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

January 9, 2018, Morgridge Institute for Research
Healthy endothelial cells, which have an elongated shape and tend to grow in smooth, single-cell layers that comprise the inside surface of the artery. Credit: Morgridge Institute for Research

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 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, 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.

Mesenchymal arterial cells, which become more star-shaped and can pile up on one another, leading to a thickening or buildup in the arteries. Credit: Morgridge Institute for Research

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 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 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.

Explore further: Stem cell advance brings bioengineered arteries closer to reality

Related Stories

Stem cell advance brings bioengineered arteries closer to reality

July 10, 2017
Stem cell biologists have tried unsuccessfully for years to produce cells that will give rise to functional arteries and give physicians new options to combat cardiovascular disease, the world's leading cause of death.

Stem cells yield nature's blueprint for body's vasculature

May 30, 2017
In the average adult human, there are an estimated 100,000 miles of capillaries, veins and arteries—the plumbing that carries life-sustaining blood to every part of the body, including vital organs such as the heart and ...

Researchers identify target to prevent hardening of arteries

May 16, 2013
The hardening of arteries is a hallmark of atherosclerosis, an often deadly disease in which plaques, excessive connective tissue, and other changes build up inside vessel walls and squeeze off the flow of oxygen-rich blood ...

Recommended for you

Study may offer doctors a more effective way to treat neuroblastoma

December 7, 2018
A very large team of researchers, mostly from multiple institutions across Germany, has found what might be a better way to treat patients with neuroblastoma, a type of cancer. In their paper published in the journal Science, ...

Progress made in transplanting pig hearts into baboons

December 6, 2018
A large team of researchers from several institutions in Germany, Sweden, Switzerland and the U.S. has transplanted pig hearts into baboons and kept them alive for an extended period of time. In their paper published in the ...

'Chemo brain' caused by malfunction in three types of brain cells, study finds

December 6, 2018
More than half of cancer survivors suffer from cognitive impairment from chemotherapy that lingers for months or years after the cancer is gone. In a new study explaining the cellular mechanisms behind this condition, scientists ...

Hybrid prevalence estimation: Method to improve intervention coverage estimations

December 6, 2018
LSTM's Professor Joseph Valadez is senior author on a new study published today in the Proceedings of the National Academy of Sciences, which outlines proposals for a more accurate estimator of health data.

World's smallest wearable device warns of UV exposure, enables precision phototherapy

December 5, 2018
The world's smallest wearable, battery-free device has been developed by Northwestern Medicine and Northwestern's McCormick School of Engineering scientists to measure exposure to light across multiple wavelengths, from the ...

Are scientists studying the wrong kind of mice?

December 5, 2018
Mice represent well over half of the non-human subjects of biomedical research, and the vast majority of those mice are inbred. Formed by generation after generation of mating between brothers and sisters, inbred mice are ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.