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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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Spontaneous regeneration of lymphatics after tissue transfer can be used to bypass damaged lymphatics.A. Gross photographs comparing nude mice that had undergone tail excision with (right) and without (left) skin grafting are shown 6 weeks after surgery. Note obvious difference in tail swelling. B. Tail volume measurements in nude mice that had undergone tail excision with or without skin grafting. Data are presented as percent change from baseline (i.e. preoperatively) with mean ± SD (*p<0.05). C, D. Representative lymphoscintigraphy of nude mice that had undergone tail excision with or without skin grafting. E. Representative photomicrograph (5x) of H&E stained tails sections from nude mice treated with (left) or without (right) 6 weeks after surgery. Dashed box delineates area of skin graft. Note decreased inflammation (cellularity) and dermal thickness in skin-grafted mice distal (to the left) of the wound. F. High power (40x) photomicrographs of tail skin harvested 5 mm distal to the excision site. Note decreased cellularity in skin-grafted section (left) as compared with excision section (right; arrow). Also note decreased dermal thickness. G. Dermal thickness measurements and representative figures (40x) in nude mice that had undergone tail excision with or without skin grafting 6 weeks following surgery (*p<0.05). H. Scar index measurements in tail tissues localized just distal to the site of lymphatic injury 6 weeks after treatment with excision with or without skin grafting. Representative Sirius red birefringence images are shown to the right. Orange-red is indicative of scar; yellow-green is consistent with normal (i.e. non-fibrosed) tissue (*p<0.01).
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pone-0017201-g007: Spontaneous regeneration of lymphatics after tissue transfer can be used to bypass damaged lymphatics.A. Gross photographs comparing nude mice that had undergone tail excision with (right) and without (left) skin grafting are shown 6 weeks after surgery. Note obvious difference in tail swelling. B. Tail volume measurements in nude mice that had undergone tail excision with or without skin grafting. Data are presented as percent change from baseline (i.e. preoperatively) with mean ± SD (*p<0.05). C, D. Representative lymphoscintigraphy of nude mice that had undergone tail excision with or without skin grafting. E. Representative photomicrograph (5x) of H&E stained tails sections from nude mice treated with (left) or without (right) 6 weeks after surgery. Dashed box delineates area of skin graft. Note decreased inflammation (cellularity) and dermal thickness in skin-grafted mice distal (to the left) of the wound. F. High power (40x) photomicrographs of tail skin harvested 5 mm distal to the excision site. Note decreased cellularity in skin-grafted section (left) as compared with excision section (right; arrow). Also note decreased dermal thickness. G. Dermal thickness measurements and representative figures (40x) in nude mice that had undergone tail excision with or without skin grafting 6 weeks following surgery (*p<0.05). H. Scar index measurements in tail tissues localized just distal to the site of lymphatic injury 6 weeks after treatment with excision with or without skin grafting. Representative Sirius red birefringence images are shown to the right. Orange-red is indicative of scar; yellow-green is consistent with normal (i.e. non-fibrosed) tissue (*p<0.01).

Mentions: In order to determine if spontaneous regeneration of lymphatics can be used to bypass surgically damaged lymphatic vessels, we compared lymphatic function in mice that underwent skin excision with animals that had skin excision and repair with full-thickness skin grafting. Evaluation of animals grossly demonstrated marked differences in tail swelling at all time points evaluated (Figure 7A). These findings were corroborated by tail volume calculation demonstrating significantly higher tail volumes in excision-only animals at every time point evaluated (Figure 7B). Skin-grafted animals had a 4-fold decrease in tail swelling at the 2 week time point (19±5.9% vs. 74±7.8%, p<0.05) and their tail volumes returned to baseline 6 weeks after surgery. In contrast, excision-only animals demonstrated a persistent increase even 6 weeks postoperatively (26±8%, p<0.01). The differences in tail volumes observed in our study were associated with significantly improved lymphatic function as assessed by lymphoscintigraphy (Figures 7C–D). At both the 2 and 6 week time points, the skin-grafted animals demonstrated a significantly increased total uptake of Tc99 in the lymph nodes at the base of the tail (3.74% vs. 0.61% at 2 weeks; 10.70% vs. 4.23% at 6 weeks; p<0.01 for both time points). In addition, the lymphatic uptake occurred more rapidly as reflected by a more rapid increase in the slope of the asymptotic curve.


Mechanisms of lymphatic regeneration after tissue transfer.

