Review
Copyright ©The Author(s) 2021.
World J Stem Cells. Dec 26, 2021; 13(12): 1881-1904
Published online Dec 26, 2021. doi: 10.4252/wjsc.v13.i12.1881
Table 1 Modifying genes essential for the development of intervertebral disc
Ref.
Protein (Gene)
Key findings
Choi et al[14], 2012Sonic Hedgehog (SHH) Sclerotome tissue formation, annulus fibrosus formation, chondrogenesis of sclerotome cells
Wijgerde et al[15], 2005Noggin (NOG) Antagonist of the BMP pathway, promotes Shh intracellular signaling cascade and Pax1 gene activation
Murtaugh et al[16], 1999Bone Morphogenetic Protein (BMP) family In the presence of Shh, promotes chondrocyte differentiation of somite-derived IVD progenitors
Peters et al[21], 1999Paired Box 1 (PAX1) Chondrogenic commitment of sclerotome cells
Sugimoto et al[27], 2013SRY-Box 9 (SOX) Regulates IVD tissue growth and development
Sohn et al[30], 2010Transforming growth factor-β (TGF-β) Development of vertebral bodies
Pearson et al[31], 2005Homeodomain Protein (HOX) Somite Patterning
Table 2 Variation in properties of different sources of stem cell types
Properties
MSCs
ESCs
iPSCs
SourcesPerinatal and adult tissuesEmbryo at blastocyst stageGenetically reprogrammed specialized cells
PlasticityMultipotentPluripotentPluripotent
Teratoma formationNoYesYes
GrowthLimitedHighHigh
Ethical concernsNoYesNo
Immune rejectionNoYesNo
Cell transplantationAutologous and allogenic AllogenicAutologous
Clinical trials in human patientsOngoingLimitedIn vitro/in vivo only
Use in genetic disorderDeficient (Carry mutated gene)SuperiorDeficient (Carry mutated gene)
Ease of isolationYesNoNo
Table 3 Human umbilical cord-derived mesenchymal stem cells compared with other stem cells sources
Properties
Perinatal
Adult
Embryonic
Ability to differentiate into various cell type
Plastic adherence
High in vitro proliferation ability
Low risk of tumorigenicity
Ethical issues
Lower risk of viral contamination
Capacity for autologous transplantation
Established/proven treatment in human patients
Ease of collection
Less need for stringent antigen typing
Table 4 Summary of studies on cellular therapeutic approaches for regenerative potential of the degenerated disc
Type of stem cells
Gene
Preconditioning outcomes
Ref.
In vitro human cultured NP cells and MSCsTGF-β1TGF-β1 stimulates collagen-1 expression in cultured NP cells and in MSCs, increased collagen-1 and sox-9 expression. Co-cultured MSCs with NP cells showed high expression of collagen-1, aggrecan and sox-9 expression via TGF-β-dependent effect[126]
Chick periosteum-derived MSCs Rabbit bone marrow-derived MSCs Rat MSCsTGF-β1Stimulate chondrogenesis and inhibits osteogenesis. Facilitates in vitro chondrogenic differentiation of rabbit BM-MSCs. Increased MAPK activity and upregulation of mRNA expression of sox-9, aggrecan, and collagen type II[190,122,123]
Human adipose-derived MSCs and bone marrow-derived MSCsTGF-β3, GDF-5, or GDF-6In the presence of GDF-6, AD-MSCs leads to differentiation into an NP-like phenotype and results in a richer proteoglycan matrix with low rigidity[158]
Human bone marrow-derived MSCsTGF-β1, and GDF-5Hypoxic TGF-β1 and GDF-5 both increased aggrecan and collagen II mRNA levels and GAGs accumulation[159]
In vitro human bone marrow-derived MSCsTGF-β3, dexamethasone, and ascorbatePreconditioned BM-MSCs expressed higher level of chondrocytes differentiation markers than culture-expanded human IVD cells and articular chondrocytes[193]
In vivo murine IVD cellsTGF-β3, GDF-5, FGF, or IGF-1After four weeks of GDF-5 treatment, showed significantly increase in IVD height[72]
Human adipose-derived MSCsTGF-β1 and GDF-5Both distinctly efficient in promoting an NP cell phenotype[160]
Human cultured NP cellsTGF-β1, and IL-1βTGF-β1 improved NP cell proliferation, downregulation of mRNA expression of ADAMTS-4 and -5, upregulation expression of TIMP-3. IL-1β inhibited NP cells proliferation, increase of ADAMTS-4 and -5[161]
