Exosome-mediated lymphatic regeneration: Mechanisms, therapeutic strategies, and translational opportunities

Abstract

Lymphatic dysfunction, clinically presenting as secondary lymphedema and chronic inflammatory conditions, remains a significant clinical challenge following oncologic therapy and tissue trauma. Current therapeutic strategies offer limited long-term efficacy, and cell-based regenerative approaches are constrained by safety concerns and scalability limitations. Within this therapeutic landscape, exosomes have emerged as promising mediators of lymphatic vessel repair. However, their specific role in lymphatic regeneration has not yet been fully elucidated. These nanovesicles, derived from diverse cellular sources, carry diverse molecular constituents that precisely modulate cellular processes critical for lymphangiogenesis. Compelling evidence highlights the essential role of exosome-mediated networks in lymphangiogenic processes. Exosomes influence lymphatic endothelial cell behavior by engaging multiple canonical signaling pathways. Current reviews predominantly address exosome biology or lymphatic pathophysiology in isolation, lacking a systematic analysis of exosomal regulatory mechanisms. This review aims to delineate the multifunctional role of exosomes as modulators of the lymphatic regenerative niche. We further discuss current tissue engineering strategies that utilize exosomes to promote lymphatic vessel regeneration, identify persistent gaps, and seek to establish a theoretical foundation for exosome-based lymphatic regeneration.

Keywords

Lymphatic vessel / Lymphangiogenesis / Exosome / Microenvironment / Lymphedema

References

[1] T. Tammela, K. Alitalo, Lymphangiogenesis: Molecular Mechanisms and Future Promise, Cell 140 (4) (2010) 460-476.

[2] M. Skobe, M. Detmar, Structure, function, and molecular control of the skin lymphatic system, Journal of Investigative Dermatology Symposium Proceedings, Elsevier, 2000.

[3] H. Wiig, M.A.J.Pr Swartz, Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer, Physiol. Rev. 92 (3) (2012) 1005-1060.

[4] M. Schaupper, M. Jeltsch, S. Rohringer, H. Redl, W. Holnthoner, Lymphatic vessels in regenerative medicine and tissue engineering, Tissue Eng. Part B Rev. 22 (5) (2016) 395-407.

[5] J.B. Dixon, S. Raghunathan, M.A. Swartz, A tissue-engineered model of the intestinal lacteal for evaluating lipid transport by lymphatics, Biotechnol. Bioeng. 103 (6) (2009) 1224-1235.

[6] H. Liu, L. Liu, Y. Zhang, Q. Tian, Z. Ding, J. Chen, A.P. Kusumbe, Lymphatic-immune interactions in the musculoskeletal system, Front. Immunol. 16 (2025) 1578847.

[7] L. Biswas, J. Chen, J. De Angelis, A. Singh, C. Owen-Woods, Z. Ding, J.M. Pujol, N. Kumar, F. Zeng, S.K. Ramasamy, A.P. Kusumbe, Lymphatic vessels in bone support regeneration after injury, Cell 186 (2) (2023) 382-397 e24.

[8] Y. Zheng, L. Cong, L. Zhao, P. Wang, L. Xing, J. Liu, H. Xu, N. Li, Y. Zhao, L. Yuan, Q. Shi, X. Sun, Q. Liang, Y. Wang, Lymphatic platelet thrombosis limits bone repair by precluding lymphatic transporting DAMPs, Nat. Commun. 16 (1) (2025) 829.

[9] Z.Y. Qin, H.B. Jiang, R.Y. Xu, Lymphatic Vessels Orchestrate Immune And Lipid Homeostasis During Bone Regeneration, International. Dental. Journal. 75 (1) (2025) 105869.

[10] Z. Qin, H. Xie, P. Su, Z. Song, R. Xu, S. Guo, Y. Fu, P. Zhang, H. Jiang, Targeting endoplasmic reticulum stress-induced lymphatic dysfunction for mitigating bisphosphonate-related osteonecrosis, Clin. Transl. Med. 14 (11) (2024) e70082.

[11] G. Shim, R. Hall, Z. Zhang, I.M. Shokry, A. To, L. Cruz, M.C. Adam, H. Prentice, J.Y. Wu, H. Su, R. Tao, I. For The Alzheimer's Disease Neuroimaging, Three-Dimensional PET Imaging Reveals Canal-like Networks for Amyloid Beta Clearance to the Peripheral Lymphatic System, Cells 14 (22) (2025) 1754.

[12] S. Brown, J.H. Dayan, R.P. Kataru, B.J. Mehrara, The vicious circle of stasis, inflammation, and fibrosis in lymphedema, Plast. Reconstr. Surg. 151 (2) (2023) 330e-341e.

[13] R. Deldar, S. Duquette, E.P. Ceppa, M. Lester, R. Sood, J. Socas, An alternative approach to combined autologous breast reconstruction with vascularized lymph node transfer, Microsurgery 37 (5) (2017) 463-464.

[14] A.H. Hassanein, J.M. Sacks, D.S.J.M. Cooney, Optimizing perioperative lymphatic-venous anastomosis localization using transcutaneous vein illumination, isosulfan blue, and indocyanine green lymphangiography, Microsurgery 37 (8) (2017) 956-957.

[15] G.E. Hespe, G.G. Nores, J.J. Huang, B.J. Mehrara, Pathophysiology of lymphedema-Is there a chance for medication treatment? J. Surg. Oncol. 115 (1) (2017) 96-98.

[16] S.F. Shaitelman, K.D. Cromwell, J.C. Rasmussen, N.L. Stout, J.M. Armer, B.B. Lasinski, J.N. Cormier, Recent progress in the treatment and prevention of cancer-related lymphedema, CA a cancer journal clinicians 65 (1) (2015) 55-81.

[17] M. Kanapathy, N.M. Patel, D.M. Kalaskar, A. Mosahebi, B.J. Mehrara, A.M. Seifalian, Tissue-engineered lymphatic graft for the treatment of lymphedema, J. Surg. Res. 192 (2) (2014) 544-554.

[18] C. Zhao, K. Rong, P. Liu, K. Kong, H. Li, P. Zhang, X. Chen, Q. Fu, X. Wang, Preventing periprosthetic osteolysis in aging populations through lymphatic activation and stem cell-associated secretory phenotype inhibition, Commun. Biol. 7 (1) (2024) 962.

[19] T. Yao, X. Dong, X. Wang, X. Liu, L. Fu, L. Li, Engineering exosomes for mRNA delivery: a review, Int. J. Biol. Macromol. 316 (2025) 144662.

[20] X. Wang, J. Xia, L. Yang, J. Dai, L. He, Recent progress in exosome research: isolation, characterization and clinical applications, Cancer gene Ther. 30 (8) (2023) 1051-1065.

[21] K. O'brien, K. Breyne, S. Ughetto, L.C. Laurent, X.O. Breakefield, RNA delivery by extracellular vesicles in mammalian cells and its applications, Nat. Rev. Mol. Cell Biol. 21 (10) (2020) 585-606.

[22] S.A. Stacker, S.P. Williams, T. Karnezis, R. Shayan, S.B. Fox, M.G. Achen, Lymphangiogenesis and lymphatic vessel remodelling in cancer, Nat. Rev. Cancer 14 (3) (2014) 159-172.

[23] L. Vachon, G. Jean, A. Milasan, et al., Platelet extracellular vesicles preserve lymphatic endothelial cell integrity and enhance lymphatic vessel function, Commun. Biol. 7 (1) (2024) 975.

[24] M. Koc, M. Wald, Z. Varaliová, B. Ondrůjová, T. Čížková, M. Brychta, J. Kračmerová, L. Beranová, J. Pala, V. Šrámková, M. Šiklová, J. Gojda, L. Rossmeislová, Lymphedema alters lipolytic, lipogenic, immune and angiogenic properties of adipose tissue: a hypothesis-generating study in breast cancer survivors, Sci. Rep. 11 (1) (2021) 8171.

[25] X. Wang, H. Wang, J. Cao, C. Ye, Exosomes from Adipose-Derived Stem Cells Promotes VEGF-C-Dependent Lymphangiogenesis by Regulating miRNA-132/TGF-β Pathway, Cell. Physiol. Biochem. 49 (1) (2018) 160-171.

[26] W. Shu, Y. Wang, M. Chen, X. Zhu, F. Wang, C. Chen, P. Du, A. Bartolomucci, X. Su, X. Wang, Extracellular vesicles derived from creeping fat stem cells promote lymphatic function and restrain inflammation of Crohn's disease, Clin. Transl. Med. 14 (12) (2024) e70086.

