Nav: Home

A simple method to improve heart-attack repair using stem cell-derived heart muscle cells

August 07, 2019

BIRMINGHAM, Ala. - The heart cannot regenerate muscle tissue after a heart attack has killed part of the muscle wall. That dead tissue can strain surrounding muscle, leading to a lethal heart enlargement.

Biomedical engineers believe they can aid the failing heart by using pluripotent stem cells to grow heart muscle cells outside of the body, and then injecting those muscle cells or adding a patch made from those cells, at or near the site of the dead heart tissue. Experimental and clinical trial evidence with this approach has shown moderate improvement of the pumping ability of the heart's left ventricle.

However, the ability of the delivered cells to remuscularize the heart and improve cardiac function depends on the quality of those cells. A challenge has been low rates of engraftment by the transplanted cells.

University of Alabama at Birmingham researchers now report a simple method to improve the quality of the delivered cells, and they found that this method -- tested in a mouse heart attack model -- doubled the engraftment rate of the injected stem cell-derived cardiomyocytes. In a research letter in the journal Circulation, co-senior authors Ramaswamy Kannappan, Ph.D., and Jianyi "Jay" Zhang, M.D., Ph.D., say their robust approach to select functionally competent, intact-DNA cells from a heterogeneous population can be easily adopted in clinical settings to yield cells that are better able to repopulate the ischemic myocardium and improve the performance of a failing heart.

Zhang is chair of UAB Biomedical Engineering, a joint department of the UAB School of Medicine and School of Engineering, and holds the T. Michael and Gillian Goodrich Endowed Chair of Engineering Leadership. Kannappan is an assistant professor in the UAB Department of Biomedical Engineering.

Cardiac cell transplantation requires millions of stem cells or their differentiated derivatives. Cell propagation under accelerated growth conditions is a common way to get these large numbers of cells; but accelerated growth causes culture stress, including lethal DNA damage. These DNA-damaged cells are not suitable for cell transplantation and have to be removed from cell preparations.

The researchers found they could activate transcription factor p53 in induced pluripotent stem cells to selectively induce programmed cell death, or apoptosis, specifically in DNA-damaged cells, while sparing DNA damage-free cells. They used Nutlin-3a, an MDM2 inhibitor, to activate the p53. After Nutlin-3a treatment, the dead cells were washed from the culture, and the remaining DNA damage-free cells were cultured normally and differentiated into cardiomyocytes.

They then injected 900,000 of the derived cardiomyocytes into the border zone in the left ventricle of the mouse heart-attack model. Four weeks later, the researchers found a significantly higher engraftment rate, about 14 percent, in hearts that received the DNA damage-free cardiomyocytes. Engraftment of the control derived cardiomyocytes was about 7 percent.

"To our knowledge," Kannappan and Zhang said, "this is the first study to show that DNA damage-free induced pluripotent stem cells can be selected by p53 activation in induced pluripotent stem cell cultures, and that DNA damage-free cardiomyocytes have enhanced cardiac engraftment potential."

Previous research by others has shown that DNA-damaged senescent cells do not undergo cell death. Instead, they remain within the tissue, with altered functions that can change the tissue microenvironment and promote aging phenotypes of other cells. This may be one explanation for the engraftment advantage of DNA damage-free derived cardiomyocytes.

The method to remove DNA-damaged cells may have wider application, Kannappan says.

"As this is a small molecule based approach to select DNA damage-free cells," he said, "it can be applied to any type of stem cells, though selection conditions would need to be optimized and evaluated. Other stem cell approaches for diseases such as neurodegenerative diseases, brain and spinal cord injuries, and diabetes might benefit by adopting our method."
-end-
Co-authors with Kannappan and Zhang for the study, "Functionally competent DNA damage-free induced pluripotent stem cell-derived cardiomyocytes for myocardial repair," are James F. Turner, Jessica M. Miller, Chengming Fan, M.D., and Amanda G. Rushdi, UAB Department of Biomedical Engineering; and Namakkal Soorappan Rajasekaran, Ph.D., UAB Department of Pathology and UAB Department of Biomedical Engineering.

Support came from National Institutes of Health grants HL 95077, HL114120, HL 131017, HL138023, HL134764 and HL118067; American Heart Association Scientist Development Grant 17SDG33670677; and startup funding from the UAB Department of Pathology.

University of Alabama at Birmingham

Related Science Articles:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.
Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.
Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.
Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.
World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.
PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.
Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.
Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.
More Science News and Science Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Accessing Better Health
Essential health care is a right, not a privilege ... or is it? This hour, TED speakers explore how we can give everyone access to a healthier way of life, despite who you are or where you live. Guests include physician Raj Panjabi, former NYC health commissioner Mary Bassett, researcher Michael Hendryx, and neuroscientist Rachel Wurzman.
Now Playing: Science for the People

#544 Prosperity Without Growth
The societies we live in are organised around growth, objects, and driving forward a constantly expanding economy as benchmarks of success and prosperity. But this growing consumption at all costs is at odds with our understanding of what our planet can support. How do we lower the environmental impact of economic activity? How do we redefine success and prosperity separate from GDP, which politicians and governments have focused on for decades? We speak with ecological economist Tim Jackson, Professor of Sustainable Development at the University of Surrey, Director of the Centre for the Understanding of Sustainable Propserity, and author of...
Now Playing: Radiolab

An Announcement from Radiolab