Nav: Home

New stem cell method sheds light on a tell-tale sign of heart disease

January 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.
-end-


Morgridge Institute for Research

Related Endothelial Cells Articles:

A protein that stem cells require could be a target in killing breast cancer cells
Researchers have identified a protein that must be present in order for mammary stem cells to perform their normal functions.
Approaching a decades-old goal: Making blood stem cells from patients' own cells
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.
Turning skin cells into blood vessel cells while keeping them young
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.
New system developed that can switch on immune cells to attack cancer cells
Researchers have developed an artificial structure that mimics the cell membrane, which can switch on immune cells to attack and destroy a designated target.
Researchers convert cirrhosis-causing cells to healthy liver cells in mice
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.
Scientists turn skin cells into heart cells and brain cells using drugs
In a major breakthrough, scientists at the Gladstone Institutes transformed skin cells into heart cells and brain cells using a combination of chemicals.
Protease-activated receptors differentially regulate endothelial nitric oxide synthase
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.
Gene family turns cancer cells into aggressive stem cells that keep growing
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.
Polyurethane phase morphology induces endothelial cell organization
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 Cells Volume 1, 2, & 3 : 3 Volume Set
by Una S. (editor) Ryan (Author)

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


The Zebrafish: Cellular and Developmental Biology, Part A Cellular Biology, Volume 133, Fourth Edition (Methods in Cell Biology)
by H. William Detrich III (Editor), Monte Westerfield (Editor), Leonard Zon (Editor)

The Zebrafish: Cellular and Developmental Biology, Part A Cellular Biology, is the latest edition in the Methods in Cell Biology series that looks at methods for analyzing cellular and developmental biology of zebrafish. Chapters cover such topics as cell biology and developmental and neural biology.

Covers sections on model systems and functional studies, imaging-based approaches, and emerging studiesWritten by experts in the fieldContains cutting-edge material on the topic of developmental biology in zebrafishNew two part edition of this important... View Details


Cardiovascular Biology: Endothelial Cell in Health and Hypertension: Volume 1 (Biomedical and Health Research)
by J.-F. Stoltz (Author)

This volume has a focus on Vascular Endothelium, NO and Hypertension and is a continuum of the volumes on Mechanobiology of Cartilage and Chondrocyte. Indeed, vascular endothelial plays a significant role in regulating blood flow, and endothelial cells (EC) have highly active metabolic functions. They generate vasoactive mediators like prostacyclin, nitric oxide (NO) and endothelin (ET-1). Endothelial cells also synthesize various proteins like von Willebrand's factor, growth factors, and tissue plasminogen activators. They have also enzymes that inactivate bradykinin and convert angiotensin... 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


Leukocyte Recruitment, Endothelial Cell Adhesion Molecules, and Transcriptional Control: Insights for Drug Discovery
by Tucker Collins (Editor)

The localized attachment of circulating leukocytes to endothelium has been recognized as the cellular hallmark of the inflammatory response. This adhesive interaction, a necessary antecedent to the emigration of leukocytes from the blood into the tissues, is mediated by vascular adhesion molecules. Leukocyte Recruitment, Endothelial Cell Adhesion Molecules and Transcriptional Control: Insights for Drug Discovery outlines some of the cellular and molecular mechanisms of inflammation with contributions from top researchers.
This volume provides an overview 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.

Robert Buckingham, MD, FACP, exposes the truth about the gun and... View Details


Endothelial Biomedicine
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


Genes, Environment and Alzheimer's Disease
by Orly Lazarov (Editor), Giuseppina Tesco (Editor)

Genes, Environment and Alzheimer's Disease discusses the role that activities such as exercise can play in cardiovascular health, while also highlighting the fact that the last 10 years have brought great discoveries in the strong environmental component of brain disorders, neurodegeneration, and cognitive decline.

It is now clear that brain insult is an environmental risk factor for AD, while on the other hand, lifestyle components such as exercise and level of education may play a protective role, delaying the onset and/or severity of the disease. Evidence from experiments... View Details

Best Science Podcasts 2018

We have hand picked the best science podcasts for 2018. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

The Big Five
What are the five biggest global challenges we face right now — and what can we do about them? This hour, TED speakers explore some radical solutions to these enduring problems. Guests include geoengineer Tim Kruger, president of the International Rescue Committee David Miliband, political scientist Ian Bremmer, global data analyst Sarah Menker, and historian Rutger Bregman.
Now Playing: Science for the People

#456 Inside a Conservation NGO
This week we take a close look at conservation NGOS: what they do, how they work, and - most importantly - why we need them. We'll be speaking with Shyla Raghav, the Climate Change Lead at Conservation International, about using strategy and policy to tackle climate change. Then we'll speak with Rebecca Shaw, Lead Scientist at the World Wildlife Fund, about how and why you should get involved with conservation initiatives.