Biomaterial Properties and Differentiation Strategies for Tenogenic Differentiation of Mesenchymal Stem Cells
Abstract
:1. Introduction
1.1. Tendon Structure and Function
1.2. Tendon Healing
1.3. Tendinopathy and Associated Risk Factors
1.4. Current Challenges Associated with Tendon Repair and Engineering
2. Molecular Mechanisms Regulating Tenogenic Differentiation
2.1. SMAD Signalling Pathway
2.2. Non-SMAD Signalling
2.3. Topography-Based Signalling
3. Biomaterial Characteristics to Consider When Designing Tenogenic Differentiation Protocols
3.1. Introduction to Biomaterials
3.2. 2D vs. 3D Cell Culture
3.3. Topography
3.4. Stiffness
3.5. Tensile Loading
3.6. Customisation
3.7. Advantages and Limitations of Currently Used Biomaterial Fabrication Techniques
4. Growth Factors Stimulating Tenogenic Differentiation
Growth Factor | Cell Type | Concentration | Duration | Effect | Reference |
---|---|---|---|---|---|
L-ascorbic acid | ASCs | 500 µM (AA-2P) 50 µg/mL | 5 days and 14 days | Increased Scx expression. Increased extracellular deposition of Col I and III. Optimal concentration was 50 µg/mL. | [126,139] |
TGF-β1 | ASCs, BMSCs, MSCs PDLSCs | 10 ng/mL, 20 ng/mL | 7 days, 10 days, and 14 days | Upregulates Scx, Mkx, Tnmd, THBS-4, TNC, Col I, and Col III. Inhibits DCN. Activates AKT-mTOR signalling. Optimal concentration was 10 ng/mL. | [62,125,126,132] |
TGF-β2 | BMSCs, MSCs | 1 ng/mL, 50 ng/mL | 72 h, 14 days, and 21 days | Increased Scx, Tnmd, Col I and TNC expression. Signalling is mediated by AKT-mTOR. | [61,127,128] |
TGF-β3 | ASCs, BMSCs, TMSCs PDLSCs | 1 ng/mL, 5 ng/mL, 10 ng/mL, 20 ng/mL | 72 h, 7 days, 10 days, and 14 days | Increased Scx, Tnmd, TNC, Col I and Col III expression. Reduces proliferation while enhancing metabolic activity. Inhibits DCN. Signalling is mediated by Smad2/3 phosphorylation and enhanced by ROCK inhibition. Optimal concentration was 5 ng/mL. | [72,113,114,129,130,131,132] |
CTGF | ASCs, BMSCs | 100 ng/mL | 10 days and 14 days | Upregulated Scx, Tnmd, and Col I expression. Increased proliferation. Suppressed osteogenesis. Signalling is mediated through ERK1/2 and FAK pathways. Synergistic effect on TGF-β1. Optimal concentration was 100 ng/mL. | [67,125] |
bFGF or FGF-2 | ASCs, BMSCs, PDLSCs | 5 ng/mL, 10 ng/mL, 50 ng/mL, 100 ng/mL | 7 days, 10 days, and 28 days | Maintains DCN expression after tenogenic induction. Stimulates TNC and DCN expression in prolonged culture. Antagonizing effect on TGF-β1, should be sequentially separated. | [129,132,142,143] |
PDGF-BB | ASCs | 20 ng/mL | 14 days | Induced Scx expression. Increased collagen deposition and Col I expression. | [140] |
BMP-12 or GDF-7 | BMSCs | 10 ng/mL, 50 ng/mL, 100 ng/mL | 5 days and 14 days | Stimulated Scx, Mkx, DCN, TNC, Col I, and Tnmd expression. Enhanced expression of adipocyte markers. Synergizes with TGF-β3 to increase collagen production and metabolic activity. | [126,130,144,145] |
BMP-13 or GDF-6 | ASCs, BMSCs | 20 ng/mL | 14 days | Induced Scx and Tnmd expression. Increased collagen deposition and Col I and III expression. | [140,147] |
BMP-14 or GDF-5 | ADSCs, BMSCs | 100 ng/mL | 10 days, 12 days, and 14 days | Induced Scx expression, Tnmd, and Col I. Synergizes with TGF-β3 to increase collagen production and TNC expression. Induces differentiation via p38. | [65,130,148,149] |
