Connor Roper

Background: Tendons are constantly responsible for a proportionally high force load and are crucial to normal function¹. Tendon injuries, including tendinitis and tendinopathy, can severely impact life quality and reportedly affect over 100 million people globally². Mechanical overuse and age-related degeneration of tenocytes most often contribute to tendon injuries, both acute and chronic^1,3,4. Patients experiencing tendon injury present clinically with varying levels of pain and impaired functionality, which are evaluated by physical examination and MRI/Ultrasound¹. Current intervention options are limited and primarily focus on pain reduction through pain medication, physical therapy, or surgical repair^3,4. However, existing treatment options fail to address the underlying causes contributing to tendon injury. Interestingly, recent reports have correlated injured tendon tissue with proteomic alterations in tenocytes and their progenitor stem cells⁵. Such changes likely affect the extracellular matrix composition, inflammation response, and progenitor differentiation patterns⁶. Current efforts focus on identifying and targeting specific tendon progenitor cell proteins that control tendon healing^2,4,7.

Objective: This review intends to evaluate the mechanism of YAP in tendon progenitor cell differentiation and its effective delivery by exosomes.

Search Methods: Web of Science and PubMed databases were searched from 2019-2024 using the following search terms: “YAP”, “exosomes”, “tendinopathy”, “platelet-derived exosomes”, and “tenocyte differentiation”.

Results: YAP expression intimately relates to the differentiation properties of tendon progenitor stem cells, thereby promoting tendon regeneration^2,7,8. In progenitor cells, YAP is the driving component of the Hippo pathway and functions with TAZ to regulate transcription^2,7. Modulating the expression of YAP in stem cells demonstrated that YAP increased the expression of scleraxis, tenomodulin, and Type I Collagen, three proteins essential for differentiation into tenocytes⁷. Additionally, delivery of YAP to tendon stem cells reduced the phosphorylation of Iκ-bα and subsequently inhibited the NF-κB pathway, thereby preventing inflammatory signals induced by oxidative damage². Phosphorylation regulates Yap activity. When YAP is phosphorylated, it remains in the cytoplasm. In contract, when dephosphorylated, YAP translocates to the nucleus and interreacts with transcription factors⁸. Multiple protein and RNA pulldowns highlighted that H19, a long noncoding RNA, serves as a cross-bridge between YAP and protein phosphatase 1⁸. H19 overexpression effectively reduced YAP phosphorylation and increased nuclear expression⁸. Moreover, YAP protein can be delivered to tendon progenitor stem cells utilizing platelet-derived exosomes². Platelet-derived exosomes without YAP were sufficient to increase the expression of the growth factors b-FGF, TGF-β-1, VEGF-A, and PDGF-BB in tendon progenitor stem cells⁶. When YAP was additionally loaded into platelet-derived exosomes, they evaded immunological response and increased the healing capacity of a damaged tendon in a rat model². Damaged rat tendons treated with a PEG scaffold embedded with YAP-loaded platelet-derived exosomes exhibited tendon thickness, weight, histological score, and macroscopic score most similar to undamaged controls². While YAP treatment is a lucrative approach for tendon injury, YAP expression of tendon stem progenitor cells increases in diabetic models, and likely influences cell death by ferroptosis⁹, indicating potential adverse effects of YAP delivery.

Conclusion: YAP influences tendon stem cell differentiation and tendon regeneration and oxidative stress-induced NF-kB signaling. Regulating YAP activity with H19 or delivering YAP with platelet-derived exosomes have shown promising results in the regeneration of damaged rat tendons. However, further research is needed to investigate the adverse effects of YAP treatment to develop it as a safe treatment for tendon injury.

Works Cited:

1. Citro V, Clerici M, Boccaccini AR, Della Porta G, Maffulli N, Forsyth NR. Tendon tissue engineering: An overview of biologics to promote tendon healing and repair. Journal of Tissue Engineering. 2023;14:20417314231196275. doi:10.1177/20417314231196275
2. Lu J, Yang X, He C, et al. Rejuvenation of tendon stem/progenitor cells for functional tendon regeneration through platelet-derived exosomes loaded with recombinant Yap1. Acta Biomaterialia. 2023/04/15/ 2023;161:80-99. doi:https://doi.org/10.1016/j.actbio.2023.02.018
3. Ilaltdinov AW, Gong Y, Leong DJ, et al. Advances in the development of gene therapy, noncoding RNA, and exosome-based treatments for tendinopathy. Annals of the New York Academy of Sciences. 2021/04/01 2021;1490(1):3-12. doi:https://doi.org/10.1111/nyas.14382
4. Zhang Y, Ju W, Zhang H, Mengyun L, Shen W, Chen X. Mechanisms and therapeutic prospects of mesenchymal stem cells-derived exosomes for tendinopathy. Stem Cell Research & Therapy. 2023/10/26 2023;14(1):307. doi:10.1186/s13287-023-03431-3
5. Zhang S, Shang J, Gu Z, et al. Global research trends and hotspots on tendon-derived stem cell: a bibliometric visualization study. Front Bioeng Biotechnol. 2023;11:1327027. doi:10.3389/fbioe.2023.1327027
6. Graça AL, Domingues RMA, Calejo I, Gómez-Florit M, Gomes ME. Therapeutic Effects of Platelet-Derived Extracellular Vesicles in a Bioengineered Tendon Disease Model. Int J Mol Sci. Mar 9 2022;23(6)doi:10.3390/ijms23062948
7. Xu L, Chen Z, Geng T, et al. Irisin promotes the proliferation and tenogenic differentiation of rat tendon-derived stem/progenitor cells via activating YAP/TAZ. In vitro cellular & developmental biology Animal. 2022;58(8):658-668. doi:10.1007/s11626-022-00699-2
8. Tao SC, Huang JY, Li ZX, Zhan S, Guo SC. Small extracellular vesicles with LncRNA H19 “overload”: YAP Regulation as a Tendon Repair Therapeutic Tactic. iScience. Mar 19 2021;24(3):102200. doi:10.1016/j.isci.2021.102200
9. Wang G, Wang S, Ouyang X, et al. Glycolipotoxicity conferred tendinopathy through ferroptosis dictation of tendon-derived stem cells by YAP activation. IUBMB Life. Dec 2023;75(12):1003-1016. doi:10.1002/iub.2771