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$2 million to study role-switching cells in heart failure

The National Institutes of Health has awarded more than $2 million to a team of scientists from Washington University in St. Louis and InvivoSciences, a biotechnology startup with WUSTL roots, to construct artificial tissue models that will allow the rapid testing of new drugs for heart failure.

According to the Centers for Disease Control, about 5.8 million people in the United States have heart failure, and many of them will die of their disease.

Drugs used to treat heart failure, such as the ACE inhibitors or beta blockers, improve the symptoms and allow patients to live longer and feel better. They may even reverse pathological changes in the heart tissue to some degree.

But heart failure is still the leading hospital discharge diagnosis and trials for several promising drugs for this disease have been costly failures.

The WUSTL research focuses on the role in heart disease of role-switching cells called myofibroblasts that proliferate in over-stressed or injured hearts. In response to a heart attack, fibroblasts convert to this cell type, which secretes collagen and contracts the matrix of fibers around the injured heart tissue to repair the defect.

But heart cells never truly regenerate in the damaged tissue, and myofibroblasts compensate for their absence by forming a stiff, collagenous scar that interferes with the heart’s ability to maintain stable heart rhythms and to expand and contract forcefully to pump blood.

Fibroblasts also convert to myofibroblasts in response to high blood pressure, or hypertension. The resulting diffuse invasion of myofibroblasts also interferes with the electrical and mechanical functions of the tissue, and can lead to heart failure.

“Drugs that block the effects of myofibroblasts on the electrical or mechanical properties of heart tissue or that coax them to revert to fibroblasts might be more effective than current therapies,” says Guy M. Genin, PhD, associate professor of mechanical engineering and materials science in WUSTL’s School of Engineering & Applied Science, who is one of three co-primary investigators (PI) on the grant.

A wound-healer run amok
In the 1970s, a scientist at the University of Geneva in Switzerland discovered cells in healing wounds that seemed to be intermediate in character between fibroblasts, which secrete fibers such as collagen that make up the matrix that holds cells together in tissues, and smooth muscle cells, like those in the intestines and blood vessels.

These cells, which were named myofibroblasts to reflect their double nature, secrete fibers to fill in a wound and then contract to bring together its edges. And after the wound is healed, they disappear, either by committing cell suicide or perhaps by reverting to their original cell type.

But not always.

The heart is made up predominantly of two types of cells, Genin says: the fibroblasts, which maintain the collagen and other structural proteins within the heart, and the cardiomyocytes, which do the pumping.

After a heart attack, some of the fibroblasts will convert to myofibroblasts to restore tissue integrity, and many persist even after their work is done. If blood pressure is high enough to provoke fibroblasts to become myofibroblasts, the cells also may get stuck in their helper state.

The cardiomyocytes don’t proliferate, but the myofibroblasts keep dividing, gradually replacing healthy tissue with fiber-stiffened (fibrotic) tissue.

This phenomenon is not limited to the heart. Myofibroblasts can proliferate elsewhere in the body as well — although they may arise from different cell types in different tissues — and fibrotic remodeling of the kidney, liver (cirrhosis of the liver) and lungs follows a similar progression, Genin says.

The severe consequences of myofibroblast dysfunction motivate the effort to better understand these enigmatic cells.

Artificial heart tissue

“There’s a lot we don’t understand about what these cells do in the heart,” Genin says.

“We don’t know why conversion of fibroblasts to the contractile phenotype is sometimes helpful and sometimes harmful. We don’t know how these cells alter the electrical and mechanical properties of heart tissue, or the degree to which these changes are to blame for the ultimate shutdown of the heart.

“We think that a therapy that would control the number and properties of myofibroblasts in the heart might be useful, but we don’t know that for sure,” Genin adds. “Nor do we know how to reverse the transition to this cell phenotype once it has occurred.”

Many of these questions would be very difficult to sort out in real tissue, so the scientists use model tissues invented at WUSTL in Eliot Elson’s lab. Elson, PhD, the Alumni Endowed Professor of Biochemistry and Molecular Biophysics in the Department of Biochemistry and Molecular Biophysics at WUSTL’s School of Medicine, is the second of three co-PIs on the grant.

To make the tissues, the scientists crack open fertilized chicken eggs, pull fibroblasts and muscle cells out of the embryos’ hearts, and mix them together with collagen.

“Over the course of time, the cells interact with each other and the collagen to form pieces of artificial heart that beat on their own in a Petri dish,” Elson says.

The scientists can control the number of myofibroblasts in the tissue (most fibroblasts convert to myofibroblasts when they are plated out) and their distribution. In this way, they can mimic the fibrotic changes characteristic of a heart attack and those characteristic of hypertension.

“For a model of myocardial infarction, we want to create an island of wound-healing cells inside a patch of heart tissue, and for hypertension, we try to create what’s called interstitial fibrosis, in which the myofibroblasts are interspersed between the contractile cells,” Genin says.

The electrical and mechanical activity of the manufactured tissues then can be investigated with the help of a variety of sophisticated imaging and force measurement techniques, many developed at WUSTL in the laboratories of Elson and Genin, and of Igor Efimov, PhD, the Lucy and Stanley Lopata Distinguished Professor of Biomedical Engineering in the School of Engineering & Applied Science.

At the same time, the scientists are developing computer models that are digital analogs of the artificial tissues, including electrophysiological models pioneered by Yoram Rudy, PhD, the Fred Saigh Distinguished Professor of Engineering in the School of Engineering & Applied Science. The back and forth between the tissue models and the computer models will allow them to test basic biophysical theories explaining their experimental observations.

