Vascularized Composite Allotransplantation: A Functional Hind Limb Model in Mice

Summary Vascularized composite allotransplants (VCAs) seem to have several unique features of clinical and experimental importance, including uniquely definable lymphatic drainage that can be easily accessed at the level of ipsilateral regional node beds. Thus, VCA offers a unique opportunity to assess the relative contribution of peripheral and secondary lymphoid tissue to the process of rejection. We transplanted hind limb grafts from C3H donors to six different groups of C57BL/6 recipients: Spleen+Map3k14−/−; Spleen−Map3k14−/−; Spleen+Node−Map3k14−/−; and Spleen−Node−Map3k14−/−. As positive controls, we used Map3k14+/− with or without spleen. Map3k14+/− mice demonstrated an average graft survival of 9.6 and 9.2 days for Spleen− and Spleen+Map3k14+/−, respectively. Rejection in the Map3k14−/− group was considerably delayed (28.4 days, P = 0.002) in all recipients. The Spleen−Map3k14−/− mice rejected their hind limb allografts in an even more delayed fashion compared to Spleen+Map3k14−/− (54.4 days, P = 0.02). Histological analysis of skin showed that acute rejection in both Map3k14+/− mice groups was graded as Banff III or Banff IV. In the Map3k14−/− groups, rejection was graded as Banff III. We demonstrated that in the absence of lymph nodes, grafts reject in a delayed fashion. Also, splenectomy in alymphoplastic mice further extends graft survival, but does not eliminate rejection all together.

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“…Hind limb transplantation was performed as previously described [10]. Five animals per group were included in the analysis.…”

Section: Methodsmentioning

confidence: 99%

“…In this work, we have adopted a recently established mouse hind limb transplant model [10] to highlight the utility of VCAs in mechanistic exploration. We go on to demonstrate that in the absence of lymph nodes, limb grafts reject in a delayed fashion.…”

Section: Introductionmentioning

confidence: 99%

Vascularized composite allotransplants as a mechanistic model for allograft rejection – an experimental study

et al. 2021

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“…For example, developing heterotrophic osteomyocutaneus flap transplant protocols in Lewis rats furthered our understanding of the mechanisms and pathways involved in the immune response underlying tissue transplant rejection [ 113 ]. Likewise, in an experiment with five syngeneic mice and allografts—using a donor-supplied aorta and inferior vena cava—end-to-end anastomosis of those structures showed a 74% success rate as a technique for hind limb transplants [ 114 ]. In another study, Tee et al [ 115 ] performed grafts of engineered cardiac muscle flaps in the epicardium of 8 rats.…”

Section: Animal Models and Their Application In Distinct Fields Of Cu...mentioning

confidence: 99%

The Importance of Animal Models in Biomedical Research: Current Insights and Applications

Domínguez-Oliva

Hernández-Ávalos

Martı́nez-Burnes

et al. 2023

Animals

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Animal research is considered a key element in advance of biomedical science. Although its use is controversial and raises ethical challenges, the contribution of animal models in medicine is essential for understanding the physiopathology and novel treatment alternatives for several animal and human diseases. Current pandemics’ pathology, such as the 2019 Coronavirus disease, has been studied in primate, rodent, and porcine models to recognize infection routes and develop therapeutic protocols. Worldwide issues such as diabetes, obesity, neurological disorders, pain, rehabilitation medicine, and surgical techniques require studying the process in different animal species before testing them on humans. Due to their relevance, this article aims to discuss the importance of animal models in diverse lines of biomedical research by analyzing the contributions of the various species utilized in science over the past five years about key topics concerning human and animal health.

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“…Current anticoagulation protocols rely mainly on unfractionated heparin, which does not suffice the anticoagulation need in such a complicated model and often results in higher frequency of vascular complications. 15 , 16 For instance, Sucher and colleagues identified that vascular thrombosis due to insufficient anticoagulation was the major cause of graft failure in the mouse model of hind limb transplantation. 13 Thus, there is a critical need of optimizing anticoagulation protocols for this model.…”

Section: Introductionmentioning

confidence: 99%

Moderate LMWH Anticoagulation Improves Success Rate of Hind Limb Allotransplantation in Mice

Kern,

Ashraf,

Reutzel-Selke

et al. 2023

Plastic and Reconstructive Surgery - Global Open

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Background: The mouse hind limb model represents a powerful research tool in vascularized composite tissue allotransplantation, but its applicability is limited due to poor graft survival (62%–83%). Vascular thrombosis and massive hemorrhage are the major causes for these drop-outs. We hypothesize that because of better anticoagulation effect and lower risk of thrombocytopenia, application of low molecular weight heparin (LMWH) will minimize vascular complications and enhance graft and animal survival. Methods: Fifty allogeneic hind limb transplantations were performed (C57BL/6 to DBA/2 mice) using five different anticoagulation protocols. Bleeding and thromboembolic events were recorded macroscopically by postoperative hemorrhage and livid discoloration of the graft, respectively. Graft perfusion and survival were monitored daily by capillary-refill-time of graft toes within 2–3 seconds. Vascular congestion and tissue necrosis were examined by histological evaluation of hematoxylin-eosin-stained tissue sections. Results: All transplantations were technically successful. Increase in thromboembolic events and a concomitant decrease in bleeding events were observed with the decreasing concentration of heparin in the perfusion solution. Although treatment of donor and recipient with low dose of LMWH could not reduce thromboembolic events, moderate dose effectively reduced these events. Compared with the poor outcome of graft perfusion with heparin alone, additional treatment of donor and recipient with low dose of LMWH improved graft and animal survival by 18%. Interestingly, animals treated with moderate dose of LMWH demonstrated 100% graft and animal survival. Conclusions: Treatment of donor and recipient mice with a moderate dose of LMWH prevents vascular complications and improves the outcome of murine hind limb transplants.

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Vascularized Composite Allotransplantation: A Functional Hind Limb Model in Mice

Cited by 4 publications

References 18 publications

Vascularized composite allotransplants as a mechanistic model for allograft rejection – an experimental study

Vascularized composite allotransplants as a mechanistic model for allograft rejection – an experimental study

The Importance of Animal Models in Biomedical Research: Current Insights and Applications

Moderate LMWH Anticoagulation Improves Success Rate of Hind Limb Allotransplantation in Mice

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