Canine cultured NP cellsTGF-β, and IL-10Suppressed IL1-β and TNF-α expression inhibiting inflammatory reaction[200]
In vitro human cultured NP cells. E19 rat cultured AF cellTGF-β1, and IGF-1Stimulation of human NP cells in a dose and time-dependent manner. TGF-β1 pushed AF cells to fibrocartilaginous phenotype. IGF-1 showed an upregulation of ECM[79,162]
Murine ESCsTGF-β, IGF, ascorbic acid, and cis-retinoic acidAll promotes differentiation toward chondrogenic lineage[175]
Human bone marrow-derived stromal cellsTGF-β1, rhGDF-5, or bovine NPCsStimulates cytokeratin-19 and aggrecan/type II collagen ratio distinguish chondrogenic from IVD cell phenotype[163]
Human bone marrow-derived MSCsTGF-β3, and dexamethasoneNotochordal cell conditioned medium expressed higher level of NP-like phenotype markers and GAGs deposition than chondrogenic medium or TGF-β groups[194]
Human cultured NP cellsTGF-β3, and dexamethasoneEnhanced NP proliferation, cell metabolism and reduce catabolism[195]
Rabbit cultured NP cellsTGF-β1, and BMP-2Robust restoration of ECM. Increased mRNA expression of aggrecan, type I and type II collagen[133]
In vitro porcine cultured AF cellsBMP-2, and TGF-β1Decrease in MMP-1 and increase in aggrecan synthesis[73]
Mouse MSCsBMP-2, 7, 13Proliferate and differentiate into osteoblastic and chondrogenic lineages and no adverse effects on proliferation on undifferentiated MSCs[164]
Human bone marrow-derived MSCsBMP-7Promotes both chondrogenic and osteogenic differentiation of MSCs[165]
In vitro rat cultured AF cellsBMP-2Increased mRNA expression of aggrecan and type II collagen. Also, up-regulates BMP-7 and TGFβ-3 mRNA expression[166]
Mouse embryonic-derived MSCsBMP-4, Insulin, triiodothyronine, or TGF-β3All BMP-4, Insulin, and triiodothyronine suppressed adipogenesis and develop osteogenic phenotype. TGFβ-3 promotes chondrogenesis[128]
In vitro human bone marrow-derived MSC cocultured with human cultured NP cellsBMP2, BMP4, BMP6, and BMP7BMP4 showed a high potential for IVDs regeneration. Although, BMP2 and BMP7 showed no potent inducer for degenerated human NP cell’s regeneration[167]
Human bone marrow-derived MSCsBMP-13Inhibited osteogenic differentiation of human BM-MSCs and increased proteoglycan synthesis[168]
Human adult MSCsBMP-3, and TGFβ-1Enhanced cell proliferation, GAGs content and differentiation into NP-like phenotype. Upregulated smad-3 signaling pathway[126]
Human adipose tissue-derived MSCsBMP-2, BMP-6, BMP-7, and TGF-β2Both TGFβ-2 and BMP-7 induces chondrogenic potential[76]
Human cultured NP and AF IVD cellsrhBMP-2, rhBMP-12, and adenoviralBMP-12Both rhBMP-2 and rhBMP-12 increased NP collagen and proteoglycan but least effects on AF. Though, adenoviral BMP-12 increased ECM protein formation in equally NP and AF[99]
Human and bovine cultured NP cellsBMP-7/OP-1 with BMP-2Enhanced GAGs production and NP cells proliferation[77]
Human cultured NP cellsrhBMP-7Inhibited apoptotic effects, decreased caspase-3 activity and maintained ECM production[169]
Bovine cultured NP cellsBMP-7, and IGF-1Both BMP-7 and IGF-1 induces Smad signaling pathways and suppresses noggin expression via PI3-kinase/Akt pathways[170]
Human cultured NP and AF IVD cellsBMP-2Improved newly synthesized proteoglycan and increased mRNA expression of aggrecan, type I and type II collagen[171]
In vitro cultured NP cellsIGF-1Increase of matrix synthesis in well-nourished regions[180]
In vitro canine cultured IVD cellsIGF-1, FGF, EGF, or TGF-β3TGF-β3 and EGF both produced higher proliferative responses than FGF. Also, IGF-1 showed a slightly significant responses in NP but no contribution in AF and transition zone[74]
Horse cultured articular cartilage cells. Bovine cultured NP cellsIGF-1Maintained differentiated chondrocyte morphology and enhanced synthesis of ECM molecules. Increased proteoglycan synthesis[178,191]
Bovine cultured AF and NP cellsIGF-1, bFGF, and PDGFStrengthened cell proliferation[81]