[27] Y. Yang, X.B. Li, Y. Li, T.X. Li, P. Li, G.M. Deng, Q. Guo, X. Zhou, X.H. Chen, Extracellular vesicles derived from hypoxia-conditioned adipose-derived mesenchymal stem cells enhance lymphangiogenesis, Cell Transplant. 31 (2022) p. 09636897221107536.

[28] J.L. Campos, G. Pons, A.M. Al-Sakkaf, I.L. Lusetti, L. Pires, F.J. Vela, E. Ramos, V. Crisóstomo, F.M. Sánchez-Margallo, E. Abellán, J. Masiá, Lymphatic regeneration after popliteal lymph node excision and implantation of aligned nanofibrillar collagen scaffolds: an experimental rabbit model, J. Funct. Biomater. 15 (8) (2024) 235.

[29] F. Teng, M.J.A.S. Fussenegger, Shedding light on extracellular vesicle biogenesis and bioengineering, Adv. Sci. (Weinh). 8 (1) (2020) 2003505.

[30] X. Xu, L. Xu, J. Xia, C. Wen, Y. Liang, Y. Zhang, Harnessing knee joint resident mesenchymal stem cells in cartilage tissue engineering, Acta Biomater. 168 (2023) 372-387.

[31] X. Xiao, S. Yu, S. Li, J. Wu, R. Ma, H. Cao, Y. Zhu, J. Feng, Exosomes: decreased sensitivity of lung cancer A549 cells to cisplatin, PloS One 9 (2) (2014) e89534.

[32] H.W. King, M.Z. Michael, J.M.J.Bc Gleadle, Hypoxic enhancement of exosome release by breast cancer cells, BMC Cancer 12 (1) (2012) 421.

[33] A. Takahashi, R. Okada, K. Nagao, Y. Kawamata, A. Hanyu, S. Yoshimoto, M. Takasugi, S. Watanabe, M.T. Kanemaki, C. Obuse, E. Hara, Exosomes maintain cellular homeostasis by excreting harmful DNA from cells, Nat. Commun. 8 (1) (2017) 15287.

[34] C.-J. Li, Q.H. Fang, M.L. Liu, J.N. Lin, Current understanding of the role of Adipose-derived Extracellular Vesicles in Metabolic Homeostasis and Diseases: Communication from the distance between cells/tissues, Theranostics 10 (16) (2020) 7422-7435.

[35] P. Wu, B. Zhang, D. Ocansey, W. Xu, H. Qian, Extracellular vesicles: A bright star of nanomedicine, Biomaterials 269 (2021) 120467.

[36] C. Crewe, J.B. Funcke, S. Li, N. Joffin, C.M. Gliniak, A.L. Ghaben, Y.A. An, H.A. Sadek, R. Gordillo, Y. Akgul, S. Chen, D. Samovski, P. Fischer-Posovszky, C.M. Kusminski, S. Klein, P.E. Scherer, Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes, Cell Metab. 33 (9) (2021) 1853-1868 e11.

[37] L. Xia, C. Zhang, N. Lv, Z. Liang, T. Ma, H. Cheng, Y. Xia, L. Shi, AdMSC-derived exosomes alleviate acute lung injury via transferring mitochondrial component to improve homeostasis of alveolar macrophages, Theranostics 12 (6) (2022) 2928-2947.

[38] M. Rosina, V. Ceci, R. Turchi, L. Chuan, N. Borcherding, F. Sciarretta, M. Sánchez-Díaz, F. Tortolici, K. Karlinsey, V. Chiurchiù, C. Fuoco, R. Giwa, R.L. Field, M. Audano, S. Arena, A. Palma, F. Riccio, F. Shamsi, G. Renzone, M. Verri, A. Crescenzi, S. Rizza, F. Faienza, G. Filomeni, S. Kooijman, S. Rufini, A. de Vries, A. Scaloni, N. Mitro, Y.H. Tseng, A. Hidalgo, B. Zhou, J.R. Brestoff, K. Aquilano, D. Lettieri-Barbato, Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue, Cell Metab. 34 (4) (2022) 533-548 e12.

[39] Y. Zhang, F. Liang, D. Zhang, S. Qi, Y. Liu, Metabolites as extracellular vesicle cargo in health, cancer, pleural effusion, and cardiovascular diseases: An emerging field of study to diagnostic and therapeutic purposes, Biomed. Pharmacother. 157 (2023) 114046.

[40] R.J. Lobb, L.G. Lima, A. Möller, Exosomes: Key mediators of metastasis and pre-metastatic niche formation, Seminars in cell & developmental biology, Elsevier, 2017.

[41] N. Kosaka, Y. Yoshioka, N. Tominaga, K. Hagiwara, T. Katsuda, T. Ochiya, Dark side of the exosome: the role of the exosome in cancer metastasis and targeting the exosome as a strategy for cancer therapy, Future Oncol. (Lond. Engl.) 10 (4) (2014) 671-681.

[42] M. Adamiak, G. Cheng, S. Bobis-Wozowicz, L. Zhao, S. Kedracka-Krok, A. Samanta, E. Karnas, Y.T. Xuan, B. Skupien-Rabian, X. Chen, U. Jankowska, M. Girgis, M. Sekula, A. Davani, S. Lasota, R.J. Vincent, M. Sarna, K.L. Newell, O.L. Wang, N. Dudley, Z. Madeja, B. Dawn, E.K. Zuba-Surma, Induced pluripotent stem cell (iPSC)-derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs, Circ. Res. 122 (2) (2018) 296-309.

[43] C. Grange, S. Tritta, M. Tapparo, M. Cedrino, C. Tetta, G. Camussi, M.F. Brizzi, Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy, Sci. Rep. 9 (1) (2019) 4468.

[44] S. Arif, S. Larochelle, V.J. Moulin, PLGF-1 contained in normal wound myofibroblast-derived microvesicles stimulated collagen production by dermal fibroblasts, J. Cell Commun. Signal. 14 (4) (2020) 427-438.

[45] S. Srinivasan, F.O. Vannberg, J.B.J.Sr Dixon, Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node, Sci. Rep. 6 (1) (2016) 24436.

[46] J.L. Hood, R.S. San, S.A.J.Cr Wickline, Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis, Cancer Res. 71 (11) (2011) 3792-3801.

[47] A. Becker, B.K. Thakur, J.M. Weiss, H.S. Kim, H. Peinado, D. Lyden, Extracellular vesicles in cancer: cell-to-cell mediators of metastasis, Cancer Cell 30 (6) (2016) 836-848.

[48] N. Kosaka, Y. Yoshioka, Y. Fujita, T. Ochiya, Versatile roles of extracellular vesicles in cancer, J. Clin. Investig. 126 (4) (2016) 1163-1172.

[49] J. Hou, K.X. Chen, C. He, X.X. Li, M. Huang, Y.Z. Jiang, Y.R. Jiao, Q.N. Xiao, W.Z. He, L. Liu, N.Y. Zou, M. Huang, J. Wei, Y. Xiao, M. Yang, X.H. Luo, C. Zeng, G.H. Lei, C.J. Li, Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence, Nat. Aging 4 (11) (2024) 1562-1581.

[50] X. Zhou, B.A. Brown, A.P. Siegel, M.S. El Masry, X. Zeng, W. Song, A. Das, P. Khandelwal, A. Clark, K. Singh, P.R. Guda, M. Gorain, L. Timsina, Y. Xuan, S.C. Jacobson, M.V. Novotny, S. Roy, M. Agarwal, R.J. Lee, C.K. Sen, D.E. Clemmer, S. Ghatak, Exosome-mediated crosstalk between keratinocytes and macrophages in cutaneous wound healing, ACS nano 14 (10) (2020) 12732-12748.

[51] Y. Yuan, F. Gao, Y. Chang, Q. Zhao, X. He, Advances of mRNA vaccine in tumor: a maze of opportunities and challenges, Biomark. Res. 11 (1) (2023) 6.

[52] Z. Iqbal, K. Rehman, A. Mahmood, M. Shabbir, Y. Liang, L. Duan, H. Zeng, Exosome for mRNA delivery: strategies and therapeutic applications, J. nanobiotechnology 22 (1) (2024) 395.

[53] F. Tan, X. Li, Z. Wang, J. Li, K. Shahzad, J. Zheng, Clinical applications of stem cell-derived exosomes, Signal Transduct. Target. Ther. 9 (1) (2024) 17.