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

Spontaneous regeneration of lymphatics after tissue transfer can be used to bypass damaged lymphatics.A. Gross photographs comparing nude mice that had undergone tail excision with (right) and without (left) skin grafting are shown 6 weeks after surgery. Note obvious difference in tail swelling. B. Tail volume measurements in nude mice that had undergone tail excision with or without skin grafting. Data are presented as percent change from baseline (i.e. preoperatively) with mean ± SD (*p<0.05). C, D. Representative lymphoscintigraphy of nude mice that had undergone tail excision with or without skin grafting. E. Representative photomicrograph (5x) of H&E stained tails sections from nude mice treated with (left) or without (right) 6 weeks after surgery. Dashed box delineates area of skin graft. Note decreased inflammation (cellularity) and dermal thickness in skin-grafted mice distal (to the left) of the wound. F. High power (40x) photomicrographs of tail skin harvested 5 mm distal to the excision site. Note decreased cellularity in skin-grafted section (left) as compared with excision section (right; arrow). Also note decreased dermal thickness. G. Dermal thickness measurements and representative figures (40x) in nude mice that had undergone tail excision with or without skin grafting 6 weeks following surgery (*p<0.05). H. Scar index measurements in tail tissues localized just distal to the site of lymphatic injury 6 weeks after treatment with excision with or without skin grafting. Representative Sirius red birefringence images are shown to the right. Orange-red is indicative of scar; yellow-green is consistent with normal (i.e. non-fibrosed) tissue (*p<0.01).
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Related In: Results  -  Collection

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pone-0017201-g007: Spontaneous regeneration of lymphatics after tissue transfer can be used to bypass damaged lymphatics.A. Gross photographs comparing nude mice that had undergone tail excision with (right) and without (left) skin grafting are shown 6 weeks after surgery. Note obvious difference in tail swelling. B. Tail volume measurements in nude mice that had undergone tail excision with or without skin grafting. Data are presented as percent change from baseline (i.e. preoperatively) with mean ± SD (*p<0.05). C, D. Representative lymphoscintigraphy of nude mice that had undergone tail excision with or without skin grafting. E. Representative photomicrograph (5x) of H&E stained tails sections from nude mice treated with (left) or without (right) 6 weeks after surgery. Dashed box delineates area of skin graft. Note decreased inflammation (cellularity) and dermal thickness in skin-grafted mice distal (to the left) of the wound. F. High power (40x) photomicrographs of tail skin harvested 5 mm distal to the excision site. Note decreased cellularity in skin-grafted section (left) as compared with excision section (right; arrow). Also note decreased dermal thickness. G. Dermal thickness measurements and representative figures (40x) in nude mice that had undergone tail excision with or without skin grafting 6 weeks following surgery (*p<0.05). H. Scar index measurements in tail tissues localized just distal to the site of lymphatic injury 6 weeks after treatment with excision with or without skin grafting. Representative Sirius red birefringence images are shown to the right. Orange-red is indicative of scar; yellow-green is consistent with normal (i.e. non-fibrosed) tissue (*p<0.01).
Mentions: In order to determine if spontaneous regeneration of lymphatics can be used to bypass surgically damaged lymphatic vessels, we compared lymphatic function in mice that underwent skin excision with animals that had skin excision and repair with full-thickness skin grafting. Evaluation of animals grossly demonstrated marked differences in tail swelling at all time points evaluated (Figure 7A). These findings were corroborated by tail volume calculation demonstrating significantly higher tail volumes in excision-only animals at every time point evaluated (Figure 7B). Skin-grafted animals had a 4-fold decrease in tail swelling at the 2 week time point (19±5.9% vs. 74±7.8%, p<0.05) and their tail volumes returned to baseline 6 weeks after surgery. In contrast, excision-only animals demonstrated a persistent increase even 6 weeks postoperatively (26±8%, p<0.01). The differences in tail volumes observed in our study were associated with significantly improved lymphatic function as assessed by lymphoscintigraphy (Figures 7C–D). At both the 2 and 6 week time points, the skin-grafted animals demonstrated a significantly increased total uptake of Tc99 in the lymph nodes at the base of the tail (3.74% vs. 0.61% at 2 weeks; 10.70% vs. 4.23% at 6 weeks; p<0.01 for both time points). In addition, the lymphatic uptake occurred more rapidly as reflected by a more rapid increase in the slope of the asymptotic curve.

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