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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 occurs in part from spontaneous reconnection of recipient and donor lymphatic vessels.A. Co-localization of LYVE-1 (left panel) and podoplanin (middle panel) of mouse tail sections harvested 6 weeks after surgery (40x). Overlay of images demonstrates connection of LYVE-1+ (i.e. recipient) and LYVE-1- (i.e. donor) derived podoplanin-stained lymphatics. Yellow line marks the junction of the skin graft and native tail skin. Distal junction of the skin graft and mouse tail is shown to the left. B. Three-dimensional rendering of podoplanin/LYVE-1 co-localization at the junction of the skin graft and native tail skin (yellow line). Note connection between LYVE-1+ and LYVE-1- lymphatic. Also note presence of both recipient (podoplanin+/LYVE-1+) and donor (podoplanin+/LYVE-1-) vessels in the section.
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pone-0017201-g002: Lymphatic regeneration after tissue transfer occurs in part from spontaneous reconnection of recipient and donor lymphatic vessels.A. Co-localization of LYVE-1 (left panel) and podoplanin (middle panel) of mouse tail sections harvested 6 weeks after surgery (40x). Overlay of images demonstrates connection of LYVE-1+ (i.e. recipient) and LYVE-1- (i.e. donor) derived podoplanin-stained lymphatics. Yellow line marks the junction of the skin graft and native tail skin. Distal junction of the skin graft and mouse tail is shown to the left. B. Three-dimensional rendering of podoplanin/LYVE-1 co-localization at the junction of the skin graft and native tail skin (yellow line). Note connection between LYVE-1+ and LYVE-1- lymphatic. Also note presence of both recipient (podoplanin+/LYVE-1+) and donor (podoplanin+/LYVE-1-) vessels in the section.

Mentions: To investigate the relative contribution of donor and recipient lymphatic vessels to lymphatic regeneration in the transplanted skin, immunofluorescence staining with the lymphatic endothelial cell markers LYVE-1 and podoplanin was performed and the number of donor- and recipient-derived lymphatic vessels were evaluated at various regions of the skin graft (distal, middle, and proximal portions) 2 or 6 weeks following surgery (Figures 2A–B). This analysis, similar to our GFP/LYVE-1 co-localization, demonstrated connections between LYVE-1+ and LYVE-1- lymphatic vessels suggesting that lymphatic vessels from the recipient and donor tissues spontaneously reconnect. This phenomenon is seen in 3-D reconstructions of z-stacked confocal images (Figure 2B).


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 occurs in part from spontaneous reconnection of recipient and donor lymphatic vessels.A. Co-localization of LYVE-1 (left panel) and podoplanin (middle panel) of mouse tail sections harvested 6 weeks after surgery (40x). Overlay of images demonstrates connection of LYVE-1+ (i.e. recipient) and LYVE-1- (i.e. donor) derived podoplanin-stained lymphatics. Yellow line marks the junction of the skin graft and native tail skin. Distal junction of the skin graft and mouse tail is shown to the left. B. Three-dimensional rendering of podoplanin/LYVE-1 co-localization at the junction of the skin graft and native tail skin (yellow line). Note connection between LYVE-1+ and LYVE-1- lymphatic. Also note presence of both recipient (podoplanin+/LYVE-1+) and donor (podoplanin+/LYVE-1-) vessels in the section.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040774&req=5

pone-0017201-g002: Lymphatic regeneration after tissue transfer occurs in part from spontaneous reconnection of recipient and donor lymphatic vessels.A. Co-localization of LYVE-1 (left panel) and podoplanin (middle panel) of mouse tail sections harvested 6 weeks after surgery (40x). Overlay of images demonstrates connection of LYVE-1+ (i.e. recipient) and LYVE-1- (i.e. donor) derived podoplanin-stained lymphatics. Yellow line marks the junction of the skin graft and native tail skin. Distal junction of the skin graft and mouse tail is shown to the left. B. Three-dimensional rendering of podoplanin/LYVE-1 co-localization at the junction of the skin graft and native tail skin (yellow line). Note connection between LYVE-1+ and LYVE-1- lymphatic. Also note presence of both recipient (podoplanin+/LYVE-1+) and donor (podoplanin+/LYVE-1-) vessels in the section.
Mentions: To investigate the relative contribution of donor and recipient lymphatic vessels to lymphatic regeneration in the transplanted skin, immunofluorescence staining with the lymphatic endothelial cell markers LYVE-1 and podoplanin was performed and the number of donor- and recipient-derived lymphatic vessels were evaluated at various regions of the skin graft (distal, middle, and proximal portions) 2 or 6 weeks following surgery (Figures 2A–B). This analysis, similar to our GFP/LYVE-1 co-localization, demonstrated connections between LYVE-1+ and LYVE-1- lymphatic vessels suggesting that lymphatic vessels from the recipient and donor tissues spontaneously reconnect. This phenomenon is seen in 3-D reconstructions of z-stacked confocal images (Figure 2B).

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