[54] A. Turchinovich, O. Drapkina, A.J.Fii Tonevitsky, Transcriptome of extracellular vesicles: state-of-the-art, Front. Immunol. 10 (2019) 202.

[55] F. Felicetti, A. De Feo, C. Coscia, R. Puglisi, F. Pedini, L. Pasquini, M. Bellenghi, M.C. Errico, E. Pagani, A. Carè, Exosome-mediated transfer of miR-222 is sufficient to increase tumor malignancy in melanoma, J. Transl. Med. 14 (1) (2016) 56.

[56] K. Hashimoto, H. Ochi, S. Sunamura, N. Kosaka, Y. Mabuchi, T. Fukuda, K. Yao, H. Kanda, K. Ae, A. Okawa, C. Akazawa, T. Ochiya, M. Futakuchi, S. Takeda, S. Sato, Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A, Proc. Natl. Acad. Sci. USA 115 (9) (2018) 2204-2209.

[57] I. Wortzel, S. Dror, C.M. Kenific, D. Lyden, Exosome-mediated metastasis: communication from a distance, Dev. Cell 49 (3) (2019) 347-360.

[58] C. He, S. Zheng, Y. Luo, B. Wang, Exosome theranostics: biology and translational medicine, Theranostics 8 (1) (2018) 237-255.

[59] S. Gurung, D. Perocheau, L. Touramanidou, J. Baruteau, The exosome journey: from biogenesis to uptake and intracellular signalling, Cell communication signaling CCS 19 (1) (2021) 47.

[60] R. Kalluri, V.S. LeBleu, The biology, function, and biomedical applications of exosomes, Science 367 (6478) (2020).

[61] L. Cheng, A.F.J.N.R.D.D. Hill, Therapeutically harnessing extracellular vesicles, Nat. Rev. Drug Discov. 21 (5) (2022) 379-399.

[62] S. Yang, Y. Sun, C.J.Jo.N. Yan, Recent advances in the use of extracellular vesicles from adipose-derived stem cells for regenerative medical therapeutics, J. nanobiotechnology 22 (1) (2024) 316.

[63] Y. Song, Y. You, X. Xu, J. Lu, X. Huang, J. Zhang, L. Zhu, J. Hu, X. Wu, X. Xu, W. Tan, Y. Du, Adipose-derived mesenchymal stem cell-derived exosomes biopotentiated extracellular matrix hydrogels accelerate diabetic wound healing and skin regeneration, Advanced science (Weinheim BadenWurttemberg Germany) 10 (30) (2023) 2304023.

[64] Z. Zhang, F. Ye, H. Zhang, X. Li, W. Mu, K. Li, B. Yan, Reprogramming Lymphatic Endothelial Glucose Metabolism for the Treatment of Lymphangiogenesis-Related Disease, Pharmacol. Res. 218 (2025) 107827.

[65] A. Łabędź-Masłowska, L. Vergori, S. Kędracka-Krok, E. Karnas, S. Bobis-Wozowicz, M. Sekuła-Stryjewska, M. Sarna, R. Andriantsitohaina, E.K. Zuba-Surma, Mesenchymal stem cell-derived extracellular vesicles exert pro-angiogenic and pro-lymphangiogenic effects in ischemic tissues by transferring various microRNAs and proteins including ITGa5 and NRP1, J. nanobiotechnology 22 (1) (2024) 60.

[66] C.-A. Wang, S.-J.J.E.B. Tsai, and Medicine, Regulation of lymphangiogenesis by extracellular vesicles in cancer metastasis. Exp. Biol. Med. (Maywood N. J.) 246 (19) (2021) 2048-2056.

[67] W. Niu, Q. Xiao, X. Wang, J. Zhu, J. Li, X. Liang, Y. Peng, C. Wu, R. Lu, Y. Pan, J. Luo, X. Zhong, H. He, Z. Rong, J.B. Fan, Y. Wang, A biomimetic drug delivery system by integrating grapefruit extracellular vesicles and doxorubicin-loaded heparin-based nanoparticles for glioma therapy, Nano Lett. 21 (3) (2021) 1484-1492.

[68] Y. Liang, Z. Iqbal, J. Lu, J. Wang, H. Zhang, X. Chen, L. Duan, J. Xia, Cell-derived nanovesicle-mediated drug delivery to the brain: principles and strategies for vesicle engineering, Mol. Ther. 31 (5) (2023) 1207-1224.

[69] Z. Han, S. Liu, Y. Pei, Z. Ding, Y. Li, X. Wang, D. Zhan, S. Xia, T. Driedonks, K.W. Witwer, R.G. Weiss, P. van Zijl, J. Bulte, L. Cheng, G. Liu, Highly efficient magnetic labelling allows MRI tracking of the homing of stem cell-derived extracellular vesicles following systemic delivery, J. Extracell. vesicles 10 (3) (2021) e12054.

[70] S. Kamerkar, V.S. LeBleu, H. Sugimoto, S. Yang, C.F. Ruivo, S.A. Melo, J.J. Lee, R. Kalluri, Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer, Exosomes Facil. Ther. Target. Oncog. KRAS Pancreat. Cancer 546 (7659) (2017) 498-503.

[71] R. Kar, R. Dhar, S. Mukherjee, S. Nag, S. Gorai, N. Mukerjee, D. Mukherjee, R. Vatsa, M. Chandrakanth Jadhav, A. Ghosh, A. Devi, A. Krishnan, N.D. Thorat, Exosome-based smart drug delivery tool for cancer theranostics, ACS Biomater. Sci. Eng. 9 (2) (2023) 577-594.

[72] L. Han, H. He, Y. Yang, Q. Meng, F. Ye, G. Chen, J. Zhang, Distinctive clinical and pathologic features of immature teratomas arising from induced pluripotent stem cell-derived beta cell injection in a diabetes patient, Stem Cells Dev. 31 (5-6) (2022) 97-101.

[73] S. Song, J. Fan, G. Ding, J. Yin, W. Lu, L. Huang, J. Hu, X. Gong, B. Gao, Q. Jie, K. Cheah, C. Zheng, L. Yang, Descendants of hypertrophic chondrocytes promote angiogenesis by secreting THBS4 during bone growth and injury repair, Bone Res. 13 (1) (2025) 92.

[74] E. Huethorst, M.M. Krebber, J.O. Fledderus, H. Gremmels, Y.J. Xu, J. Pei, M.C. Verhaar, C. Cheng, Lymphatic vascular regeneration: The next step in tissue engineering, Tissue Eng. Part B Rev. 22 (1) (2016) 1-14.

[75] K.J.N. Alitalo, m., The lymphatic vasculature in disease. Nat. Med. 17 (11) (2011) 1371-1380.

[76] M.E. Baldwin, M.M. Halford, S. Roufail, R.A. Williams, M.L. Hibbs, D. Grail, H. Kubo, S.A. Stacker, M.G. Achen, Vascular endothelial growth factor D is dispensable for development of the lymphatic system, Mol. Cell. Biol. 25 (6) (2005) 2441-2449.

[77] S.A. Stacker, C. Caesar, M.E. Baldwin, G.E. Thornton, R.A. Williams, R. Prevo, D.G. Jackson, S. Nishikawa, H. Kubo, M.G. Achen, VEGF-D promotes the metastatic spread of tumor cells via the lymphatics, Nat. Med. 7 (2) (2001) 186-191.

[78] T. Karnezis, R. Shayan, C. Caesar, S. Roufail, N.C. Harris, K. Ardipradja, Y.F. Zhang, S.P. Williams, R.H. Farnsworth, M.G. Chai, T.W. Rupasinghe, D.L. Tull, M.E. Baldwin, E.K. Sloan, S.B. Fox, M.G. Achen, S.A. Stacker, VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium, Cancer Cell 21 (2) (2012) 181-195.

[79] T. Mäkinen, et al., Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3, EMBO. J. 20 (17) (2001) 4762-4773.

[80] Y.Z. Tan, et al., CD34+ VEGFR-3+ progenitor cells have a potential to differentiate towards lymphatic endothelial cells, J. Cell. Mol. Med. 18 (3) (2014) 422-433.

[81] H. Suzuki, T. Watabe, M. Kato, K. Miyazawa, K. Miyazono, Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells, Blood 105 (6) (2005) 2372-2379.

[82] H. Saijo, K. Suzuki, H. Yoshimoto, Y. Imamura, S. Yamashita, K. Tanaka, Paracrine effects of adipose-derived stem cells promote lymphangiogenesis in irradiated lymphatic endothelial cells, Plast. Reconstr. Surg. 143 (6) (2019) 1189e-1200e.

