Primary Human Lung Pericytes Support and Stabilize In Vitro Perfusable Microvessels

Significance Statement

Microvessels play a particular role in the lung, where they optimally distribute blood around the alveoli for oxygenation. In lung diseases such as pulmonary hypertension, blood vessels are constricted and remodeled, but the cause and the mechanisms of these changes remain largely unknown. To study microvascular remodeling more closely, we developed an in vitro microfabricated platform where primary human lung cells self-assembled into long-living microvascular networks. The microvessels were perfusable, functionally responsive to a vasoconstrictor and showed physiologically relevant permeability values. In this study, functional microvessels were built with primary human lung cells only for the first time and the role of pericytes highlighted. These cells line the endothelium and stabilize the microvasculature. Most strikingly, upon exposure to phenylephrine a vascoconstrictor, microvessels surrounded by pericytes contracted. Such functional microvascular model opens up new ways to study microvascular remodeling in vitro and test pharmacological compounds in an in vivo-like setting.

Figure: chip and perfused microvascular network.
Left: Microfluidic chip with two compartments in which lung microvasculature is reproduced.
Right: Detail view of perfusable and stable microvasculature with vessel sizes ranging from 20 to 130 micrometers.

Primary Human Lung Pericytes Support and Stabilize In Vitro Perfusable Microvessels- Global Medical Discovery

Journal Reference

Tissue Eng Part A. 2015 Aug;21(15-16):2166-76.
Bichsel CA1,2, Hall SR3,4, Schmid RA3,4, Guenat OT1,2,3, Geiser T2,4.

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1Lung Regeneration Technologies, ARTORG Center, University of Bern , Bern, Switzerland .
2Division of Pulmonary Medicine, University Hospital of Bern , Bern, Switzerland .
3Division of Thoracic Surgery, University Hospital of Bern , Bern, Switzerland .
4Department of Clinical Research, University of Bern , Bern, Switzerland.


The formation of blood vessels is a complex tissue-specific process that plays a pivotal role during developmental processes, in wound healing, cancer progression, fibrosis, and other pathologies. To study vasculogenesis and vascular remodeling in the context of the lung, we developed an in vitro microvascular model that closely mimics the human lung microvasculature in terms of three-dimensional architecture, accessibility, functionality, and cell types. Human pericytes from the distal airway were isolated and characterized using flow cytometry. To assess their role in the generation of normal microvessels, lung pericytes were mixed in fibrin gel and seeded into well-defined microcompartments together with primary endothelial cells (human umbilical cord vein endothelial cells). Patent microvessels covering an area of 3.1 mm(2) formed within 3-5 days and were stable for up to 14 days. Soluble signals from the lung pericytes were necessary to establish perfusability, and pericytes migrated toward endothelial microvessels. Cell-cell communication in the form of adherens and tight junctions, as well as secretion of basement membrane were confirmed using transmission electron microscopy and immunocytochemistry on chip. Direct coculture of pericytes with endothelial cells decreased the microvascular permeability by one order of magnitude from 17.8×10(-6) to 2.0×10(-6) cm/s and led to vessels with significantly smaller and less variable diameter. Upon phenylephrine administration, vasoconstriction was observed in microvessels lined with pericytes, but not in endothelial microvessels only. Perfusable microvessels were also generated with human lung microvascular endothelial cells and lung pericytes. Human lung pericytes were thus shown to have a prominent influence on microvascular morphology, permeability, vasoconstriction, and long-term stability in an in vitro microvascular system. This biomimetic platform opens new possibilities to test functions and interactions of patient-derived cells in a physiologically relevant microvascular setting.

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About the author

Colette Bichsel is a PhD candidate at the ARTORG Center for Biomedical Engineering at the University of Bern, in collaboration with the Division of Pulmonary Medicine at the University Hospital of Bern. She holds a MSc. degree in Bioengineering from the Swiss Federal Institute of Technology (EPFL), and has expertise in microfabrication, microfluidics, mammalian cell culture, microscopy and molecular biology.

About the author

Dr. Sean R. R. Hall is Group Leader at the Department of Thoracic Surgery of the University Hospital of Berne in Switzerland. His research theme is dedicated to studying stromal immunobiology in organ repair and regeneration and cancer. He holds a Bachelor of Science studies in Anatomy and Cell Biology from McGill University, Montreal, Quebec Canada. He then completed a Master of Science and a Doctorate in Pharmacology & Toxicology at Queen’s University, Ontario, Canada. He then carried out a postgraduate work as a Merck Frost Pharmacology Fellow at Queen’s University and a Research Fellow at Brigham & Women’s Hospital, Harvard Medical School, Boston USA. Following completion of research fellowship, he took up a Senior Scientist position in a Biotech startup at NeoStem Inc., located in Cambridge, MA USA. After a short stint in Biotech, he relocated to Rotterdam, NL to work in the Division of Transplantation Surgery, Erasmus Medical Center as a Senior Scientist.

About the author

Prof. Dr. med. Ralph A. Schmid is the Director of the Division of General Thoracic Surgery at the University Hospital Bern, Switzerland since 1999. He is the immediate Past President of the Swiss Society of Surgery. He graduated from the University of Zürich Medical School and completed the surgical training at the University Hospital in Zürich. The initial research focus was the field of lung transplantation and gene transfer to improve postoperative allograft function and reduce rejection. In the last five years the focus of the thoracic surgery research lab he supervises was on cancer research and the role of tumor stem cells / tumor initiating cells in lung cancer. Thoracic Surgery and Pulmonary Medicine are part of the Lung Regeneration Technologies Group at the Artificial Organs Center for Biomedical Engineering Research (ARTORG) at the University of Berne in Switzerland.

About the author

Prof. Dr. Olivier T. Guenat is the Head of the Lung Regeneration Technologies Group at the Artificial Organs Center for Biomedical Engineering Research (ARTORG) at the University of Berne in Switzerland. He is associated with the Pulmonary Medicine and the Thoracic Surgery Divisions of the University Hospital of Berne. His research focuses on the development of organs-on-chip, in particular lung-on-chips that mimic the healthy and diseased in-vivo cellular microenvironments of the lung. Prior to his position at the University of Berne, he held a position at the Swiss Center for Electronics and Microelectronics (CSEM), at the Ecole Polytechnique de Montréal (QC, Canada), before which he performed a post-doc at Harvard Medical School in Boston and at the University of Neuchâtel in Switzerland. He has received several awards such as a fellowship for advanced researchers from the Swiss National Foundation. He is also the founder of AlveoliX, a biotech start-up that aims at bringing organs-on-chip on the market.

About the author

Prof. Dr. med. Thomas Geiser is Director of the Department of Pulmonary Medicine at the University Hospital of Bern, Switzerland, since 2009. He graduated from the University of Bern and pursued his postgraduate studies at the University of Zurich, Bern and at the University of California in San Francisco at the Cardiovascular Research Institute und Lung Biology Center. One of his clinical and scientific research foci is the development of novel treatment strategies in patients suffering from interstitial lung disease including lung fibrosis. The Department of Pulmonary Medicine is a national reference center for lung fibrosis, which take care of over 100 patients/year. His research aims at better understanding the pathomechanisms of interstitial lung diseases, in order to develop novel therapies.



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