Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH PUBLISHING LLC
GLOBETECH PUBLISHING LLC
GLOBETECH MEDIA

Heart Cells Created in the Lab Devised for Drug Testing, Disease Research

By BiotechDaily International staff writers
Posted on 02 May 2012
Heart-like cells created in the lab from the skin of patients with a common cardiac disorder have been shown to contract less strongly than similarly created cells from unaffected family members. The cells also exhibit abnormal structure and respond only slightly to the wave of calcium signals that trigger each heartbeat.

Investigators used induced pluripotent stem (iPS) cell technology to create heart-muscle-like cells from the skin of patients with dilated cardiomyopathy, which is one of the leading causes of heart failure and heart transplantation in the United States. It adds to a growing body of evidence indicating that iPS cells can accurately reflect the disease status of the patients from whom they are derived.

Using the newly created diseased and normal cells, the researchers, the Stanford University School of Medicine (Stanford, CA, USA), were able to directly observe for the first time the effect of a common beta blocker drug, as well as validate the potential usefulness of a gene therapy approach currently in clinical trials.

“Primary human cardiac cells are difficult to obtain and don’t live long under laboratory conditions,” said Joseph Wu, MD, PhD, associate professor of cardiovascular medicine. Instead, researchers have relied on studies of cells from rat hearts, which beat much more rapidly, to determine more about human heart disease. “Now we’ve created heart cells from iPS cells derived from skin that allow us to study in detail the mechanisms of a common cardiac disease and how these cells respond to clinical interventions.”

Dr. Wu is the senior author of the research, which was published April 18, 2012, in the journal Science Translational Medicine. Postdoctoral scholar Ning Sun, MD, PhD, is the first author. The research is the latest in a type of research that is at times referred to as “disease-in-a-dish” studies. Employing iPS technology, other researchers have created stem cells from patients with disorders including Parkinson’s disease, amyotrophic lateral sclerosis, and Marfan syndrome.

The implications of such research are huge. According to Dr. Wu, one of the major reasons cardiac drugs are pulled from the market is unexpected cardiac toxicity--that is, they are damaging the very hearts they are meant to help. Presently, such drugs are prescreened for toxic effects on common laboratory cell lines derived from either hamster ovaries or human embryonic kidney cells. Even though these ovarian and kidney cells have been artificially induced to mimic the electrophysiology of human heart cells, they are still very different from the real thing. A reliable source of diseased and normal human heart cells on which to test the drugs’ effect prior to clinical use could improve drug screening, save billions of dollars and improve the lives of countless patients.

Dilated cardiomyopathy occurs when a part of the heart muscle enlarges and begins to lose the ability to pump blood efficiently.
Ultimately, the enlarged muscle starts to weaken and fail, requiring either medication or even transplant. Dilated cardiomyopathy, although in many instances, sporadically and without an obvious cause, can also be inherited from a range of genetic mutations.

The scientists performed skin biopsies on seven members of three generations of a family with the inherited form of the condition (called familial dilated cardiomyopathy). Four of the family members had inherited a specific genetic mutation--in a gene called TNNT2--that causes the disease; the other three had not.

The researchers used iPS technology to convert skin cells from the affected and unaffected family members into stem cells, which they then coaxed to become heart muscle cells for further study. They then compared cells from unaffected family members with those who had the disease.

“We didn’t know exactly how the mutation carried in this family would impact the contractility of the cells,” said Dr. Sun. “Other studies had indicated that this mutation decreased calcium sensitivity in rodent cells, but we had no direct biochemical data on human cells. We were able to show that the force of contraction was lower in cells from patients with the mutation. We also saw that, as predicted in the rodent model, they were less responsive to calcium signaling.” (In a healthy heart, quick, periodic upsurges in calcium levels inside heart cells trigger each contraction.)

Drs. Wu and Sun also established that the diseased cells exhibit structural differences and are more susceptible to mechanical stress than unaffected cells. When the researchers treated the diseased cells with metoprolol, a beta-blocker commonly used to treat cardiomyopathy, they found that it decreased the frequency of contractions as expected. It also increased the responsiveness of the cells to calcium, and over time, helped resolve some of the structural differences between affected and unaffected cells.
Finally, they demonstrated that adding a protein called Serca2a, which may inhibit the damaging effect of the mutated TNNT2 gene, considerably improved the contraction forcefulness of the diseased cells. Serca2a is currently in clinical trials as a possible gene therapy for dilated cardiomyopathy.

“Next, we’d like to continue looking at cells from patients with other mutations associated with this disorder,” said Dr. Wu. “How do they behave in culture? Do they respond in the same way? What is the mechanism for their response? What changes if we selectively introduce different mutations into these cells? And how do we scale up drug screening using cardiac specific iPS cell lines?”

Related Links:

Stanford University School of Medicine




Channels

Genomics/Proteomics

view channel
Image: Transmission electron micrograph of norovirus particles in feces (Photo courtesy of Wikimedia Commons).

Norovirus Interacts with Gut Bacteria to Establish a Persistent Infection That Can Be Blocked by Interferon Lambda

A team of molecular microbiologists and virologists has found that norovirus requires an intimate interaction with certain gut bacteria to establish a persistent infection, and that the infective process... Read more

Biochemistry

view channel

Possible New Target Found for Treating Brain Inflammation

Scientists have identified an enzyme that produces a class of inflammatory lipid molecules in the brain. Abnormally high levels of these molecules appear to cause a rare inherited eurodegenerative disorder, and that disorder now may be treatable if researchers can develop suitable drug candidates that suppress this enzyme.... Read more

Therapeutics

view channel
Image: Cancer cells infected with tumor-targeted oncolytic virus (red). Green indicates alpha-tubulin, a cell skeleton protein. Blue is DNA in the cancer cell nuclei (Photo courtesy of Dr. Rathi Gangeswaran, Bart’s Cancer Institute).

Innovative “Viro-Immunotherapy” Designed to Kill Breast Cancer Cells

A leading scientist has devised a new treatment that employs viruses to kill breast cancer cells. The research could lead to a promising “viro-immunotherapy” for patients with triple-negative breast cancer,... Read more

Business

view channel

Program Designed to Provide High-Performance Computing Cluster Systems for Bioinformatics Research

Dedicated Computing (Waukesha, WI, USA), a global technology company, reported that it will be participating in the Intel Cluster Ready program to deliver integrated high-performance computing cluster solutions to the life sciences market. Powered by Intel Xeon processors, Dedicated Computing is providing a range of... Read more
 
Copyright © 2000-2015 Globetech Media. All rights reserved.