[83] M. Lohela, M. Bry, T. Tammela, K. Alitalo, VEGFs and receptors involved in angiogenesis versus lymphangiogenesis, Curr. Opin. Cell Biol. 21 (2) (2009) 154-165.

[84] V.-M. Leppänen, D. Tvorogov, K. Kisko, A.E. Prota, M. Jeltsch, A. Anisimov, S. Markovic-Mueller, E. Stuttfeld, K.N. Goldie, K. Ballmer-Hofer, K. Alitalo, Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation, Proc. Natl. Acad. Sci. USA 110 (32) (2013) 12960-12965.

[85] A. Salameh, F. Galvagni, M. Bardelli, F. Bussolino, S. Oliviero, Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways, Blood 106 (10) (2005) 3423-3431.

[86] Y.K. Hong, B. Lange-Asschenfeldt, P. Velasco, S. Hirakawa, R. Kunstfeld, L.F. Brown, P. Bohlen, D.R. Senger, M. Detmar, VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the α1β1 and α2β1 integrins, FASEB. J. 18 (10) (2004) 1111-1113.

[87] S. Coso, Y. Zeng, K. Opeskin, E.D. Williams, Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis, PloS One 7 (6) (2012) e39558.

[88] K.G. Kuonqui, A.C. Campbell, B.L. Pollack, J. Shin, A. Sarker, S. Brown, H.J. Park, B.J. Mehrara, R.P. Kataru, Regulation of VEGFR3 signaling in lymphatic endothelial cells, Front. Cell Dev. Biol. 13 (2025) 1527971.

[89] Y.S. Wang, Y. Wang, X.Y. Wang, et al., Biodegradable and electroactive cryogel microspheres for neurovascularized bone regeneration, Matter. 8 (9) (2025) 102366.

[90] K. Li, S. Hu, H. Li, W. Lin, D. Zhao, Z. Xu, C. Pan, H. Wang, D. Li, J. Liu, H. Chen, Regenerating aged bone marrow via a nitric oxide nanopump, Nat. Commun. 16 (1) (2025) 5677.

[91] L. Yuan, D. Moyon, L. Pardanaud, C. Bréant, M.J. Karkkainen, K. Alitalo, A. Eichmann, Abnormal lymphatic vessel development in neuropilin 2 mutant mice, Development 129 (2002) 4797-4806.

[92] T. Kärpänen, C.A. Heckman, S. Keskitalo, M. Jeltsch, H. Ollila, G. Neufeld, L. Tamagnone, K. Alitalo, Functional interaction of VEGF-C and VEGF-D with neuropilin receptors, FASEB J. 20 (9) (2006) 1462-1472.

[93] Y. Xu, L. Yuan, J. Mak, L. Pardanaud, M. Caunt, I. Kasman, B. Larrivée, R. Del Toro, S. Suchting, A. Medvinsky, J. Silva, J. Yang, J.L. Thomas, A.W. Koch, K. Alitalo, A. Eichmann, A. Bagri, Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3, J. Cell Biol. 188 (1) (2010) 115-130.

[94] A. Kaipainen, J. Korhonen, T. Mustonen, V.W. van Hinsbergh, G.H. Fang, D. Dumont, M. Breitman, K. Alitalo, Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development, Proc. Natl. Acad. Sci. USA 92 (8) (1995) 3566-3570.

[95] M.J. Karkkainen, A. Saaristo, L. Jussila, K.A. Karila, E.C. Lawrence, K. Pajusola, H. Bueler, A. Eichmann, R. Kauppinen, M.I. Kettunen, S. Yla-Herttuala, D.N. Finegold, R.E. Ferrell, K. Alitalo, A model for gene therapy of human hereditary lymphedema, Proc. Natl. Acad. Sci. USA 98 (22) (2001) 12677-12682.

[96] I. Kim, Y.S. Ryu, H.J. Kwak, S.Y. Ahn, J.L. Oh, G.D. Yancopoulos, N.W. Gale, G.Y. Koh, EphB ligand, ephrinB2, suppresses the VEGF-and angiopoietin-1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells, FASEB. J. 16 (9) (2002) 1126-1128.

[97] Z. Xiao, R. Carrasco, K. Kinneer, D. Sabol, B. Jallal, S. Coats, D.A. Tice, EphB4 promotes or suppresses Ras/MEK/ERK pathway in a context-dependent manner: Implications for EphB4 as a cancer target, Cancer Biol. Ther. 13 (8) (2012) 630-637.

[98] Y. Wang, et al., Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis, Nature 465 (7297) (2010) 483-486.

[99] K. Kuonqui, A.C. Campbell, A. Sarker, A. Roberts, B.L. Pollack, H.J. Park, J. Shin, S. Brown, B.J. Mehrara, R.P. Kataru, Dysregulation of lymphatic endothelial VEGFR3 signaling in disease, Cells 13 (1) (2023) 68.

[100] J. Murakami, M. Ishii, F. Suehiro, K. Ishihata, N. Nakamura, M. Nishimura, Vascular endothelial growth factor-C induces osteogenic differentiation of human mesenchymal stem cells through the ERK and RUNX2 pathway, Biochem. Biophys. Res. Commun. 484 (3) (2017) 710-718.

[101] V.-M. Leppänen, P. Brouillard, E.A. Korhonen, T. Sipilä, S.K. Jha, N. Revencu, V. Labarque, E. Fastré, M. Schlögel, M. Ravoet, A. Singer, C. Luzzatto, D. Angelone, G. Crichiutti, A. D'Elia, J. Kuurne, H. Elamaa, G.Y. Koh, P. Saharinen, M. Vikkula, K. Alitalo, Characterization of ANGPT2 mutations associated with primary lymphedema, Sci. Transl. Med. 12 (560) (2020) eaax8013.

[102] E.A. Korhonen, A. Murtomäki, S.K. Jha, A. Anisimov, A. Pink, Y. Zhang, S. Stritt, I. Liaqat, L. Stanczuk, L. Alderfer, Z. Sun, E. Kapiainen, A. Singh, I. Sultan, A. Lantta, V.M. Leppänen, L. Eklund, Y. He, H.G. Augustin, K. Vaahtomeri, P. Saharinen, T. Mäkinen, K. Alitalo, Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression, J. Clin. Investig. 132 (15) (2022).

[103] P. Schulz, C. Fischer, K.M. Detjen, S. Rieke, G. Hilfenhaus, Z. von Marschall, M. Böhmig, I. Koch, J. Kehrberger, P. Hauff, K.H. Thierauch, F. Alves, B. Wiedenmann, A. Scholz, Angiopoietin-2 drives lymphatic metastasis of pancreatic cancer, FASEB. J. 25 (10) (2011) 3325-3335.

[104] E. Fagiani, P. Lorentz, L. Kopfstein, G. Christofori, Angiopoietin-1 and-2 exert antagonistic functions in tumor angiogenesis, yet both induce lymphangiogenesis, Cancer Res. 71 (17) (2011) 5717-5727.

[105] Z. Cao, C. Zhao, L. Hu, F. Peng, Z. Liu, X. Yang, J. Pan, Biomaterial-Based Lymphangiogenesis-Enhanced Therapeutic Strategy for Robustly-Integrated Medication-Related Osteonecrosis of Jaw Prevention, ACS Appl. Mater. Interfaces 17 (2025) 36315-36333.

[106] H. Kubo, R. Cao, E. Brakenhielm, T. Mäkinen, Y. Cao, K. Alitalo, Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea, Proc. Natl. Acad. Sci. USA 99 (13) (2002) 8868-8873.

[107] L.K. Chang, G. Garcia-Cardeña, F. Farnebo, M. Fannon, E.J. Chen, C. Butterfield, M.A. Moses, R.C. Mulligan, J. Folkman, A. Kaipainen, Dose-dependent response of FGF-2 for lymphangiogenesis, Proc. Natl. Acad. Sci. USA 101 (32) (2004) 11658-11663.

[108] S. Dias, M. Choy, K. Alitalo, S. Rafii, Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy, Blood 99 (6) (2002) 2179-2184.

[109] R. Cao, H. Ji, N. Feng, Y. Zhang, X. Yang, P. Andersson, Y. Sun, K. Tritsaris, A.J. Hansen, S. Dissing, Y. Cao, Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis, Proc. Natl. Acad. Sci. USA 109 (39) (2012) 15894-15899.

