Review Article

Umbilical Cord Mesenchymal Stromal Cells for Cartilage Regeneration Applications

Table 3

In vitro studies of UC-MSCs or their secretome.

Study typeSourceAimCulture systemResultsRef.

Chondrogenic differentiationHuman UC-MSCsUC- and AT-MSC comparisonCultured in CM supplemented with TGFβ3 and BMP-6A more fibrous than hyaline cartilage phenotype in UC-MSCs compared to AT-MSCsHildner et al., 2010 [87]
Human WJ-MSCsDifferentiation into NP-like cellsCoculture with NPCsIncreased expression of aggrecan, collagen II, and SRY-type HMG box-9 genesRuan et al., 2012 [88]
Human UC-MSCsDifferentiation into NP-like cellsCultured in a laminin-rich pseudo-3D culture systemGAGs, collagen II, laminin α5, and laminin receptors (integrin α3 and β4) expressionChon et al., 2013 [89]
Human WJ-MSCsImmunomodulatory properties testCultured in CMDifferentiated WJ-MSCs maintain their immune privilegeLa Rocca et al., 2013 [50]
Human UC-MSCsElastic cartilage differentiationSeeded on PLGA nanofiber scaffolds with CM and CTGFIncrease of GAG/DNA ratio, collagen II, elastin mRNA and protein. No difference in collagen X or fibrillin mRNACaballero et al., 2013 [90]
Human UC-MSCsTissue-engineered (TE) elastic cartilage from UC-MSCs and human cartilage comparisonSeeded onto PLGA nanofiber scaffolds with CM supplemented with CTGFTE elastic cartilage from UC-MSCs expresses embryonic fibrillin III and similar levels of elastin, fibrillin I, collagens I and X when compared to native cartilage.Pappa et al., 2014 [120]
Human and porcine UC-MSCsEffects of periodic vibratory stimulus on UC-MSC differentiationCultured in chondrogenic or osteogenic medium and exposed to 1 or 100 Hz frequency vibrations1 Hz stimulation resulted in a cartilage phenotype while 100 Hz stimulation resulted in a bone phenotype for both human and porcine UC-MSCsCashion et al. 2014 [121]
Human UC-MSCsUC-, BM-, and AT-MSC chondrogenesis comparisonCultured in CMSlightly differences in chondrogenesis between the MSCs. BM-MSCs showed the best chondrogenic potentialDanišovič et al., 2016 [92]
Human UC-MSCsEffect of mechanical compression on UC-MSC chondrogenesisSeeded in PVA-PCL scaffold with CM and subjected to dynamic compressionIncrease in chondrogenic differentiationRemya et al., 2016 [122]
Human WJ-MSCsSimulation of the articular cartilage microenvironmentCoculture of WJ-MSCs and primary ACs in ACECM- oriented scaffoldChondrogenic differentiation of WJ-MSCs without any inducer, hyaline cartilage phenotype, and improved cytoactivity of ACsZhang et al., 2019a [96]
Human UC-MSCsInteractions between ACs and UC-MSCs.Coculture with direct cell-cell contactEnhanced differentiation of UC-MSCs and reduced dedifferentiation of chondrocytesLi et al., 2019 [97]
WJ-MSCsImmunomodulatory properties testChondrogenic differentiation in Alg/HA scaffoldDifferentiated WJ-MSCs inhibit T cell alloproliferation and maintain paracrine activity and functional immunomodulationVoisin et al., 2020 [84]
Cartilage tissue engineeringHuman UC-MSCsPGA and PLLA scaffolds comparisonSeeded on nonwoven PGA or PLLA scaffolds in CMSimilar chondrogenic potential of UC-MSCs in PLLA and PGA scaffolds.Zhao et al., 2010 [123]
Human WJ-MSCsWJ- and BM-MSCs chondrogenesis comparisonSeeded in PCL/Coll nanofibrous scaffolds in CMEnhanced cell attachment, proliferation, and chondrogenesis of WJ-MSCs over BM-MSCsFong et al., 2012 [124]
Human UC-MSCsChondrogenic differentiationEmbedded in collagen hydrogel scaffold with CMIncreased expressions of collagen II, aggrecan, COMP, and sox9Chen et al., 2013 [125]
Human UC-MSCsChondrogenic differentiation in PVA-PCL scaffoldsSeeded in PVA-PCL scaffolds with individual TGFβ1, TGFβ3, IGF, BMP2 and their combination with BMP2SOX9, collagen II and aggrecan expression. The combination TGF-β3 and BMP-2 was the more effective for chondrogenesisNirmal et al., 2013 [126]
Human WJ-MSCsFabrication of a nonscaffold tissue-engineered cartilagePellet culture combined with RCCSRCCS formed larger and condenser cartilage-like tissue enriched of GAGs and collagen II than pellet cultureLiu et al., 2014 [12]
Human WJ-MSCsWJ- and BM-MSCs chondrogenesis in agarose hydrogelEncapsulation of WJ-MSCs or BM-MSCs aggregates in agarose hydrogelsBoth BM-MSCs and WJ-MSCs did better in matrix biosynthesis and chondrogenesis when in aggregates than in free cell suspensionSridharan et al., 2015 [127]
Human UC-MSCsChondrogenic differentiation in SF/HA scaffoldSeeded in different ratios of SF/HA with CMExpression of collagen II, aggrecan, and Sox9. SF80 and SF70 scaffolds are the best for chondrogenesisJaipaew et al., 2016 [128]
