A novel mouse tail lymphedema model for observing lymphatic pump failure during lymphedema development

Abstract

It has been suggested that many forms of secondary lymphedema in humans are driven by a progressive loss of lymphatic pump function after an initial risk-inducing event. However, the link between pump failure and disease progression has remained elusive due to experimental challenges in the clinical setting and a lack of adequate animal models. Using a novel surgical model of lymphatic injury, we track the adaptation and functional decline of the lymphatic network in response to surgery. This model mimics the histological hallmarks of the typical mouse tail lymphedema model while leaving an intact collecting vessel for analysis of functional changes during disease progression. Lymphatic function in the intact collecting vessel negatively correlated with swelling, while a loss of pumping pressure generation remained even after resolution of swelling. By using this model to study the role of obesity in lymphedema development, we show that obesity exacerbates acquired lymphatic pump failure following lymphatic injury, suggesting one mechanism through which obesity may worsen lymphedema. This lymphatic injury model will allow for future studies investigating the molecular mechanisms leading to lymphedema development.

The Kinetics of Lymphatic Dysfunction and Leukocyte Expansion in the Draining Lymph Node during LTB4 Antagonism in a Mouse Model of Lymphedema

“…Interestingly these differences were most pronounced in cell populations known to be highly migratory, including monocytes and macrophages. Previous studies in our lab have shown that contractile function in the intact lymphatic vessel in this model decreases significantly by the 2W timepoint [ 19 ]. The loss of preferential proliferation and migration in the intact vessel dLN may be due to loss of function in the intact vessel [ 19 ].…”

“…To study how various immune cell populations in dLNs change during lymphedema progression, we used a single vessel ligation lymphedema mouse tail model developed by our group [ 19 ]. This model leaves one collecting vessel trunk intact, allowing for drainage from the site of injury to the LN downstream of the functioning vessel, referred to as the intact vessel dLN, while the LN downstream of the ligated vessel, referred to as the injured vessel dLN, experiences inhibited lymph inflow.…”

“…An adaptation of this lymphedema model developed previously by our lab, the single vessel ligation model, leaves a pair of collecting lymphatic vessels intact while ligating the other initial and collecting lymphatic vessels. This procedure leaves an intact drainage pathway on one side of the tail while the other pathway is completely blocked, but the progression of lymphedema in this model mirrors the typical mouse tail model even though an intact drainage pathway exists [ 19 ].…”

Multichromatic Near-Infrared Imaging to Assess Interstitial Lymphatic and Venous UptakeIn Vivo

“…Multichromatic NIR imaging was carried out using a customized NIR setup 17,24 . Briefly, the system consists of a cooled EMCCD camera (Evolve eXcelon, Photometrics) attached to a stereomicroscope with adjustable zoom (MVX10, Olympus), a shutter-controlled xenon arc light source (Lambda LS, Sutter Instrument Company), and a manual filter wheel equipped with standard Cy5.5 and ICG-B filter cubes (Chroma Technology).…”

Evidence of stage progression in a novel, validated fluorescence-navigated and microsurgical-assisted secondary lymphedema rodent model

“…Near-infrared imaging of indocyanine green (ICG) is a standard procedure in the clinical assessment of the lymphatic system [26][27][28][29]. ICG based NIR imaging has been used both to evaluate lymphatic function in animal models and NIR functional imaging [20,[29][30][31], nevertheless, it has not been used as a standardized tool for pre-and intraoperative lymphangiographic navigation to guide a precise lymphatic injury for in-vivo studies.…”