[110] I. Choi, S. Lee, H. Kyoung Chung, Y. Suk Lee, K. Eui Kim, D. Choi, E.K. Park, D. Yang, T. Ecoiffier, J. Monahan, W. Chen, B. Aguilar, H.N. Lee, J. Yoo, C.J. Koh, L. Chen, A.K. Wong, Y.K. Hong, 9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema, Circulation 125 (7) (2012) 872-882.

[111] R. Cao, M.A. Björndahl, P. Religa, S. Clasper, S. Garvin, D. Galter, B. Meister, F. Ikomi, K. Tritsaris, S. Dissing, T. Ohhashi, D.G. Jackson, Y. Cao, PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis, Cancer Cell 6 (4) (2004) 333-345.

[112] M. Kodama, Y. Kitadai, T. Sumida, M. Ohnishi, E. Ohara, M. Tanaka, K. Shinagawa, S. Tanaka, W. Yasui, K. Chayama, Expression of platelet-derived growth factor (PDGF)-B and PDGF-receptor β is associated with lymphatic metastasis in human gastric carcinoma, Cancer Sci. 101 (9) (2010) 1984-1989.

[113] J. Cassuto, A. Folestad, J. Göthlin, H. Malchau, J. Kärrholm, VEGF-A,-C,-D, VEGFR1,-2,-3, PDGF-BB and FGF-2 join forces to induce vascular and lymphatic angiogenesis during bone healing of hip implants, Bone Rep. 26 (2025) 101856.

[114] L. Zhang, J. Yuan, D. Kofi Wiredu Ocansey, B. Lu, A. Wan, X. Chen, X. Zhang, W. Qiu, F. Mao, Exosomes derived from human umbilical cord mesenchymal stem cells regulate lymphangiogenesis via the miR-302d-3p/VEGFR3/AKT axis to ameliorate inflammatory bowel disease, Int. Immunopharmacol. 110 (2022) 109066.

[115] C.-F. Zhou, J. Ma, L. Huang, H.Y. Yi, Y.M. Zhang, X.G. Wu, R.M. Yan, L. Liang, M. Zhong, Y.H. Yu, S. Wu, W. Wang, Cervical squamous cell carcinoma-secreted exosomal miR-221-3p promotes lymphangiogenesis and lymphatic metastasis by targeting VASH1, Oncogene 38 (8) (2019) 1256-1268.

[116] C. Chen, C. Yang, X. Tian, Y. Liang, S. Wang, X. Wang, Y. Shou, H. Li, Q. Xiao, J. Shu, M. Sun, K. Chen, Downregulation of miR-100-5p in cancer-associated fibroblast-derived exosomes facilitates lymphangiogenesis in esophageal squamous cell carcinoma, Cancer Med. 12 (13) (2023) 14468-14483.

[117] C. Chen, H. Zheng, Y. Luo, Y. Kong, M. An, Y. Li, W. He, B. Gao, Y. Zhao, H. Huang, J. Huang, T. Lin, SUMOylation promotes extracellular vesicle-mediated transmission of lncRNA ELNAT1 and lymph node metastasis in bladder cancer, J. Clin. Investig. 131 (8) (2021).

[118] C. Chen, Y. Luo, W. He, Y. Zhao, Y. Kong, H. Liu, G. Zhong, Y. Li, J. Li, J. Huang, R. Chen, T. Lin, Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer, J. Clin. Investig. 130 (1) (2020) 404-421.

[119] Y. Luo, Z. Li, Y. Kong, W. He, H. Zheng, M. An, Y. Lin, D. Zhang, J. Yang, Y. Zhao, C. Chen, R. Chen, KRAS mutant-driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer, J. Clin. Investig. 132 (14) (2022).

[120] S.H. Wang, G.G. Liou, S.H. Liu, J.S. Chang, J.R. Hsiao, Y.C. Yen, Y.L. Chen, W.L. Wu, J.Y. Chang, Y.W. Chen, Laminin γ2-enriched extracellular vesicles of oral squamous cell carcinoma cells enhance in vitro lymphangiogenesis via integrin α3-dependent uptake by lymphatic endothelial cells, Int. J. Cancer 144 (11) (2019) 2795-2810.

[121] C.-A. Wang, I.H. Chang, P.C. Hou, Y.J. Tai, W.N. Li, P.L. Hsu, S.R. Wu, W.T. Chiu, C.F. Li, Y.S. Shan, S.J. Tsai, DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination, J. Extracell. vesicles 9 (1) (2020) 1746529.

[122] W.-N. Li, K.Y. Hsiao, C.A. Wang, N. Chang, P.L. Hsu, C.H. Sun, S.R. Wu, M.H. Wu, S.J. Tsai, Extracellular vesicle-associated VEGF-C promotes lymphangiogenesis and immune cells infiltration in endometriosis, Proc. Natl. Acad. Sci. USA 117 (41) (2020) 25859-25868.

[123] K. Lu, The Significance of Ang-2 Expression in Cutaneous Squamous Cell Carcinoma and Mechanism of its Regulation on Lymphangiogenesis via Exosomes. Jiangsu University. 2023. DOI: 10.27170/d.cnki.gjsuu.2023.001693.

[124] Y. Shi, X. Yang, X. Xue, D. Sun, P. Cai, Q. Song, B. Zhang, L. Qin, HANR promotes lymphangiogenesis of hepatocellular carcinoma via secreting miR-296 exosome and regulating EAG1/VEGFA signaling in HDLEC cells, J. Cell. Biochem. 120 (10) (2019) 17699-17708.

[125] X. Wang, G. Luo, K. Zhang, J. Cao, C. Huang, T. Jiang, B. Liu, L. Su, Z. Qiu, Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis, Cancer Res. 78 (16) (2018) 4586-4598.

[126] S. García-Silva, A. Benito-Martín, L. Nogués, A. Hernández-Barranco, M.S. Mazariegos, V. Santos, M. Hergueta-Redondo, P. Ximénez-Embún, R.P. Kataru, A.A. Lopez, C. Merino, S. Sánchez-Redondo, O. Graña-Castro, I. Matei, J.Á. Nicolás-Avila, R. Torres-Ruiz, S. Rodríguez-Perales, L. Martínez, M. Pérez-Martínez, G. Mata, A. Szumera-Ciećkiewicz, I. Kalinowska, A. Saltari, J.M. Martínez-Gómez, S.A. Hogan, H.U. Saragovi, S. Ortega, C. Garcia-Martin, J. Boskovic, M.P. Levesque, P. Rutkowski, A. Hidalgo, J. Muñoz, D. Megías, B.J. Mehrara, D. Lyden, H. Peinado, Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism, Nat. Cancer 2 (12) (2021) 1387-1405.

[127] N. Leary, S. Walser, Y. He, N. Cousin, P. Pereira, A. Gallo, V. Collado-Diaz, C. Halin, S. Garcia-Silva, H. Peinado, L.C. Dieterich, Melanoma-derived extracellular vesicles mediate lymphatic remodelling and impair tumour immunity in draining lymph nodes, J. Extracell. vesicles 11 (2) (2022) e12197.

[128] W. Ju, significance of foxc2 expression in cutaneous malignant melanoma and its mechanism of regulating lymphangiogenesis through exosomes pathway. Jiangsu University. 2023. DOI: 10.27170/d.cnki.gjsuu.2023.001689.

[129] C. Lu, et al., Small extracellular vesicles derived from Helicobacter pylori-infected gastric cancer cells induce lymphangiogenesis and lymphatic remodeling via transfer of miR-1246, Small. 20 (13) (2024) 2308688.

[130] T. Kuang, et al., Effect of exosomal miR-217 on lymphangiogenesis of cervical cancer cells (Siha) by down-regulating E-cadherin protein, J. Hunan Norm. Univ. (Medical Sciences) 18 (3) (2021) 1-4.

[131] T. He, W. Tao, J. Zhang, T.L. Xia, B. Xu, L.Y. Li, Extracellular vesicle-mediated transmission of circPDLIM5 promotes lymphatic metastasis in prostate cancer, Journal experimental clinical cancer research CR 44 (1) (2025) 188.

[132] X. Song, J. Xiao, X. Ai, Y. Li, L. Sun, L. Chen, An injectable thermosensitive hydrogel delivering M2 macrophage-derived exosomes alleviates osteoarthritis by promoting synovial lymphangiogenesis, Acta Biomater. 189 (2024) 130-142.

[133] S. Arif, M. Richer, S. Larochelle, V.J. Moulin, Microvesicles derived from dermal myofibroblasts modify the integrity of the blood and lymphatic barriers using distinct endocytosis pathways, J. Extracell. Biol. 3 (5) (2024) e151.

