Diseases of the lung vasculature, including primary pulmonary hypertension, capillary leak syndrome/ARDS, and inhalation injury, are difficult to study in vivo. The complexity and dynamism of the lung microvascular interface with the alveolar air sacs makes it almost impossible to capture the evolution of lung disease processes over time, and therefore difficult to understand the disease etiologies. The overall objective of this proposal is to develop an experimental platform that mimics the pulmonary microvasculature, and that can simulate native cellular phenotypes and functions in vitro, during normal homeostasis and during disease states such as multi-organ failure, severe inflammation, and sepsis. Pulmonary microvascular endothelium, which displays distinct molecular profiles and functions as compared to endothelium from large vessels and other organs, is critical to controlling thromboresistance, vascular barrier, and vessel wall inflammation in the lung. Physiological lung microvascular niche characteristics, such as hemodynamics, extracellular matrix composition, cytokine concentrations, and oxygen tension are all of pivotal importance to maintaining endothelial function and vascular homeostasis. We previously derived a purified population of microvascular endothelial cells and made a prototype microvascular platform, using perfusable microchannels and controlled luminal flow. In this study, we will 1) test purified pulmonary microvascular endothelium in the current engineered platform, and compare single-cell gene expression profiles to those from the native lung. Then, we will 2) utilize unprecedented single-cell RNA-sequencing data to identify physiological factors that may help to maintain microvascular homeostasis, in terms of barrier formation, and thromboresistance; and 3) include critical lung niche constituents, to include proper matrix components, and their mechanical signals, soluble local factors, to increase the fidelity of the microvascular in vitro model with the native lung. This work will lead to the creation of a novel platform which, unlike previous microvascular platforms, specifically resembles many physiological aspects of the native lung environment. Such a platform could be used for pulmonary vascular disease modeling and drug testing.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|