Human cultured AF cellsIGF-1, and PDGFSignificant reduced in apoptotic cell level[182]
Chondroitinase ABC injection rabbit modelOP-1Increase in disk height and matrix synthesis[172]
Rabbit cultured NP and AF IVD cellsOP-1Restored collagens and upregulated proteoglycan synthesis[173]
Human cultured NP and AF cellsOP-1Improved in the proteoglycan contents, total DNA, and collagen[174]
Human cultured NP cellsOP-1Partially repaired GAGs content, depends on a very high doses[175]
Gene therapy, in vitro human IVD cells. Gene therapy, in vivo rabbit IVDTIMP-1Increased proteoglycan synthesis. Less MRI and histologic evidence of degeneration[102,103]
In vitro cultured AF cells and chondrocytesLMP-1Increased proteoglycan synthesis, upregulation of mRNA expression of aggrecan, collagen types I and II, BMP-2 and -7[105]
Human synovium derived stem cellsFGF-2, and FGF-10FGF-2 stimulates chondrogenic gene expression, GAGs deposition and promotes both chondrogenic and osteogenic lineages[176]
Ovine bone marrow-derived MSCsFGF-2, and FGF-18Promotes both chondrogenic and osteogenic lineages of MSCs[177]
In vitro cultured human NP cellsFGF2Increased proliferative potential, redifferentiation gene expression and GAGs deposition[178]
Bone marrow-derived MSCsbFGF, TGFβ-1 and TCH gelGreater survival and repair effect on the degenerated IVDs[179]
In vitro rat cultured NP cellsrGDF-5Dose-dependency high expression of aggrecan and collagen type II genes was induced by rGDF-5 disc cells from GDF-5-deficient mouse[82]
In vitro bovine cultured. NP and AF cells, in vivo rabbit IVD modelrhGDF-5Increased DNA and proteoglycan level in vitro. In vivo, rhGDF-5 injection improved IVD height, MRI and histological grade score[183]
In vivo mice and rabbit modelGDF-5Structural and functional maintenance of IVD[184]
Canine BM peri-adipocyte cells (BM-PACs)GDF-5, TGFβ-1, BMP-2, and IGF-1GDF-5 promoted GAGs production and collagen type II without increasing collagen-10 mRNA expression[199]
Adult bone marrow-derived MSCsEGFIn the presence of EGF, promotes osteogenic differentiation and enhance paracrine secretion of BM-MSCs both in vitro and in vivo[80]
In vivo rat bone marrow-derived MSCsrhGCSFIncrease of end plates cell proliferation but no contribution in IVD regeneration or maintenance[185]
Human synovium-derived MSCsIL-1β, and TNF-αEnhanced synovial MSCs proliferation and chondrogenic ability[205,206]
Human bone marrow-derived MSCs. In vitro cultured porcine AF cellsIL-1β, and TNF-αBoth IL-1β and TNF-α suppressed chondrogenesis in a dose-selective manner. Increased expression of MMP-1[73,207]
Gene therapy, in vitro cultured NP cellsIL-1 and IL-1RaIL-1Ra decreased extracellular matrix degradation[101]
Mouse bone marrow-derived MSCsSOX-9Stimulate chondrogenesis[95]
Gene therapy, in vivo in rabbit IVDSOX-9Chondrocyte phenotype of IVD, restored architecture of NP[96]
Gene therapy, in vitro bovine AF cellsSox-9, and BMPIncreased proteoglycan and/or collagen type II synthesis[97]
Gene therapy, in vitro human NP cellsWNT-3A, WNT-5A, and WNT-11Increased expression of redifferentiation NP genes and GAGs accumulation[100]
Human bone marrow-derived MSCsWNT-3A and FGF2Synergistically both promoted MSC proliferation, chondrogenesis and cartilage formation[186]
VEGFR-1 and VEGFR-2 lacZ/+ NP cellsVEGFRaise NP survival[208]
Rhesus monkey cultured NP cellsCTGFStimulation of collagen type II and proteoglycan synthesis[187]
Human cultured NP cellsPRPEnhanced NP proliferation and differentiation into chondrogenic lineage[134]
Porcine cultured NP and AF cells; Porcine IVDD organPRPStimulation of IVDD cells proliferation. Increased mRNA expression levels of chondrogenesis and matrix formation[83,84]
Bovine cultured AF cellsPRPUpregulation of cell numbers and matrix synthesis[85]
In vitro porcine cultured AF cellsPRP and other cytokinesDecreased enzymes expression causing degradation and increased matrix proteins synthesis[86]