[134] G.V. Niel, G. DʹAngelo, G. Raposo . Shedding light on the cell biology of extracellular vesicles, Nat. Rev. Mol. Cell. Biol. 19 (4) (2018) 213-228.

[135] Y. Matsuzaka, R.J.I.Jo.M.S. Yashiro, Therapeutic strategy of mesenchymal-stem-cell-derived extracellular vesicles as regenerative medicine, Int. J. Mol. Sci. 23 (12) (2022) 6480.

[136] W. Chen, F. Lin, X. Feng, Q. Yao, Y. Yu, F. Gao, J. Zhou, Q. Pan, J. Wu, J. Yang, J. Yu, H. Cao, L. Li, MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation, Asian J. Pharm. Sci. 19 (1) (2024) 100889.

[137] Z.-J. Li, E. Yang, Y.Z. Li, Z.Y. Liang, J.Z. Huang, N.Z. Yu, X. Long, Application and prospect of adipose stem cell transplantation in treating lymphedema, World J. stem Cells 12 (7) (2020) 676-687.

[138] H. Zheng, C. Chen, Y. Luo, M. Yu, W. He, M. An, B. Gao, Y. Kong, Y. Ya, Y. Lin, Y. Li, K. Xie, J. Huang, T. Lin, Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer, Clin. Transl. Med. 11 (7) (2021) e497.

[139] W. Yao, X. Jia, L. Zhu, L. Xu, Q. Zhang, T. Xia, L. Wei, Exosomal circ_0026611 contributes to lymphangiogenesis by reducing PROX1 acetylation and ubiquitination in human lymphatic endothelial cells (HLECs), Cell. Mol. Biol. Lett. 28 (1) (2023) 13.

[140] L. Zhang, C. Ye, P. Li, C. Li, W. Shu, Y. Zhao, X. Wang, ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κ B pathway by the secretome, Stem Cell Res. Ther. 13 (1) (2022) 448.

[141] Q. Ma, Q. Fan, J. Xu, J. Bai, X. Han, Z. Dong, X. Zhou, Z. Liu, Z. Gu, C. Wang, Calming cytokine storm in pneumonia by targeted delivery of TPCA-1 using platelet-derived extracellular vesicles, Matter 3 (1) (2020) 287-301.

[142] S. Schwager, M.J.Fii Detmar, Inflammation and lymphatic function, Front. Immunol. 10 (2019) 308.

[143] L. Vachon, G. Jean, A. Milasan, S. Babran, E. Lacroix, D. Guadarrama Bello, L. Villeneuve, J. Rak, A. Nanci, T. Mihalache-Avram, J.C. Tardif, V. Finnerty, M. Ruiz, E. Boilard, N. Tessier, C. Martel, Platelet extracellular vesicles preserve lymphatic endothelial cell integrity and enhance lymphatic vessel function, Commun. Biol. 7 (1) (2024) 975.

[144] C. Zhou, Y. Zhang, R. Yan, L. Huang, A.L. Mellor, Y. Yang, X. Chen, W. Wei, X. Wu, L. Yu, L. Liang, D. Zhang, S. Wu, W. Wang, Exosome-derived miR-142-5p remodels lymphatic vessels and induces IDO to promote immune privilege in the tumour microenvironment, Cell death Differ. 28 (2) (2021) 715-729.

[145] Z. Wu, S. Guo, H. Yue, H. Huang, Z. Zhang, X. Chen, C. Lan, L. Ren, P. Hei, X. Wang, N. Wang, X. Li, Effect of M2-macrophage treated lymphatic endothelial cells on angiogenesis that promoted osteointegration, Exp. Cell Res. 439 (1) (2024) 114096.

[146] L. Ducoli, M.J.D.C. Detmar, Beyond PROX1: transcriptional, epigenetic, and non-coding RNA regulation of lymphatic identity and function, Dev. Cell 56 (4) (2021) 406-426.

[147] R. Pirlog, G.A.J.T.Jo.C.I. Calin, KRAS mutations as essential promoters of lymphangiogenesis via extracellular vesicles in pancreatic cancer, J. Clin. Investig. 132 (14) (2022).

[148] K.G. Zhu, J. Yang, Y. Zhu, Q. Zhu, W. Pan, S. Deng, Y. He, D. Zuo, P. Wang, Y. Han, H.Y. Zhang, The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism, Cell Death Dis. 14 (2023) 708.

[149] Y. Cui, Z.J.Po Liu, AKR1C2 silencing promotes ferroptosis and inhibits proliferation, migration, and invasion in lung cancer cells, PloS One 20 (6) (2025) e0325995.

[150] Y. Yang, X.Q. Chen, Y.X. Jia, J. Ma, D. Xu, Z.L. Xiang, Circ-0044539 promotes lymph node metastasis of hepatocellular carcinoma through exosomal-miR-29a-3p, Cell death Dis. 15 (8) (2024) 630.

[151] N. Odehnalová, V. Šandriková, R. Hromadka, M. Skaličková, P. Dytrych, D. Hoskovec, Z. Kejík, J. Hajduch, F. Vellieux, M.K. Vašáková, P. Martásek, M. Jakubek, The potential of exosomes in regenerative medicine and in the diagnosis and therapies of neurodegenerative diseases and cancer, Front. Med. 12 (2025) 1539714.

[152] J.N. Cormier, R.L. Askew, K.S. Mungovan, Y. Xing, M.I. Ross, J.M. Armer, Lymphedema beyond breast cancer: A systematic review and meta-analysis of cancer-related secondary lymphedema, Cancer 116 (22) (2010) 5138-5149.

[153] S.G. Rockson, K.K.J.AotN.Y.Ao.S. Rivera, Estimating the population burden of lymphedema, Ann. N. Y. Acad. Sci. 1131 (1) (2008) 147-154.

[154] H. Schulze, M. Nacke, C. Gutenbrunner, C. Hadamitzky, Worldwide assessment of healthcare personnel dealing with lymphoedema, Health Econ. Rev. 8 (1) (2018) 10.

[155] Y. Saito, et al., Lymphedema and therapeutic lymphangiogenesis, Biomed. Res. Int. 2013 (1) (2013) 804675.

[156] J.A. Petrek, M.C.J.C.I.I.JotA.C.S. Heelan, Incidence of breast carcinoma-related lymphedema, Cancer 83 (S12B) (1998) 2776-2781.

[157] J.A. Petrek, R.T. Senie, M. Peters, P.P. Rosen, Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis, Cancer 92 (6) (2001) 1368-1377.

[158] G.E. Naoum, S. Roberts, C.L. Brunelle, A.M. Shui, L. Salama, K. Daniell, T. Gillespie, L. Bucci, B.L. Smith, A.Y. Ho, A.G. Taghian, Quantifying the impact of axillary surgery and nodal irradiation on breast cancer-related lymphedema and local tumor control: long-term results from a prospective screening trial, J. Clin. Oncol. 38 (29) (2020) 3430-3438.

[159] T. DiSipio, S. Rye, B. Newman, S. Hayes, Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis, Lancet Oncol. 14 (6) (2013) 500-515.

[160] W. Fu, T. Li, H. Chen, S. Zhu, C. Zhou, Research progress in exosome-based nanoscale drug carriers in tumor therapies, Front. Oncol. 12 (2022) 919279.

[161] K. Zhou, Z.Z. Li, Z.M. Cai, N.N. Zhong, L.M. Cao, F.Y. Huo, B. Liu, Q.J. Wu, L.L. Bu, Nanotheranostics in cancer lymph node metastasis: the long road ahead, Pharmacol. Res. 198 (2023) 106989.

[162] Y. Li, H. Zheng, Y. Luo, Y. Lin, M. An, Y. Kong, Y. Zhao, Y. Yin, L. Ai, J. Huang, C. Chen, An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis, Cancer communications (London England) 43 (12) (2023) 1289-1311.

[163] X. Diao, C. Guo, H. Zheng, K. Zhao, Y. Luo, M. An, Y. Lin, J. Chen, Y. Li, Y. Li, X. Gao, J. Zhang, M. Zhou, W. Bai, L. Liu, G. Wang, L. Zhang, X. He, R. Zhang, Z. Li, C. Chen, S. Li, SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer, Signal Transduct. Target. Ther. 8 (1) (2023) 426.

[164] B. Ye, Y. Duan, M. Zhou, Y. Wang, Q. Lai, K. Yue, J. Cao, Y. Wu, X. Wang, C. Jing, Hypoxic tumor-derived exosomal miR-21 induces cancer-associated fibroblast activation to promote head and neck squamous cell carcinoma metastasis, Cell. Signal. 108 (2023) 110725.

