A Novel, Transgenic, Inducible Animal Model Of Scrotal Lymphedema
Jason Gardenier, MD, Jung-Ju Huang, MD, Raghu Kataru, PhD, Ira Savetsky, MD, Gabriela Garcia Nores, MD, Jessie Yu, MD, Geoffrey Hespe, BS, Babak Mehrara, MD.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Scrotal lymphedema is a challenging problem and affects nearly 30 million men worldwide. Treatments are radical and deforming, and development of therapies has been limited by a lack of adequate animal models. To address this gap, we developed a novel transgenic animal model of scrotal lymphedema by ablating the lymphatic system with diphtheria toxin.
We created Cre-lox mice that express the human diphtheria toxin receptor selectively on lymphatic endothelial cells (LECs) using a lymphatic specific promoter (FLT-4). This receptor binds diphtheria toxin (DT) avidly and results in selective ablation of the target cells. We then injected DT in the scrotum to selectively ablate the lymphatic vessels in this region and analyzed development of scrotal lymphedema as well as its pathological changes over time.
One week after ablation, scrotal volumes increased to 520% of normal, and this volume increase was sustained for at least 4 weeks. We noted a 66% reduction in dermal capillary lymphatic vessel density (p=0.003) and an 88% reduction in collecting lymphatic vessels (p<0.001). There was a 70% increase in T cell soft tissue infiltration (p=0.038), but no difference in macrophages. There was also an 80% increase in epidermal thickness (p<0.001). Residual lymphatics were highly abnormal and had significant accumulation of perilymphatic inflammatory cells.
We have created and described the first animal model of scrotal lymphedema. Further experiments with this model may allow for new discoveries of scrotal lymphatic function/dysfunction and will allow for the testing of surgical and pharmacological treatment possibilities.
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