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Updated: Apr 24, 2026
A Microphysiological System to Study Leukocyte-Endothelial Cell Interaction during Inflammation
Published on: December 9, 2021
Human microvascular pericyte basement membrane remodeling regulates neutrophil recruitment
Parid Sava1, Ian O Cook, Rajwant S Mahal
1Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.
Objective:
Neutrophil extravasation at post-capillary venules, consisting of EC, PC, and the shared ECM, increases following fibrotic remodeling in the lung, liver, and skin. The role of fibrotic pericyte-derived ECM in regulating EC activation and neutrophil recruitment remains unexplored.
Methods:
To elucidate the role of human pericyte-derived ECM in EC activation, we characterized PC-derived ECM following transforming growth factor-β1, IL-1β, CCL2, or bleomycin activation, and examined surface adhesion molecule expression and neutrophil recruitment by EC cultured on PC-ECM.
Results:
Pro-inflammatory activation of PC-induced deposition of compositionally distinct ECM compared with non-activated control. Bleomycin activation induced fibronectin-rich and collagen-poor ECM remodeling by PC, facilitating increased neutrophil transendothelial migration when compared with non-activated pericyte ECM (49.9 ± 3.4% versus 29.7 ± 1.4%). Increases in fibronectin compared to collagen I, are largely responsible for ECM-regulated neutrophil recruitment, as EC cultured on fibronectin supported increased neutrophil transmigration compared to collagen I (51.6 ± 6.2% versus 28.0 ± 4.8%). We attribute this difference to increased expression of ICAM-1 and its redistribution to EC borders.
Conclusions:
This is the first demonstration of human pericyte sensitivity to inflammatory stimuli, inducing fibrotic matrix deposition that regulates EC adhesion molecule expression and neutrophil recruitment.
Insights
Inflammatory stimuli activate human pericytes to deposit extracellular matrix (ECM), altering endothelial cell (EC) activation and increasing neutrophil recruitment. Fibronectin-rich ECM enhances neutrophil migration more than collagen-rich ECM.
Area of Science:
- Cell Biology
- Immunology
- Tissue Engineering
Background:
- Neutrophil extravasation is crucial for immune response but contributes to fibrotic diseases.
- Pericyte-derived extracellular matrix (ECM) plays a role in regulating endothelial cell (EC) function.
- The specific contribution of fibrotic pericyte ECM to EC activation and neutrophil recruitment is not well understood.
Purpose of the Study:
- To investigate the role of human pericyte-derived ECM in regulating EC activation and neutrophil recruitment.
- To characterize the composition of ECM deposited by activated pericytes.
Main Methods:
- Human pericytes were activated with inflammatory stimuli (TGF-β1, IL-1β, CCL2, bleomycin).
- Pericyte-derived ECM was characterized, and ECs were cultured on this ECM.
- Surface adhesion molecule expression and neutrophil recruitment by ECs on PC-ECM were examined.
Main Results:
- Pro-inflammatory activation induced distinct ECM deposition by pericytes.
- Bleomycin-activated pericytes produced fibronectin-rich, collagen-poor ECM, increasing neutrophil transmigration.
- Increased fibronectin, compared to collagen I, in ECM enhanced neutrophil recruitment by upregulating ICAM-1 on ECs.
Conclusions:
- Human pericytes respond to inflammatory stimuli by depositing fibrotic ECM.
- This pericyte-derived fibrotic ECM modulates EC adhesion molecule expression.
- The study demonstrates a novel mechanism for regulating neutrophil recruitment in fibrotic conditions.
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