[165] C. Lou, X. Ma, Z. Chen, Y. Zhao, Q. Yao, C. Zhou, X. Zhao, X. Meng, The mtDNA fragments within exosomes might be novel diagnostic biomarkers of non-small cell lung cancer, Pathol. Res. Pract. 249 (2023) 154718.

[166] K. Miyazaki, Y. Wada, K. Okuno, T. Murano, Y. Morine, T. Ikemoto, Y. Saito, H. Ikematsu, Y. Kinugasa, M. Shimada, A. Goel, An exosome-based liquid biopsy signature for pre-operative identification of lymph node metastasis in patients with pathological high-risk T1 colorectal cancer, Mol. Cancer 22 (1) (2023) 2.

[167] L. Dai, W. Hu, H. Jiang, Y. Wang, Q. Le, X. Wu, X. Meng, The diagnostic potential of two exosome-derived circRNAs for papillary thyroid cancer, Int. J. Clin. Oncol. 28 (11) (2023) 1461-1474.

[168] P. Fayyazpour, A. Fayyazpour, K. Abbasi, Y. Vaez-Gharamaleki, M.S. Zangbar, M. Raeisi, A. Mehdizadeh, The role of exosomes in cancer biology by shedding light on their lipid contents, Pathol. Res. Pract. 250 (2023) 154813.

[169] X. Luo, C. Cheng, Z. Tan, N. Li, M. Tang, L. Yang, Y. Cao, Emerging roles of lipid metabolism in cancer metastasis, Mol. Cancer 16 (1) (2017) 76.

[170] X. Luo, X. Zhao, C. Cheng, N. Li, Y. Liu, Y. Cao, The implications of signaling lipids in cancer metastasis, Exp. Mol. Med. 50 (9) (2018) 1-10.

[171] S. Beloribi-Djefaflia, C. Siret, D.J.O. Lombardo, Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR4-SDF-1α signaling axis, Oncoscience 2 (1) (2014) 15-30.

[172] F. Ahmed, H.W. Zafar, A. Buture, M. Khalil, Does analgesic overuse matter? Response to OnabotulinumtoxinA in patients with chronic migraine with or without medication overuse, Springerplus 4 (2015) 589.

[173] J.H. Dayan, C.L. Ly, R.P. Kataru, B.J. Mehrara, Lymphedema: pathogenesis and novel therapies, Annu. Rev. Med. 69 (2018) 263-276.

[174] Y. Zheng, P. Wang, L. Zhao, L. Xing, H. Xu, N. Li, Y. Zhao, Q. Shi, Q. Liang, Y. Wang, A novel therapy for fracture healing by increasing lymphatic drainage, J. Orthop. Transl. 45 (2024) 66-74.

[175] R. Ogino, T. Yokooji, M. Hayashida, S. Suda, S. Yamakawa, K. Hayashida, Emerging anti-inflammatory pharmacotherapy and cell-based therapy for lymphedema, Int. J. Mol. Sci. 23 (14) (2022) 7614.

[176] Shi, Y., et al., Vascular and Lymphatic Dysregulation via Non-EndoMT Col2a1 Signaling in Bisphosphonate-Related Osteonecrosis of the Jaw, bioRxiv 2025.09.27. 678999.

[177] X. Ge, F. Zeng, Q. Chen, Z. Zhao, H. Xie, G. Wu, E. Yan, Y. Shi, S. Homaeigohar, H. Jiang, W. Fan, Q. Chen, K. Zheng, R. Xu, Inflammation-responsive biodegradable nanocomposite hydrogels for enhanced metalloimmunotherapy in chronic periodontitis, Acta Biomater. 208 (2025) 293-308.

[178] M. Sano, S. Hirakawa, T. Sasaki, K. Inuzuka, K. Katahashi, T. Kayama, Y. Yamanaka, H. Tsuyuki, Y. Endo, E. Naruse, Y. Yokoyama, K. Sato, K. Yamauchi, H. Takeuchi, N. Unno, Role of subcutaneous adipose tissues in the pathophysiology of secondary lymphedema, Lymphat. Res. Biol. 20 (6) (2022) 593-599.

[179] J.W. Breslin, et al., Lymphatic vessel network structure and physiology, Compr. Physiol. 9 (1) (2019) 207-299.

[180] L. Ozdowski and V. Gupta, Physiology, Lymphatic system. 2023.

[181] C. Bowman, S.G.J.Ijoms Rockson, The role of inflammation in lymphedema: a narrative review of pathogenesis and opportunities for therapeutic intervention, Int. J. Mol. Sci. 25 (7) (2024) 3907.

[182] X. Jiang, M.R. Nicolls, W. Tian, S.G. Rockson, Lymphatic dysfunction, leukotrienes, and lymphedema, Annu. Rev. Physiol. 80 (1) (2018) 49-70.

[183] W. Tian, S.G. Rockson, X. Jiang, J. Kim, A. Begaye, E.M. Shuffle, A.B. Tu, M. Cribb, Z. Nepiyushchikh, A.H. Feroze, R.T. Zamanian, G.S. Dhillon, N.F. Voelkel, M. Peters-Golden, J. Kitajewski, J.B. Dixon, M.R. Nicolls, Leukotriene B4 antagonism ameliorates experimental lymphedema, Sci. Transl. Med. 9 (389) (2017) eaal3920.

[184] Y. Chen, et al., The pro-inffammatory cytokine TNF- α inhibits lymphatic pumping via activation of the NF- κ B-iNOS signaling pathway, Microcirculation 24 (3) (2017) e12364.

[185] Y. Jian, Y. Li, Y. Zhang, M. Tang, M. Deng, C. Liu, M. Cheng, S. Xiao, C. Deng, Z. Wei, Lymphangiogenesis: novel strategies to promote cutaneous wound healing, Burns Trauma 12 (2024) tkae040.

[186] I. Martínez-Corral, D. Olmeda, R. Diéguez-Hurtado, T. Tammela, K. Alitalo, S. Ortega, vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis, Proc. Natl. Acad. Sci. USA 109 (16) (2012) 6223-6228.

[187] A. Bianchi, K.J. Painter, J.A.J.Bomb Sherratt, Spatio-temporal models of lymphangiogenesis in wound healing, Bull. Math. Biol. 78 (9) (2016) 1904-1941.

[188] J. Song, W. Chen, X. Cui, Z. Huang, D. Wen, Y. Yang, W. Yu, L. Cui, C.Y. Liu, CCBE1 promotes tumor lymphangiogenesis and is negatively regulated by TGFβ signaling in colorectal cancer, Theranostics 10 (5) (2020) 2327-2341.

[189] J. Zhu, Y. Luo, Y. Zhao, Y. Kong, H. Zheng, Y. Li, B. Gao, L. Ai, H. Huang, J. Huang, Z. Li, C. Chen, circEHBP1 promotes lymphangiogenesis and lymphatic metastasis of bladder cancer via miR-130a-3p/TGFβR1/VEGF-D signaling, Mol. Ther. 29 (5) (2021) 1838-1852.

[190] F. Renò, M.J.B. Sabbatini, Breaking a vicious circle: lymphangiogenesis as a new therapeutic target in wound healing, Biomedicines 11 (3) (2023) 656.

[191] K. Alitalo and P. Carmeliet, Molecular mechanisms of lymphangiogenesis in health and disease, Cancer. Cell. 1 (3) (2002) 219-227.

[192] A. Saaristo, T. Tammela, A. Farkkilā, M. Kärkkäinen, E. Suominen, S. Yla-Herttuala, K. Alitalo, Vascular endothelial growth factor-C accelerates diabetic wound healing, Am. J. Pathol. 169 (3) (2006) 1080-1087.

[193] C. Wetzler, H. Kämpfer, B. Stallmeyer, J. Pfeilschifter, S. Frank, Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair, J. Invest. Dermatol. 115 (2) (2000) 245-253.

[194] J.P. Scallan, M.A. Hill, M.J.J.Cr Davis, Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling, Cardiovasc. Res. 107 (1) (2015) 89-97.

[195] V. Falanga, Classifications for wound bed preparation and stimulation of chronic wounds, Wound. Repair. Regen. 8 (5) (2000) 347-352.

[196] N. Kumar, P. Saraber, Z. Ding, A.P. Kusumbe, Diversity of vascular niches in bones and joints during homeostasis, ageing, and diseases, Front. Immunol. 12 (2021) 798211.

