intervertebral disc degeneration be treated with mesenchymal stem cells? JOR Spine, 2019; 2(1):e1043; doi: 10.1002/jsp2.1043
114.
VadalaG, AmbrosioL, RussoF, et al.Stem cells and intervertebral disc regeneration overview-What They Can and Can’t Do. Int J Spine Surg, 2021; 15(s1):40–53; doi: 10.14444/8054
115.
KahriziMS, MousaviE, KhosraviA, et al.Recent advances in pre-conditioned mesenchymal stem/stromal cell (MSCs) therapy in organ failure; a comprehensive review of preclinical studies. Stem Cell Res Ther, 2023; 14(1):155; doi: 10.1186/s13287-023-03374-9
GilbertHTJ, HodsonN, BairdP, et al.Acidic pH promotes intervertebral disc degeneration: Acid-sensing ion channel -3 as a potential therapeutic target. Sci Rep, 2016; 6:37360; doi: 10.1038/srep37360
118.
KitanoT, ZerwekhJE, UsuiY, et al.Biochemical changes associated with the symptomatic human intervertebral disk. Clin Orthop Relat Res, 1993; 293(293):372–377.
119.
NachemsonA. Intradiscal measurements of pH in patients with lumbar rhizopathies. Acta Orthop Scand, 1969; 40(1):23–42; doi: 10.3109/17453676908989482
120.
ZhaK, LiX, YangZ, et al.Heterogeneity of mesenchymal stem cells in cartilage regeneration: From characterization to application. NPJ Regen Med, 2021; 6(1):14; doi: 10.1038/s41536-021-00122-6
121.
TangSN, WalterBA, HeimannMK, et al.In vivo mouse intervertebral disc degeneration models and their utility as translational models of clinical discogenic back pain: A comparative review. Front Pain Res (Lausanne), 2022; 3:894651; doi: 10.3389/fpain.2022.894651
122.
TangSN, BonillaAF, ChahineNO, et al.Controversies in spine research: Organ culture versus in vivo models for studies of the intervertebral disc. JOR Spine, 2022; 5(4):e1235; doi: 10.1002/jsp2.1235
123.
ChoudheryMS. Strategies to improve regenerative potential of mesenchymal stem cells. World J Stem Cells, 2021; 13(12):1845–1862; doi: 10.4252/wjsc.v13.i12.1845
124.
Moeinabadi-BidgoliK, BabajaniA, YazdanpanahG, et al.Translational insights into stem cell preconditioning: From molecular mechanisms to preclinical applications. Biomed Pharmacother, 2021; 142:112026; doi: 10.1016/j.biopha.2021.112026
125.
HuC, LiL. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. J Cell Mol Med, 2018; 22(3):1428–1442; doi: 10.1111/jcmm.13492
126.
HuH, WangZ, YangH, et al.Hypoxic preconditional engineering small extracellular vesicles promoted intervertebral disc regeneration by activating Mir-7-5p/NF-Kappab/Cxcl2 axis. Adv Sci (Weinh), 2023; 10(35):e2304722; doi: 10.1002/advs.202304722
127.
MaS, XueR, ZhuH, et al.Selenomethionine preconditioned mesenchymal stem cells derived extracellular vesicles exert enhanced therapeutic efficacy in intervertebral disc degeneration. Int Immunopharmacol, 2024; 132:112028; doi: 10.1016/j.intimp.2024.112028
128.
TawfeekGA, KasemHA, ElshoalaSE. Curcumin Nanofiber PCL/PLGA/Collagen enhanced the therapeutic efficacy of mesenchymal stem cells against liver fibrosis in animal model and prevented its recurrence. Nanotheranostics, 2023; 7(3):299–315; doi: 10.7150/ntno.81019
129.
KadirND, YangZ, HassanA, et al.Electrospun fibers enhanced the paracrine signaling of mesenchymal stem cells for cartilage regeneration. Stem Cell Res Ther, 2021; 12(1):100; doi: 10.1186/s13287-021-02137-8
130.
HeoSJ, SzczesnySE, KimDH, et al.Expansion of mesenchymal stem cells on electrospun scaffolds maintains stemness, mechano-responsivity, and differentiation potential. J Orthop Res, 2018; 36(2):808–815; doi: 10.1002/jor.23772
131.
ZhangJ, ZhangM, LinR, et al.Chondrogenic preconditioning of mesenchymal stem/stromal cells within a magnetic scaffold for osteochondral repair. Biofabrication, 2022; 14(2); doi: 10.1088/1758-5090/ac5935
132.
LomboniDJ, SteevesA, SchockS, et al.Compounded topographical and physicochemical cueing by micro-engineered chitosan substrates on rat dorsal root ganglion neurons and human mesenchymal stem cells. Soft Matter, 2021; 17(21):5284–5302; doi: 10.1039/d0sm02170a
