New stem cell method sheds light on a tell-tale sign of heart diseaseJanuary 09, 2018
MADISON -- While refining ways to grow arterial endothelial cells in the lab, a regenerative biology team at the Morgridge Institute for Research unexpectedly unearthed a powerful new model for studying a hallmark of vascular disease.
The team, led by Morgridge Institute Fellow Dave Vereide, describes in the Jan. 9, 2018 issue of Stem Cell Research a new method of creating human arterial endothelial cells from cord blood and adult bone marrow sources. These cells, which have been notoriously difficult to grow in stable quantities, are essential to any future tissue engineering efforts to combat heart disease.
But a second feature of these cells may prove more influential. Vereide says the cells exhibit two distinct states: One that retains its healthy arterial properties over many generations of growth; and a second that fairly quickly shifts identity to a compromised cell type that is strongly linked to arteriosclerosis, or hardening of the arteries.
This change in identity, known as the endothelial to mesenchymal transition, is widely recognized as a major risk factor for congenital heart disease, fibrosis of vital organs, hypertension and heart attacks.
Vereide says the structural changes in the two cell types are quite visible. Endothelial cells have an elongated shape, and tend to grow in smooth, single-cell layers that comprise the inside surface of the artery. By contrast, mesenchymal cells become more star-shaped and they can deposit a calcified extracellular matrix that is prone to building up in the artery. Vereide says mesenchymal cells also can pile up on one another, leading to a thickening or buildup in the arteries that constricts blood flow.
Having these new cell lines neatly assemble in a dish in two forms -- one resistant to the mesenchymal transition, the other remarkably susceptible to it -- could be a huge boon not only to understanding the basic biology of this change, but in discovering drugs to suppress it, Vereide says.
"We think we've found this really interesting reservoir for new studies and insights on a major disease factor," says Vereide. "The fact that we have these two states makes it really easy to study, because you can sort of corral the biology into a corner and whittle down the distinctions between the two."
In creating the new cell lines, the team used two transcription factors -- or proteins that control specific genetic functions -- that were known to be important for a wide range of cell types. But it turned out that when combined, they almost exclusively regulate arterial endothelial cell growth.
That was a "super-lucky" coincidence, Vereide says. For the vast majority of things that can go wrong in the human circulatory system, almost all of them relate to artery dysfunction. That makes the arterial endothelium a prime target for discovery. Until recently, scientists had trouble getting these cells to grow in vitro, relying on arterial cells from cadavers that quickly lose their arterial traits and do not proliferate very long.
This advance provides a second valuable source for these cells. The other advance, which also came from the Morgridge regenerative biology lab in summer 2017 led by stem cell pioneer James Thomson, produced, for the first time, functional arterial cells from pluripotent stem cells at both the quality and scale to be relevant for tissue engineering, including the creation of arterial banks for use in heart surgery.
"Now we have one line of research focused on cellular therapy and another focused on drug discovery, so we're covering all the bases," he says.
What is happening in the endothelial to mesenchymal transition? Vereide says it's likely a normal process gone awry.
"My suspicion is there is a naturally occurring transition that's probably healthy, like in a response to injury," he says. "This is probably part of the normal homeostatic balance. What I think happens during disease progression is that the balance shifts, and now there's too much transition taking place and you get these massive deleterious effects."
The next big challenge will be to find the genetic differences between these cells that makes one group more resistant. Vereide says the hope is finding targets for drugs or small molecules that could restrain this disease transition. In the same way that a broad class of statin drugs has revolutionized treatment of high cholesterol, there could be a new class of drugs that attack this prime precursor to arteriosclerosis, he says.
It could also have value for cellular therapies. "You could imagine a test to predict whether your cells are going to be permissive or resistant to the transition and steer clinicians to the cells that will perform best in the human body," he says.
Arterial stem cell research is a primary focus of the Thomson lab. The vascular system in humans collectively stretches over 60,000 miles and supplies the oxygen and nutrients for every part of the body. Cardiovascular disease is the leading cause of death worldwide.
Morgridge Institute for Research
Related Endothelial Cells Articles:
Researchers have identified a protein that must be present in order for mammary stem cells to perform their normal functions.
Researchers at Boston Children's Hospital have, for the first time, generated blood-forming stem cells in the lab using pluripotent stem cells, which can make virtually every cell type in the body.
Researchers from the University of Illinois at Chicago have identified a molecular switch that converts skin cells into cells that make up blood vessels, which could ultimately be used to repair damaged vessels in patients with heart disease or to engineer new vasculature in the lab.
Researchers have developed an artificial structure that mimics the cell membrane, which can switch on immune cells to attack and destroy a designated target.
A team of researchers led by UC San Francisco scientists has demonstrated in mice that it is possible to generate healthy new liver cells within the organ itself, making engraftment unnecessary.
In a major breakthrough, scientists at the Gladstone Institutes transformed skin cells into heart cells and brain cells using a combination of chemicals.
In a new Cell Reports paper, a team led by John P.
It has been established that the activation of protease-activated receptor-2 (PAR-2) phosphorylates endothelial nitric oxide synthase (eNOS)-Ser-1177 through a distinct signaling pathway that leads to the production of the potent vascular vasodilator nitric oxide (NO), while PAR-1 activation phosphorylates eNOS-Thr-495 and decreases NO production through a separate pathway.
