title: Mechanisms of lymphatic regeneration after tissue transfer.
abstract: BACKGROUND
  Lymphedema is the chronic swelling of an extremity that occurs commonly after lymph node resection for cancer treatment. Recent studies have demonstrated that transfer of healthy tissues can be used as a means of bypassing damaged lymphatics and ameliorating lymphedema. The purpose of these studies was to investigate the mechanisms that regulate lymphatic regeneration after tissue transfer.
  
  
  METHODS
  Nude mice (recipients) underwent 2-mm tail skin excisions that were either left open or repaired with full-thickness skin grafts harvested from donor transgenic mice that expressed green fluorescent protein in all tissues or from LYVE-1 knockout mice. Lymphatic regeneration, expression of VEGF-C, macrophage infiltration, and potential for skin grafting to bypass damaged lymphatics were assessed.
  
  
  RESULTS
  Skin grafts healed rapidly and restored lymphatic flow. Lymphatic regeneration occurred beginning at the peripheral edges of the graft, primarily from ingrowth of new lymphatic vessels originating from the recipient mouse. In addition, donor lymphatic vessels appeared to spontaneously re-anastomose with recipient vessels. Patterns of VEGF-C expression and macrophage infiltration were temporally and spatially associated with lymphatic regeneration. When compared to mice treated with excision only, there was a 4-fold decrease in tail volumes, 2.5-fold increase in lymphatic transport by lymphoscintigraphy, 40% decrease in dermal thickness, and 54% decrease in scar index in skin-grafted animals, indicating that tissue transfer could bypass damaged lymphatics and promote rapid lymphatic regeneration.
  
  
  CONCLUSIONS
  Our studies suggest that lymphatic regeneration after tissue transfer occurs by ingrowth of lymphatic vessels and spontaneous re-connection of existing lymphatics. This process is temporally and spatially associated with VEGF-C expression and macrophage infiltration. Finally, tissue transfer can be used to bypass damaged lymphatics and promote rapid lymphatic regeneration.
authors.affiliation: The Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Yan
authors.forename: Tomer
authors.initials: T
authors.lastname: Avraham
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Zampell
authors.forename: Seth Z
authors.initials: SZ
authors.lastname: Aschen
authors.forename: Babak J
authors.initials: BJ
authors.lastname: Mehrara
mesh_terms: D000818:Animals; D020405:Dermis / Q000033:anatomy & histology / Q000502:physiology; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D008208:Lymphatic System / Q000502:physiology*; D042601:Lymphatic Vessels / Q000000981:diagnostic imaging / Q000637:transplantation*; D008209:Lymphedema / Q000473:pathology / Q000534:rehabilitation / Q000601:surgery; D008220:Lymphography; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008846:Micromanipulation / Q000379:methods; D009929:Organ Size; D012038:Regeneration / Q000502:physiology*; D016038:Skin Transplantation; D013623:Tail / Q000166:cytology / Q000000981:diagnostic imaging / Q000502:physiology / Q000601:surgery
chemical_list: D006023:Glycoproteins; D026901:Membrane Transport Proteins; C492273:LYVE1 protein, mouse