Obesity-Associated Conditions Hinder Solute Drainage Function of Engineered Human Lymphatic Vessels
Obesity is a growing global health issue, closely linked to metabolic diseases such as cardiovascular diseases and diabetes, as well as lymphatic dysfunction. The lymphatic system plays a crucial role in maintaining fluid balance, immune responses, and fat metabolism. However, lymphatic function is often impaired in obese patients, leading to complications such as lymphedema. Although the association between obesity and lymphatic dysfunction is known, the specific mechanisms remain unclear. It is still uncertain whether the chronic inflammation, hypoxia, and hyperlipidemia associated with obesity directly affect the function of lymphatic endothelial cells (LECs) or indirectly impact lymphatic function by altering the mechanical properties or cellular composition of the surrounding tissue.
To explore these mechanisms, researchers developed an engineered human lymphatic vessel model to simulate the obesity-associated microenvironment and study its effects on lymphatic solute drainage function. This study not only helps to understand the relationship between obesity and lymphatic dysfunction but may also provide a theoretical basis for developing new therapeutic strategies.
Source of the Paper
The research was conducted by Alex J. Seibel, Cheyanne L. Frosti, Abderrahman R. Tlemçani, Nikhil Lahiri, Joely A. Brammer-Depuy, Matthew D. Layne, and Joe Tien from Boston University. The paper was published online on January 23, 2025, in the journal Cellular and Molecular Bioengineering, titled “Obesity-associated conditions hinder solute drainage function of engineered human lymphatic vessels.”
Research Process
1. Construction of the Engineered Lymphatic Vessel Model
Researchers first constructed blind-ended lymphatic vessels in type I collagen gels. These lymphatic vessels were created by seeding lymphatic endothelial cells (LECs) into channels formed in polydimethylsiloxane (PDMS) chambers. To simulate the obesity-associated microenvironment, researchers added tumor necrosis factor-alpha (TNF-α), cobalt chloride (CoCl₂), and oleate to the culture medium, modeling inflammation, hypoxia, and hyperlipidemia, respectively.
2. Experimental Groups and Treatments
The study was divided into several experimental groups, including: - Control Group: Lymphatic vessels were not exposed to obesity-associated conditions. - Obesity Simulation Group: Lymphatic vessels were exposed to a combination of TNF-α, CoCl₂, and oleate. - Matrix Stiffening Group: Lymphatic vessels were cultured in stiffened collagen gels to simulate obesity-associated fibrosis. - Adipocyte Co-culture Group: Lymphatic vessels were cultured in collagen gels containing adipocytes to mimic the adipocyte environment in obese tissue.
3. Solute Drainage Function Assessment
Researchers used fluorescently labeled dextran as a solute to evaluate the drainage function of lymphatic vessels. By measuring changes in fluorescence intensity over time, they calculated solute drainage rates and solute leakage. Additionally, immunofluorescence staining was used to assess the integrity of endothelial junctions in the lymphatic vessels.
4. Gene Expression Analysis
To study the effects of obesity-associated conditions on adipocytes, researchers performed gene expression analysis on adipocytes exposed to the obesity simulation conditions, measuring the expression levels of genes related to adipogenesis and inflammation.
Key Findings
1. Obesity Simulation Conditions Impair Lymphatic Solute Drainage Function
The study found that lymphatic vessels exposed to obesity simulation conditions exhibited more gaps in endothelial junctions, increased solute leakage, and significantly reduced solute drainage rates. This phenomenon was observed in both soft and stiff gels, indicating that obesity-associated conditions directly affect the function of lymphatic endothelial cells.
2. Protective Role of Adipocytes
Surprisingly, in collagen gels containing adipocytes, the obesity simulation conditions did not significantly affect the solute drainage function of lymphatic vessels. This suggests that adipocytes may protect lymphatic vessels from the detrimental effects of obesity-associated conditions through some mechanism.
3. Changes in Gene Expression
Obesity simulation conditions led to downregulation of adipogenesis-related genes (e.g., PPARγ, FABP4, and AdipoQ) and upregulation of inflammation-related genes (e.g., IL6) in adipocytes. However, conditioned medium (CM) collected from obesity-treated adipocytes did not affect the drainage function of lymphatic vessels, suggesting that adipocytes exert their protective effects through other mechanisms, such as cell-cell interactions.
Research Conclusions
This study is the first to systematically investigate the effects of the obesity-associated microenvironment on lymphatic function using an engineered human lymphatic vessel model. The findings reveal that obesity-associated inflammation, hypoxia, and hyperlipidemia directly impair the integrity of lymphatic endothelial junctions, leading to reduced solute drainage function. However, the presence of adipocytes can counteract these negative effects, suggesting a protective role of adipocytes in obesity-associated lymphatic dysfunction.
Research Value and Significance
This study not only uncovers the potential mechanisms linking obesity and lymphatic dysfunction but also provides new insights for developing therapeutic strategies targeting obesity-associated lymphedema. Future research can further explore how adipocytes protect lymphatic vessels and develop treatments based on these mechanisms. Additionally, the study demonstrates the powerful potential of engineered tissue models in studying complex physiological and pathological processes.
Research Highlights
- Innovative Model: The first use of an engineered human lymphatic vessel model to study the effects of the obesity-associated microenvironment on lymphatic function.
- Distinction Between Direct and Indirect Mechanisms: Clearly demonstrates that obesity-associated conditions directly act on lymphatic endothelial cells rather than indirectly affecting lymphatic function through the mechanical properties of surrounding tissue.
- Protective Role of Adipocytes: Reveals that adipocytes can counteract the negative effects of obesity-associated conditions on lymphatic vessels, providing a new perspective on the relationship between obesity and lymphatic dysfunction.
Other Valuable Information
The study also employed various advanced experimental techniques, such as immunofluorescence staining, gene expression analysis, and fluorescently labeled solute drainage assays, highlighting the importance of interdisciplinary approaches in biomedical research. Additionally, researchers developed automated image analysis algorithms for assessing lymphatic drainage function, providing technical references for future similar studies.