Cited by 87Lymphatic System and DiseasesLymphatic Disorders and TreatmentsParasitic Diseases Research and Treatment

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

Open access
Gong, Max M., Lugo-Cintron, Karina M., White, Bridget R., Kerr, Sheena C., Harari, Paul M., Beebe, David J.·2019·Biomaterials

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.biomaterials.2019.119225

Cites

78 of 78 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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].”

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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)
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review