Article abstract
Nature Medicine 13, 1458 - 1466 (2007)
Published online: 2 December 2007 | doi:10.1038/nm1689
Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation
Tuomas Tammela1, Anne Saaristo1,2, Tanja Holopainen1, Johannes Lyytikkä1, Anna Kotronen1, Miia Pitkonen3, Usama Abo-Ramadan3, Seppo Ylä-Herttuala4, Tatiana V Petrova5 & Kari Alitalo1
Abstract
Surgery or radiation therapy of metastatic cancer often damages lymph nodes, leading to secondary lymphedema. Here we show, using a newly established mouse model, that collecting lymphatic vessels can be regenerated and fused to lymph node transplants after lymph node removal. Treatment of lymph node–excised mice with adenovirally delivered vascular endothelial growth factor-C (VEGF-C) or VEGF-D induced robust growth of the lymphatic capillaries, which gradually underwent intrinsic remodeling, differentiation and maturation into functional collecting lymphatic vessels, including the formation of uniform endothelial cell-cell junctions and intraluminal valves. The vessels also reacquired pericyte contacts, which downregulated lymphatic capillary markers during vessel maturation. Growth factor therapy improved the outcome of lymph node transplantation, including functional reconstitution of the immunological barrier against tumor metastasis. These results show that growth factor–induced maturation of lymphatic vessels is possible in adult mice and provide a basis for future therapy of lymphedema.
- Molecular/Cancer Biology Laboratory, Haartman Institute and Ludwig Institute for Cancer Research, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland.
- Department of Plastic Surgery, Turku University Central Hospital, PO Box 52 (Kiinanmyllynkatu 8), 20521 Turku, Finland.
- Experimental MRI Laboratory, Department of Neurology, Helsinki University Central Hospital, PO Box 63 (Haartmaninkatu 8), Helsinki, Finland.
- University of Kuopio, A. I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, PO Box 1627, 70211 Kuopio, Finland.
- Development and Differentiation Laboratory, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland.
Correspondence to: Kari Alitalo1 e-mail: kari.alitalo@helsinki.fi
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