An examination of 130 gene expression studies in 10 solid cancers has found that when any of four related genes is overexpressed, patients have much worse outcomes, including reduced survival.
This study demonstrates that role of nanostructured biphasic morphology of segmental polyurethanes as a matrix signal for organization of endothelial cells into network structures.
Related Endothelial Cells Reading:
Endothelial Cell Biology in Health and Disease
by M. Simionescu (Editor), N. Simionescu (Editor)
Although blood capillaries were first observed through a flea-lens microscope by Malpighi in 1661,200 more years elapsed before the cellular nature of the vessel wall was conclusively demonstrated. Beginning with the middle of the 19th cen tury, our knowledge of the histological organization of blood vessels has steadily increased. However, the endothelium, which for a long time was considered to be just an inert barrier lining, had been barely explored until three decades ago. Since then, there has been an upsurge of interest in the fine structure and function of endothelial cells. Intense... View Details
Endothelial Cell Culture (Handbooks in Practical Animal Cell Biology)
by Roy Bicknell (Editor)
Endothelial Cell Culture contains chapters by experts on endothelial cells derived from the lung, bone marrow, brain, mammary glands, skin, adipose tissue, female reproductive system, and synovium. View Details
Endothelial Cells, Volume III
by Una S. Ryan (Author)
This three-volume compendium is the most comprehensive work, to date, on endothelium cells and their important role in the functions of the internal framework. The endothelial cell is broken down into its different properties, taking into consideration its part in metabolic, hemostatic, and immunological processes, as well as their interac-tion with each other and different cell types. Numerous illustrations featured throughout help clarify the importance of endothelium in maintaining the internal status quo. These volumes are indispens-able to researchers, physicians, and others interested... View Details
Endothelial Cells in Health and Disease
by William C. Aird (Editor)
This reference serves as the first source to gather current data from endothelial cell biologists in various disciplines to summarize recent progress in the field-providing a complete understanding of the endothelium in health and disease and demonstrating its potential as a therapeutic target. View Details
Endothelial Cell Plasticity in the Normal and Injured Central Nervous System
by Esperanza Meléndez Herrera (Editor), Bryan V. Phillips-Farfán (Editor), Gabriel Gutiérrez Ospina (Editor)
This book highlights the importance of endothelial cells as key players in the functioning of the nervous system under both normal and pathological conditions. The book demonstrates that endothelial cells are an essential and dynamic cell population in the central nervous system, with multiple and complex roles, not only in the maintenance of homeostasis, but also in the regulation of important processes. These include neurogenesis, neural control of reproduction, aging, neurodegeneration, and tumor invasion. The book exhaustively reviews the newest findings in this exciting new area of... View Details
Endothelial Signaling in Development and Disease
by Mirko HH Schmidt (Editor), Stefan Liebner (Editor)
This book surveys healthy and diseased vascular systems in a multitude of model organisms and systems. It explores a plethora of functions, characteristics, and pathologies of the vascular system such as angiogenesis, fibroblast growth factor signaling, lymphangiogenesis, junctional signaling, the extracellular matrix, vascular permeability, leukocyte extravasation, axon guidance factors, the angiopoietin system, and chronic obstructive lung disease. Following a preface from leading researcher Dr. Holger Gerhardt, the text is divided into three sections- the first examining the development of... View Details
Rejuvenation!: How the Capillary-Cell Dance Blocks Aging while Decreasing Pain and Fatigue
by Robert Buckingham (Author)
If you're like most people, there's a gun pointed to your head and you don't even know it.
Poor lifestyle choices can induce chronic inflammation that could result in serious or life-threatening illnesses and even death from heart attacks, strokes, debilitating arthritis, heart failure, dementia, cancers, and autoimmune disease.
But no alarms go off when we smoke a cigarette, eat a large bag of fries, or inhale a donut--so most of us don't see the gun barrel. It keeps taking aim until one day it goes off.
Vascular Responses to Pathogens focuses on the growing research from leaders in the field for both the short and long-term impact of pathogens on the vasculature. It discusses various organisms, including bacteria, parasites, and viruses, and their role in key events leading to vascular disease.
Formatted to discuss the topic of the interaction of pathogens with the vascular rather than individual diseases described separately, this reference demonstrates that common mechanisms are at play in many different diseases because they have a similar context, their vasculature.... View Details
by Dr William C. Aird (Editor)
The endothelium, the cell layer that forms the inner lining of blood vessels, is a spatially distributed system that extends to all reaches of the human body. Today, clinical and basic research demonstrates that the endothelium plays a crucial role in mediating homeostasis and is involved in virtually every disease, either as a primary determinant of pathophysiology or as a victim of collateral damage. Indeed, the endothelium has remarkable, though largely untapped, diagnostic and therapeutic potential. This volume endeavors to bridge the bench-to-bedside gap in endothelial biomedicine, with... View Details
Endothelial Modulation of Cardiac Function (Endothelial Cell Research)
by Malcolm J Lewis (Author), Ajay M Shah (Author)
Paracrine and autocrine regulation of cardiac function by "endothelial" mediators is becoming important both physiologically and pathophysiologically. This volume brings the researcher completely up to date with all aspects of endothelial regulation and cardiac function. Acknowledged experts in each field have contributed, making this work indispensable for researchers and of great interest to the clinical cardiologist.
The Endothelial Cell Research Series publishes significant reviews by experts in the field. The individual volumes provide invaluable guides to researchers studying... View Details