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Mechanisms of lymphatic regeneration after tissue transfer.

Yan A, Avraham T, Zampell JC, Aschen SZ, Mehrara BJ - PLoS ONE (2011)

Bottom Line: 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.This process is temporally and spatially associated with VEGF-C expression and macrophage infiltration.

View Article: PubMed Central - PubMed

Affiliation: The Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

ABSTRACT

Introduction: 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.

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Related in: MedlinePlus

Lymphatic regeneration after tissue transfer is associated with expression of VEGF-C.A. VEGF-C expression in skin-grafted tails 2 weeks after surgery. Representative low power (2x; upper panel) photomicrographs encompassing the skin-grafted area and distal/proximal portions of the recipient mouse-tail are shown. High power (20x) views of the distal and proximal junctions between recipient tissues and skin grafts are shown below. Black arrow shows large number of VEGF-C+ cells in the distal junction. Dashed box delineates skin-grafted area. B. VEGF-C expression in skin-grafted tails 6 weeks after surgery. Representative low power (2x; upper panel) and high power (20x) photomicrographs encompassing the skin-grafted area and distal/middle/proximal portions of the recipient mouse tails are shown. Dashed box delineates skin-grafted area. Note small amount of wound/skin graft contracture after repair. C. Cell counts per high power field of VEGF-C+ cells in the various tail regions (D = distal, M = middle, P = proximal) 2 and 6 weeks after surgery. Cell counts are means ± SD of at least 4 high power fields/mouse/time point. At least 6 mice were analyzed in each group (*p<0.05; #<0.01).
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pone-0017201-g004: Lymphatic regeneration after tissue transfer is associated with expression of VEGF-C.A. VEGF-C expression in skin-grafted tails 2 weeks after surgery. Representative low power (2x; upper panel) photomicrographs encompassing the skin-grafted area and distal/proximal portions of the recipient mouse-tail are shown. High power (20x) views of the distal and proximal junctions between recipient tissues and skin grafts are shown below. Black arrow shows large number of VEGF-C+ cells in the distal junction. Dashed box delineates skin-grafted area. B. VEGF-C expression in skin-grafted tails 6 weeks after surgery. Representative low power (2x; upper panel) and high power (20x) photomicrographs encompassing the skin-grafted area and distal/middle/proximal portions of the recipient mouse tails are shown. Dashed box delineates skin-grafted area. Note small amount of wound/skin graft contracture after repair. C. Cell counts per high power field of VEGF-C+ cells in the various tail regions (D = distal, M = middle, P = proximal) 2 and 6 weeks after surgery. Cell counts are means ± SD of at least 4 high power fields/mouse/time point. At least 6 mice were analyzed in each group (*p<0.05; #<0.01).

Mentions: VEGF-C is a critical regulator of lymphatic regeneration during adult lymphangiogenesis.[17] Therefore, we investigated the pattern of VEGF-C expression after tissue transfer using immunohistochemical staining. Two weeks after surgery, VEGF-C expression was highest at the periphery of the wounds with the distal wound margin displaying significantly more staining of VEGF-C+ cells/hpf than either the middle or proximal portion (110±4 in distal portion vs. 46±8 in middle portion; p<0.05; Figures 4A, C). VEGF-C staining at the peripheral margins of the grafts was associated with a modest inflammatory infiltrate into the skin graft. By 6 weeks, VEGF-C staining was primarily localized to the central region of the skin graft (73±11 in the central portion vs. 30±8 or 25±10 in proximal or distal portion; p<0.05; Figures 4B–C). This expression pattern corresponded to the infiltration of lymphatic vessels into the graft beginning at the peripheral margins and extending into the central portion.


Mechanisms of lymphatic regeneration after tissue transfer.

Yan A, Avraham T, Zampell JC, Aschen SZ, Mehrara BJ - PLoS ONE (2011)

Lymphatic regeneration after tissue transfer is associated with expression of VEGF-C.A. VEGF-C expression in skin-grafted tails 2 weeks after surgery. Representative low power (2x; upper panel) photomicrographs encompassing the skin-grafted area and distal/proximal portions of the recipient mouse-tail are shown. High power (20x) views of the distal and proximal junctions between recipient tissues and skin grafts are shown below. Black arrow shows large number of VEGF-C+ cells in the distal junction. Dashed box delineates skin-grafted area. B. VEGF-C expression in skin-grafted tails 6 weeks after surgery. Representative low power (2x; upper panel) and high power (20x) photomicrographs encompassing the skin-grafted area and distal/middle/proximal portions of the recipient mouse tails are shown. Dashed box delineates skin-grafted area. Note small amount of wound/skin graft contracture after repair. C. Cell counts per high power field of VEGF-C+ cells in the various tail regions (D = distal, M = middle, P = proximal) 2 and 6 weeks after surgery. Cell counts are means ± SD of at least 4 high power fields/mouse/time point. At least 6 mice were analyzed in each group (*p<0.05; #<0.01).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3040774&req=5

pone-0017201-g004: Lymphatic regeneration after tissue transfer is associated with expression of VEGF-C.A. VEGF-C expression in skin-grafted tails 2 weeks after surgery. Representative low power (2x; upper panel) photomicrographs encompassing the skin-grafted area and distal/proximal portions of the recipient mouse-tail are shown. High power (20x) views of the distal and proximal junctions between recipient tissues and skin grafts are shown below. Black arrow shows large number of VEGF-C+ cells in the distal junction. Dashed box delineates skin-grafted area. B. VEGF-C expression in skin-grafted tails 6 weeks after surgery. Representative low power (2x; upper panel) and high power (20x) photomicrographs encompassing the skin-grafted area and distal/middle/proximal portions of the recipient mouse tails are shown. Dashed box delineates skin-grafted area. Note small amount of wound/skin graft contracture after repair. C. Cell counts per high power field of VEGF-C+ cells in the various tail regions (D = distal, M = middle, P = proximal) 2 and 6 weeks after surgery. Cell counts are means ± SD of at least 4 high power fields/mouse/time point. At least 6 mice were analyzed in each group (*p<0.05; #<0.01).
Mentions: VEGF-C is a critical regulator of lymphatic regeneration during adult lymphangiogenesis.[17] Therefore, we investigated the pattern of VEGF-C expression after tissue transfer using immunohistochemical staining. Two weeks after surgery, VEGF-C expression was highest at the periphery of the wounds with the distal wound margin displaying significantly more staining of VEGF-C+ cells/hpf than either the middle or proximal portion (110±4 in distal portion vs. 46±8 in middle portion; p<0.05; Figures 4A, C). VEGF-C staining at the peripheral margins of the grafts was associated with a modest inflammatory infiltrate into the skin graft. By 6 weeks, VEGF-C staining was primarily localized to the central region of the skin graft (73±11 in the central portion vs. 30±8 or 25±10 in proximal or distal portion; p<0.05; Figures 4B–C). This expression pattern corresponded to the infiltration of lymphatic vessels into the graft beginning at the peripheral margins and extending into the central portion.

Bottom Line: 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.This process is temporally and spatially associated with VEGF-C expression and macrophage infiltration.

View Article: PubMed Central - PubMed

Affiliation: The Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

ABSTRACT

Introduction: 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.

Show MeSH
Related in: MedlinePlus