Human organotypic lymphatic vessel model elucidates microenvironment-dependent signaling and barrier function

Area of Science:

• Biomedical Engineering
• Vascular Biology
• Disease Modeling

Background:

• The lymphatic system is crucial in diseases like lymphedema and cancer.
• Existing 3D in vitro models lack the physiological complexity of lymphatic vessels.
• Advanced models are needed to understand lymphatic biology in disease progression.

Purpose of the Study:

• To develop a novel 3D microscale lymphatic vessel (μLYMPH) system.
• To create a human lymphatic vessel model with physiological structure and function.
• To investigate lymphatic vessel interactions within disease microenvironments.

Main Methods:

• Fabrication of a 3D microscale lymphatic vessel (μLYMPH) system.
• Characterization of vessel permeability and solute uptake under interstitial flow.
• Co-culture experiments with cancer-associated fibroblasts (CAFs).
• Analysis of growth factor and inflammatory mediator secretion.
• Assessment of IL-6/IL-6R signaling pathway in lymphatic metastasis.

Main Results:

• The μLYMPH system successfully generated human lymphatic vessels with physiological leakiness and draining function.
• Identified the follistatin/activin axis as a novel pathway in lymphatic vessel maintenance and inflammation.
• Demonstrated impaired vessel barrier function due to CAF-secreted IL-6, a potential pro-metastatic mechanism.
• Showcased the system's ability to screen therapeutic targets, as IL-6 blockade rescued vessel function.

Conclusions:

• The μLYMPH system provides a robust platform for studying lymphatic biology in health and disease.
• This model advances understanding of lymphatic vessel roles in cancer and lymphedema.
• The system facilitates the identification and validation of therapeutic targets for lymphatic-related diseases.