Mechanisms of Lymphatic Regeneration after Tissue Transfer

Abstract

IntroductionLymphedema 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.MethodsNude 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.ResultsSkin 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.ConclusionsOur 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.

Anti-inflammatory effects of flap and lymph node transfer

“…One explanation for the high VEGF-C concentration in the BR patients might be the finding that patients, who have not developed lymphedema after axillary clearance, have actually residual axillary lymph nodes [25], which are producing VEGF-C. In addition, recruited macrophages have been shown to be the source of VEGF-C after flap transfer [26].…”

SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

“…TAMs are critical regulators of angiogenesis and lymphangiogenesis; they express VEGFA and VEGFC and induce tip-cell formation and fusion (16,(30)(31)(32)(33). In addition, they are thought to directly contribute to lymphatic vessel formation by transdifferentiating into lymphatic endothelial cells (25,28,33,34).…”

Vascularized Lymph Node Transfer

“…However, two fundamental questions remain unanswered: 12 However, in clinical cases of chronic lymphedema, the zone of lymphatic abnormality has often extended distally much beyond the initial lymphadenectomy zone, which cannot be traversed by the lymph node flap. 23 This reduces the availability of "open" lymphatic channels as pointed out by Shesol et al 11…”