IGF-1 | MSCs | 10 ng/mL, 100 ng/mL | 10 days and 14 days | Upregulates collagen expression. Has a synergistic effect with BMP-12 (DCN) and TGF-β1 (BGN). Activates AKT-mTOR signalling. | [62,141] |
Soluble tECM | ASCs and MSCs | 50 µg/mL and 1 mg/mL | 6, 7, and 14 days | Upregulates Scx, Mkx, Col I, Col III, TNC, and BGN and enhanced expression of integrins and TGF-β receptors. Contains various GFs (TGF-β1, TGF-β3, bFGF, FGF-2, and IGF-1). TGF-β3 was more effective than tECM in tenogenic induction. However, tECM enhanced TGF-β3 induced tenogenesis. Increased proliferation and metabolic activity Mechanism of action integrin and TGF-β/SMAD crosstalks. Optimal concentration was 1 mg/mL | [77,150,151,152,153] |
5. Conclusions, Perspective, and Future Directive
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
2D | Two-dimensional |
3D | Three-dimensional |
AA | Ascorbic acid |
ADSCs | Adipose-derived mesenchymal stem cells |
Akt | Protein kinase B |
bFGF | Basic fibroblast growth factor |
BMP | Bone morphogenetic protein |
BMSCs | Bone-marrow-derived mesenchymal stem cells |
CTGF | Connective tissue growth factor |
ECM | Extracellular matrix |
ERK | Extracellular signal-regulated kinase |
FAK | Focal adhesion kinase |
FGF-2 | Fibroblast growth factor 2 |
GAGs | Glycosaminoglycans |
GDF | Growth differentiation factor |
GFs | Growth factors |
Hz | Hertz |
IFM | Interfascicular matrix |
IGF-1 | Insulin-like growth factor 1 |
JNK | c-Jun amino-terminal kinase |
MAPK | Mitogen-activated protein kinase |
MSCs | Mesenchymal stem cells |
PDGF | Platelet derived growth factor |
PDLSCs | Periodontal ligament derived stem cells |
PDMS | Polydimethylsiloxane |
PGs | Proteoglycans |
PI3K | Phosphatidylinositol 3-kinase |
SMAD | Suppressor of mothers against decapentaplegic |
TDSCs | Tendon-derived mesenchymal stem cells |
tECM | Tendon extracellular matrix |
TGF-β1 | Transforming growth factor beta 1 |
TGF-β2 | Transforming growth factor beta 2 |
TGF-β3 | Transforming growth factor beta 3 |
TGF-βRI | TGF-β type 1 receptor |
TGF-βRII | TGF-β type 2 receptor |
TMSCs | Tonsil-derived mesenchymal stem cells |
TNC | Tenascin-C |
Tnmd | Thrombomodulin |
YAP | Yes-associated protein |
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Roets, B.; Abrahamse, H.; Crous, A. Biomaterial Properties and Differentiation Strategies for Tenogenic Differentiation of Mesenchymal Stem Cells. Cells 2025, 14, 452. https://doi.org/10.3390/cells14060452
Roets B, Abrahamse H, Crous A. Biomaterial Properties and Differentiation Strategies for Tenogenic Differentiation of Mesenchymal Stem Cells. Cells. 2025; 14(6):452. https://doi.org/10.3390/cells14060452
Chicago/Turabian StyleRoets, Brendon, Heidi Abrahamse, and Anine Crous. 2025. "Biomaterial Properties and Differentiation Strategies for Tenogenic Differentiation of Mesenchymal Stem Cells" Cells 14, no. 6: 452. https://doi.org/10.3390/cells14060452
APA StyleRoets, B., Abrahamse, H., & Crous, A. (2025). Biomaterial Properties and Differentiation Strategies for Tenogenic Differentiation of Mesenchymal Stem Cells. Cells, 14(6), 452. https://doi.org/10.3390/cells14060452