Human organotypic lymphatic vessel model elucidates microenvironment-dependent signaling and barrier function
Open accessAbstract
The lymphatic system is an active player in the pathogenesis of several human diseases, including lymphedema and cancer. Relevant models are needed to advance our understanding of lymphatic biology in disease progression to improve therapy and patient outcomes. Currently, there are few 3D in vitro lymphatic models that can recapitulate the physiological structure, function, and interactions of lymphatic vessels in normal and diseased microenvironments. Here, we developed a 3D microscale lymphatic vessel (μLYMPH) system for generating human lymphatic vessels with physiological tubular structure and function. Consistent with characteristics of lymphatic vessels in vivo, the endothelium of cultured vessels was leaky with an average permeability of 1.38 × 10-5 ± 0.29 × 10-5 cm/s as compared to 0.68 × 10-5 ± 0.13 × 10-5 cm/s for blood vessels. This leakiness also resulted in higher uptake of solute by the lymphatic vessels under interstitial flow, demonstrating recapitulation of their natural draining function. The vessels secreted appropriate growth factors and inflammatory mediators. Our system identified the follistatin/activin axis as a novel pathway in lymphatic vessel maintenance and inflammation. Moreover, the μLYMPH system provided a platform for examining crosstalk between lymphatic vessels and tumor microenvironmental components, such as breast cancer-associated fibroblasts (CAFs). In co-culture with CAFs, vessel barrier function was significantly impaired by CAF-secreted IL-6, a possible pro-metastatic mechanism of lymphatic metastasis. Targeted blocking of the IL-6/IL-6R signaling pathway with an IL-6 neutralizing antibody fully rescued the vessels, demonstrating the potential of our system for screening therapeutic targets. These results collectively demonstrate the μLYMPH system as a powerful model for advancing lymphatic biology in health and disease.
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The presence of cancer-associated fibroblasts promotes cancer-cell migration in lymphatic vessel devices.
“In a later study, the same group showed that the presence of CAFs promotes cancer-cell migration in these devices (Figure 4F), but the role of lymphatic endothelial cells (LECs) herein remains to be investigated [121,122].”
From Cancer-on-chip models for metastasis: importance of the tumor microenvironment (2024) · cites this paper as [121]
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Self-citation
- Authors
- Gong, M. M., Lugo-Cintron, K. M., White, B. R., Kerr, S. C., Harari, P. M., & Beebe, D. J.
- Affiliations
- University of Wisconsin–Madison (US)
- University of Wisconsin–Platteville (US)
- Corresponding author
- Beebe, David J.
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 214
- Pages
- 119225
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC7032699
- OpenAlex
- W2945192934
- Cited by
- 87
- References
- 78
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 9 · 2023: 12 · 2022: 16 · 2021: 13 · 2020: 14 · 2019: 3
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Wisconsin Carbone Cancer Center
- College of Engineering, University of Wisconsin-Madison
- Natural Sciences and Engineering Research Council of Canada
- National Institutes of Health (R01EB010039)
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
- Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
- Keywords
- lymphatic vessels, lymphatic drainage, inflammation, breast cancer-associated fibroblasts, lymph node metastasis, tumor microenvironment, 3D in vitro model
- MeSH terms
- Cell Line, Humans, Organ Culture Techniques, Permeability, Signal Transduction, Lymphangiogenesis, Lymphatic Vessels, Endothelial Cells, Cellular Microenvironment, Human Umbilical Vein Endothelial Cells
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