[197] L.M. Brunner, Y. He, N. Cousin, J. Scholl, L.K. Albin, B. Schmucki, S. Supersaxo, G. Restivo, J. Hafner, D. Neri, S. Werner, M. Detmar, Promotion of lymphangiogenesis by targeted delivery of VEGF-C improves diabetic wound healing, Cells 12 (3) (2023) 472.

[198] A. Virtej, L. Marti, M. Wagner, H. Wiig, Y. Xue, A. Bletsa, E. Berggreen, Contribution of initial lymphatics to oral wound healing after tooth extraction, Eur. J. Oral. Sci. 132 (4) (2024) e13006.

[199] S. Schwager, M. Detmar, Inflammation and lymphatic function, Front Immunol. 10 (2019) 308.

[200] H.-K. Lee, S.-M. Lee, D.-I.J.I.Jo.M.S. Lee, Corneal lymphangiogenesis: current pathophysiological understandings and its functional role in ocular surface disease, Int. J. Mol. Sci. 22 (21) (2021) 11628.

[201] J. Zhou, T. Wei, Z.J.M.M. He, ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers, Mol. Med. (Camb. Mass.) 27 (1) (2021) 146.

[202] A. Villa, E. Trachsel, M. Kaspar, C. Schliemann, R. Sommavilla, J.N. Rybak, C. Rösli, L. Borsi, D. Neri, A high-affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently targets tumor neo-vasculature in vivo, Int. J. Cancer 122 (11) (2008) 2405-2413.

[203] S. Schwager, S. Renner, T. Hemmerle, S. Karaman, S.T. Proulx, R. Fetz, A.M. Golding-Ochsenbein, P. Probst, C. Halin, D. Neri, M. Detmar, Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation, JCI Insight 3 (23) (2018) e124850.

[204] W. Sun, Q. Lin, B. Zhao, M. Li, J. Xiao, X. Jin, J. Liu, Y. Wang, R. Zhang, X. Li, Z. Jiang, Lymphatic incorporated biomimetic scaffold enhances Osteoangio-lymphogenic coupling via HIF-1α mediated mitochondrial reprogramming for osteoporotic bone repair, Bioact. Mater. 56 (2026) 641-655.

[205] L. Li, F. Wang, D. Zhu, S. Hu, K. Cheng, Z. Li, Engineering exosomes and exosome-like nanovesicles for improving tissue targeting and retention, Fundam. Res. 5 (2) (2025) 851-867.

[206] S.G. Gabaran, N. Ghasemzadeh, M. Rahnama, E. Karatas, A. Akbari, J. Rezaie, Functionalized exosomes for targeted therapy in cancer and regenerative medicine: genetic, chemical, and physical modifications, Cell communication signaling CCS 23 (1) (2025) 265.

[207] X.J. Walker, M.C. Mack, B. Black, J. Dean, L.F. Kemper, S. Potter, B.M. Rogers, C.M. Truettner, Rapid assessment of biomarkers on single extracellular vesicles using “catch and display” on ultrathin nanoporous silicon nitride membranes, Fire Ecol. 21 (4) (2025) 2405505.

[208] C. Théry, et al., Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines, J. Extracell. Vesicles. 7 (1) (2018) 1535750.

[209] S.C. Jang, O.Y. Kim, C.M. Yoon, D.S. Choi, T.Y. Roh, J. Park, J. Nilsson, J. Lötvall, Y.K. Kim, Y.S. Gho, Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors, ACS nano 7 (9) (2013) 7698-7710.

[210] J.J. Rios, et al., Spatial transcriptomics implicates impaired BMP signaling in NF1 fracture pseudarthrosis in murine and patient tissues, JCI. Insight. 9 (16) (2024) e176802.

[211] C.C. Ho, et al., 3D-printed magnesium/strontium-co-doped calcium silicate scaffolds promote angiogenesis and bone regeneration through synergistic bioactive ion stimulation, J. Biol. Eng. 19 (1) (2025) 58.

[212] C. Zhou, B. Zhang, Y. Yang, Q. Jiang, T. Li, J. Gong, H. Tang, Q. Zhang, Stem cell-derived exosomes: emerging therapeutic opportunities for wound healing, Stem Cell Res. Ther. 14 (1) (2023) 107.

[213] M. Kou, L. Huang, J. Yang, Z. Chiang, S. Chen, J. Liu, L. Guo, X. Zhang, X. Zhou, X. Xu, X. Yan, Y. Wang, J. Zhang, A. Xu, H.F. Tse, Q. Lian, Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? Cell death Dis. 13 (7) (2022) 580.

[214] Y. Liu, C.J.F.I.C. Holmes, D. Biology, Tissue regeneration capacity of extracellular vesicles isolated from bone marrow-derived and adipose-derived mesenchymal stromal/stem cells, Front. Cell Dev. Biol. 9 (2021) 648098.

[215] Q. Qu, B. Fu, Y. Long, Z.Y. Liu, X.H. Tian, Current strategies for promoting the large-scale production of exosomes, Curr. Neuropharmacol. 21 (9) (2023) 1964-1979.

[216] T.D. Naquin, A.J. Canning, Y. Gu, J. Chen, C.M. Naquin, J. Xia, B. Lu, S. Yang, A. Koroza, K. Lin, H.N. Wang, W.R. Jeck, L.P. Lee, T. Vo-Dinh, T.J. Huang, Acoustic separation and concentration of exosomes for nucleotide detection: ASCENDx, Sci. Adv. 10 (10) (2024) eadm8597.

[217] X. Li, Z. Deng, W. Zhang, W. Zhou, X. Liu, H. Quan, J. Li, P. Li, Y. Li, C. Hu, F. Li, L. Niu, Z. Tian, L. Meng, H. Zheng, Oscillating microbubble array-based metamaterials (OMAMs) for rapid isolation of high-purity exosomes, Sci. Adv. 11 (16) (2025) eadu8915.

[218] R. Xu, D.W. Greening, H.J. Zhu, N. Takahashi, R.J. Simpson, Extracellular vesicle isolation and characterization: toward clinical application, J. Clin. Investig. 126 (4) (2016) 1152-1162.

[219] T. Nonaka and D.T.W. Wong, Saliva-exosomics in cancer: molecular characterization of cancer-derived exosomes in saliva, Enzymes 42 (2017) 125-151.

[220] J. Webber and A. Clayton, How pure are your vesicles? J. Extracell. Vesicles. 2 (2013).

[221] J.A. Welsh, et al., Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches, J. Extracell. Vesicles. 13 (2) (2024) e12404.

[222] J. Prescher, V. Baumgärtel, S. Ivanchenko, A.A. Torrano, C. Bräuchle, B. Müller, D.C. Lamb, Super-resolution imaging of ESCRT-proteins at HIV-1 assembly sites, PLoS Pathog. 11 (2) (2015) e1004677.

[223] B. Müller, M.J.Tim Heilemann, Shedding new light on viruses: super-resolution microscopy for studying human immunodeficiency virus, Trends Microbiol. 21 (10) (2013) 522-533.

[224] R. Agnihotram, et al., Fusion of exosomes and nanotechnology: cutting-edge cancer theranostics, ACS. Applied. Nano Materials. 7 (8) (2024) 8489-8506.

[225] Z. Qin, et al., Matrix Stiffness of GelMA Hydrogels Regulates Lymphatic Endothelial Cells toward Enhanced Lymphangiogenesis, ACS. Appl. Mater. Interfaces. 16 (41) (2024) 55130-55141.

[226] T. Shang, J. Liang, C.M. Kapron, J. Liu, Pathophysiology of aged lymphatic vessels, Aging 11 (16) (2019) 6602-6613.

[227] K.K. To, W.C.J.C.D.R. Cho, Exosome secretion from hypoxic cancer cells reshapes the tumor microenvironment and mediates drug resistance, Cancer drug resistance (Alhambra Calif.) 5 (3) (2022) 577-594.

[228] Y. Fan, M. Elkhalek, Y. Zhang, L. Liu, Q. Tian, N. Chueakula, S.K. Ramasamy, R. Dalan, S.J. Habib, A.P. Kusumbe, Bone marrow adipocytes: key players in vascular niches, aging, and disease, Front. Cell Dev. Biol. 13 (2025) 1633801.

[229] I.J.T.Joci Hyun, The bioethics of stem cell research and therapy, J. Clin. Investig. 120 (1) (2010) 71-75.

[230] N.M. King, J.J.Scr Perrin, and therapy, Ethical issues in stem cell research and therapy. Stem Cell Res. Ther. 5 (4) (2014) 85.