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3D Mechanical Stimulation Modulates Endothelial Exosomes to Promote Fibroblast Activation

ABSTRACT: Background: Mechanical forces play a crucial role in regulating cellular communication during tissue repair, yet how mechanical stimulation modulates endothelial exosome secretion and their effects on fibroblast activation remains unclear. Methods: In this study, endothelial cells were incorporated into 3D bioprinted tissue-engineered dermal constructs and cultured under static or mechanically stretched conditions. Exosomes were isolated, characterized, and applied to human dermal fibroblasts to assess their influence on proliferation, migration, and extracellular matrix formation. Data-independent acquisition proteomics was performed to analyze exosomal protein cargo and associated signaling pathways. Results: Mechanical loading increased exosome secretion by approximately 2.5-fold without altering vesicle morphology. Functionally, mechanically stimulated exosomes significantly enhanced fibroblast migration and type I collagen synthesis compared with controls. Proteomic profiling identified 4,476 proteins, of which 677 were differentially expressed. Enrichment analysis revealed activation of VEGF, HIF-1, Relaxin, and AGE–RAGE pathways, implicating roles in angiogenesis, metabolic regulation, and extracellular matrix remodeling. Conclusion: These findings demonstrate that 3D mechanical stimulation not only augments the quantity of endothelial exosomes but also reshapes their molecular cargo, thereby enhancing biomechanical communication between endothelial cells and fibroblasts. Together with prior evidence of fibroblast-derived exosomes promoting endothelial angiogenesis, this study proposes a bidirectional “mechanical stimulation–exosome–communication–tissue reconstruction” loop, providing a theoretical foundation for optimizing exosome-based strategies in skin tissue engineering.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ye Qiu

PROVIDER: PXD072415 | iProX | Thu Dec 25 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:Background: Docosahexaenoic acid (DHA) is a natural compound with anticancer and anti-angiogenesis activity that is currently under investigation as both a preventative agent and an adjuvant to breast cancer therapy. However, the precise mechanisms of DHA’s anticancer activities are unclear. It is understood that the intercommunication between cancer cells and their microenvironment is essential to tumor angiogenesis. Exosomes are extracellular vesicles that are important mediators of intercellular communication and play a role in promoting angiogenesis. However, very little is known about the contribution of breast cancer exosomes to tumor angiogenesis or whether exosomes can mediate DHA’s anticancer action. Results: Exosomes were collected from MCF7 and MDA-MB-231 breast cancer cells after treatment with DHA. We observed an increase in exosome secretion and exosome microRNA contents from the DHA-treated cells. The expression of 83 microRNAs in the MCF7 exosomes was altered by DHA (>2-fold). The most abundant exosome microRNAs (let-7a, miR-23b, miR-27a/b, miR-21, let-7, and miR-320b) are known to have anti-cancer and/or anti-angiogenic activity. These microRNAs were also increased by DHA treatment in the exosomes from other breast cancer lines (MDA-MB-231, ZR751 and BT20), but not in exosomes from normal breast cells (MCF10A). When DHA-treated MCF7 cells were co-cultured with or their exosomes were directly applied to endothelial cell cultures, we observed an increase in the expression of these microRNAs in the endothelial cells. Furthermore, overexpression of miR-23b and miR-320b in endothelial cells decreased the expression of their pro-angiogenic target genes (PLAU, AMOTL1, NRP1 and ETS2) and significantly inhibited tube formation by endothelial cells, suggesting that the microRNAs transferred by exosomes mediate DHA’s anti-angiogenic action. These effects could be reversed by knockdown of the Rab GTPase, Rab27A, which controls exosome release. Conclusions: We conclude that DHA alters breast cancer exosome secretion and microRNA contents, which leads to the inhibition of angiogenesis. Our data demonstrate that breast cancer exosome signaling can be targeted to inhibit tumor angiogenesis and provide new insight into DHA’s anticancer action, further supporting its use in cancer therapy. Examination of small RNA populations in MCF7 cells and exosomes after DHA treatment.

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3D Mechanical Stimulation Modulates Endothelial Exosomes to Promote Fibroblast Activation

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