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"PLATELET-DERIVED EXTRACELLULAR VESICLES SHOW THERAPEUTIC EFFECTS ON A 3D TENDON DISEASE MODEL
Ana Luísa Graça1,2, Rui M. A. Domingues1,2, Isabel Calejo1,2, Manuel Gómez-Florit1,2 and Manuela E. Gomes1,2
13B's Research Group, I3Bs – Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal;
2ICVS/3B’s–PT Government Associate Laboratory, Braga/Guimarães, Portugal;
Introduction: Tendon diseases are common clinical problems that can dramatically affect the quality of life of individuals across the demographic spectrum. Current clinical approaches do not tackle the etiology of the disease, underlined by an unresolved inflammatory scenario that provokes hypercellularity, neovascularization, and a dysregulation of the critical balance between extracellular matrix (ECM) remodeling proteases and their inhibitors. In this regard, extracellular vesicles (EVs), a diverse group of nanosized membrane-enclosed particles actively released by all types of cells with key roles in communication, are being considered as very attractive therapeutic agents to trigger repair/regenerative processes in injured tissues. Thus, herein, the therapeutic potential of EVs derived from platelets was evaluated using a pre-establish 3D tendon disease in vitro model.
Methodology: First, bioengineered tendon disease models consisting of electrospun isotropic nanofibrous scaffolds coated with cell-laden hydrogels encapsulating human tendon-derived cells (hTDCs), were produced. Then, different platelet-derived EVs populations were isolated by differential centrifugation, added to hTDCs culture media, and their influence in cells phenotype and ECM remodeling was assessed over culture time.
Results: As expected, after 14 days of culture, a disease-like phenotype was observed in hTDCs of the miniaturized 3D tendon units. We verified that although EVs do not have a remarkable influence in hTDCs morphology, these are able to influence their biological response. Interestingly, the addition of EVs reestablish the expression of tendon-related markers like MKX, SCX, and TNMD in diseased hTDCs and decreasing the expression of osteogenic and fibrotic markers. Moreover, EVs increased the expression of different ECM components such as COL31A and DCN, and the expression of MMP-3, important factors in the balance between the synthesis and degradation of tendon ECM. Moreover, the presence of EVs was found to modulate the inflammatory response, as demonstrated by an increase of anti-inflammatory mediators, like IL-4, which might contribute to blunt the inflammatory processes occurring in damaged tissue.
Conclusions: Overall, we showed that platelet-derived EVs have a positive influence on tendon cells cultured on a disease-like in vitro model, not only by increasing the expression of healthy tendon cells markers and promoting ECM remodeling, but also by increasing the expression of anti-inflammatory cytokines. The beneficial effects of these vesicles are worthy to be explored in further studies to provide more insights on how EVs interact with tendon cells, becoming a promising therapeutic tool for tendon injuries recovery.
Acknowledgments: ERC CoG MagTendon grant agreement 772817; EC Twinning project Achilles 810850; FCT for PhD grant PD/59/2013 and PD/BD/135255/2017, Post-Doc grant SFRH/BPD/112459/2015, CEECIND/01375/2017 and 2020.03410.CEECIND.
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