Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation.
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.
Tammela
Tuomas
T
Molecular/Cancer Biology Laboratory, Haartman Institute and Ludwig Institute for Cancer Research, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland.
Saaristo
Anne
A
Holopainen
Tanja
T
Lyytikkä
Johannes
J
Kotronen
Anna
A
Pitkonen
Miia
M
Abo-Ramadan
Usama
U
Ylä-Herttuala
Seppo
S
Petrova
Tatiana V
TV
Alitalo
Kari
K
D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000637:transplantation*; D042601:Lymphatic Vessels / Q000502:physiology*; D008209:Lymphedema / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D