Drug screening with tissue constructs
Once they understand the basic cellular biophysics of failing heart tissue, they will transfer their work to tissue models that will make it much faster and safer to test drugs for heart failure and hypertensive heart disease, the scientists say.

They plan to make the transition to drug screening with the help of InvivoSciences, whose chief scientist Tetsuro Wakatsuki, PhD, the third PI on the grant, earned a doctorate in biophysics and a master’s degree in mechanical engineering at Washington University.

InvivoSciences makes engineered heart tissues from mouse embryonic stem cells and stem cells from differentiated adult tissues in humans, such as fat and skin. The company then uses biochemical methods to convert these undifferentiated cells to tissue- or organ-specific cells, such as cardiomyocytes and fibroblasts, and to generate artificial tissues from them.

“We’ll develop the science on the much less expensive chicken egg tissues and then we’ll start our own stem cell bank here and begin making these mouse-derived tissue constructs,” Elson says. The mouse constructs are more useful because of the molecular genetic tools available for mice.

Staggering investments of time and money have failed to produce new drugs for heart failure. The scientists hope that the artificial tissues will allow many more drugs to be tested under conditions closer to those within the human body. Their hope is that drug candidates that get as far as animal testing and clinical trials will then be more likely to be safe and effective.

Tech and Biotech: Madison’s InvivoSciences to work with Rhode Island company

InvivoSciences, a Madison biotech, is teaming with Myomics, of Providence, R.I., to provide screening services using their combined resources.

InvivoSciences provides engineered human heart tissues for companies working on drugs to treat heart disease while Myomics offers engineered muscle tissues to drug companies focused on fighting muscular dystrophy.

Both companies also have developed robotic systems used to examine the tissues in three-dimensional models. They say their systems can help predict the safety and effectiveness of drug compounds early on.

InvivoSciences had a lab in Waukesha but moved all of its operations to Madison, CEO Ayla Annac said.

The company has four employees, down from nine last year, and raised $4 million in grants and private funding since it was founded in 2001. Annac said InvivoSciences is trying to raise another $3 million to $5 million to expand to the global market.

InvivoSciences was named this week as one of three finalists in the category of science or medical analytic systems for the Edison Awards, honoring innovation in product and service development. The other finalists in that category are 3M and CardioDX.

Only one other Wisconsin company was named as a finalist in the competition: Johnson Controls of Glendale is a contender for the Edison Green Award.

InvivoSciences LLC is a 2012 Edison Awards Finalist

Wisconsin Company, InvivoSciences LLC (IVS), is honored to be chosen as a finalist alongside 3M and CardioDX in the highly competitive Medical Science-Analytic Systems category by Edison Awards. Other finalist include Abbott, Johnson and Johnson, Apple, The Dow Chemical, GE Health Care, The Proctor and Gamble Company. Winning an Edison Award has become one of the highest accolades a company can receive in the name of innovation and business. The Edison Awards, celebrating its 25th year, has announced its finalists for the internationally renowned 2012 Edison Best New Product Awards. Since 1987, The Edison Awards have recognized ideas at the forefront of new products, services, marketing, design and innovation.

“The Edison Awards provide an exclusive platform for honoring innovation, recognizing innovators, and encouraging ongoing innovation among today’s development teams, researchers, designers, ‘intrapreneurs’ and entrepreneurs,” says Thomas Stat, the 2012 Edison Awards Steering Committee Chairman. “We’re inspired by our 2012 finalists and delighted to have this opportunity to recognize and promote the outstanding accomplishments they represent.”

The awards are named after Thomas Alva Edison (1847-1931) whose extraordinary new product development methods and innovative achievements garnered him 1,093 U.S. patents and made him a household name around the world. The ballot of nominees for the Edison Best New Product Awards™ is judged by a panel of more than 3,000 individuals, including members of the Marketing Executives Networking Group (MENG), an organization comprising America’s top marketing professionals and academics. The panel also includes professionals from the fields of product development & design, engineering, science and education.

Dr. Elliot Elson and Dr. Tetsuro Wakatsuki shared their excitement in recognition of their invention and their work in the areas of tissue engineering and pharmaceutical screening. NIH funded development of the novel platform technology. When Ayla Annac, CEO of IVS, was asked how she felt about being an Edison Award finalist, she stated that, “We are honored to be one of the finalists in our category. InvivoSciences will continue to contribute to the improvement of human health by establishing a new paradigm for discovering drugs that focus on diseases with limited treatment options such as cardiac fibrosis, scleroderma, and lupus in a time-effective manner while remaining safe and cost effective.”

The 2012 Edison Awards are sponsored by Nielsen, Discovery Communications, Science Channel, USA Today, CSRware and Applepeak. For more information about the Edison Awards click here.

InvivoSciences LLC, established in 2001, creates, manufactures and markets tools for three dimensional (3D) cell culture systems and provides compound screening services with them. Palpator ™ is a robotic mechanical profiler for ultra-soft materials, such as biological tissues and engineered tissue constructs of various types including human engineered heart tissues. The tissue culture tools developed by IVS, MicroChamber- 8TM (MC-8 ™) and IVS Inserts™, enable fabrication, growth, assay and storage of engineered tissue constructs without removing them from wells. With a mechanical conditioning device, Tissue Stretcher™, tissue constructs can be cultured under repetitive mechanical stimuli. IVS has been successfully providing contract research services to identify lead compounds and novel product benefits for pharmaceutical, cosmetic, biotech, food, and chemical companies. For more information, please visit www.invivosciences.com