Human WJ-MSCsChondrogenesis of WJ-MSCs in PLLA-collagen nanofibers scaffoldSeeded on PLLA-collagen nanofibers scaffold with CMPLLA-collagen nanofibers scaffold promotes the chondrogenic differentiation of WJ-MSCsWang et al., 2017 [129]
Human WJ-MSCsChondrogenesis of WJ-MSCs in hyaluronic acid-based hydrogelsSeeded in hyaluronic acid-based hydrogels with CMIncrease of GAGs, collagen II and aggrecan,Aleksander-Konert et al., 2016 [130]
Human UC-MSC- ECMEffect of decellularized UC-MSC-ECM on ACsACs seeded in culture plates coated with UC-MSC-ECMPromotion of the proliferation and differentiation of chondrocytesZhang et al., 2019b [131]
Fibrocartilage tissue engineeringHuman UC-MSCsUC- and BM-MSCs chondrogenesis comparisonSeeded onto PGA scaffolds in chondrogenic mediumMore GAGs, collagen I, and aggrecan and less collagen II in UC-MSCs than BM-MSCsWang et al., 2009a [132]
Human UC-MSCsBest density for UC-MSCs chondrogenesisSeeded on nonwoven PGA scaffold in CMMore collagen I and II, aggrecan, GAGs, and mechanical integrity in high-density groupsWang et al., 2009b [133]
Osteochondral tissue engineeringHuman UC-MSCsChondrogenic and osteogenic differentiationSeeded between chondrogenic and osteogenic PLLA constructsBoth chondrogenic and osteogenic differentiation of UC-MSCs in the respective sides of constructsWang et al., 2011 [134]
Human UC-MSCsChondrogenic and osteogenic differentiationSeeded in osteogenic scaffold and in Collagen I and III- or HA-based chondrogenic scaffolds in normoxic or hypoxic (8% O2) conditions.Both chondrogenic and osteogenic differentiation of UC-MSCs. Hypoxia improved the expression of these chondrogenic markersMarmotti et al., 2017 [31]
Orthopaedic tissue engineeringHuman UC-MSCsMultilineage differentiationCultured in adipogenic, osteogenic, chondrogenic, or myogenic mediumMultilineage differentiation potential toward bone, fat, cartilage, and muscleMarmotti et al., 2012 [91]
IVD degenerationHuman UC-MSCsUC- and D-NP-MSCs comparisonCultured with CMD-NPMSCs expressed lower expression levels of CD29 and CD105, reduced proliferation capability and differentiation potentialsWu et al., 2017 [93]
Human WJ-MSCsInteractions between WJ-MSCs and degenerative NPCsCoculture with or without direct cell-cell contactNP-like cell differentiation of WJ-MSCs and biological status of degenerative NPCs restoration. The direct cell-cell contact yielded more favorable gene expressionsHan et al., 2018 [98]
Human UC-MSCs secretomeUC-MSC-conditioned medium (CM) effect on damaged NP-MSCsTreatment of high glucose-induced degradation of NP-MSCs with UC-MSCs-CMReduction of apoptosis and ECM degradation via the p38 MAPK pathwayQi 2019 et al., 2019 [135]
Human UC-MSCs-ECMEffect of UC-MCS-ECM on IVD cellsIVD cells seeded on decellularized UC-MSCs-ECMUC-MSCs-ECM improved the degenerated phenotype of human IVD cells affecting the expression of Sox2, Sox 9 and TRPS1Penolazzi et al., 2020 [136]
OAHuman UC-MSCs secretomeComparison of articular cartilage (AC), Hoffa’s fat pad (HFP), synovial membrane (SM), and UC-MSC secretomesSecretome analysis by mass spectrometry and effect on AC chondrogenesis and immunosuppressive and anti-inflammatory effects on PBMCs and macrophagesUC-MSCs-CM displayed superior anti-inflammatory, immunomodulatory and trophic effects compared to adult MSCsIslam et al., 2019 [95]
RAHuman UC-MSCsUC-MSCs effect on FLSCocultureIncrease of FLS apoptosis, collagen II, and aggrecan; decrease of IL-1β, IL-6 and CCL-2Zeng et al., 2016 [61]
TMJ disordersHuman UC-MSCsUC-MSCs and TMJ condylar chondrocytes comparisonSeeded in PGA scaffolds in CMMore collagen I and II, GAGs, and cellular density in UC-MSCs than TMJ constructBailey et al., 2007 [94]

AC: articular cartilage cells; ACECM: acellular cartilage extracellular matrix; Alg/HA: alginate enriched in hyaluronic acid; CTGF: connective tissue growth factor; CM: chondrogenic medium; D-NP-MSCs: NP stem/progenitor cells isolated from degenerated IVD; ECM: extracellular matrix; FLS: fibroblast-like synoviocytes; GAGs: glycosaminoglycans; n.a.: not applicable; IVD: intervertebral disc; NP: nucleus pulpous; NPCs: nucleus pulposus cells; OA: osteoarthritis; PCL/Coll: polycaprolactone/collagen; PGA: polyglycolic acid; PLGA: poly L-lactide/D-lactide/glycolide; PLLA: poly-L-lactic acid; PMEF: pulsed electromagnetic field; PVA-PCL: polyvinyl alcohol-polycaprolactone; RA: rheumatoid arthritis; RCCS: rotary cell-culture system; SF/HA: silk fibroin/hyaluronic acid; TMJ: temporomandibular joint.