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June 18, 2015

COLUMBUS, Ohio -- Stem cell-based therapies have potential to transform treatment of almost every major health condition, possibly none quite as prevalent as heart disease. As the world’s number one cause of death, heart disease kills more than 7.5 million people each year and leaves millions more dependent on devices and medications to survive.

Since 2009, scientists have injected, transplanted and infused millions of different types of stem-cell derived treatments into dying human hearts with the goal of reversing heart disease – but so far, the results have been mixed. 

“We’ve seen a lot of tantalizing data over the years, but also a lot of variability in outcomes. Some people have small gains, while others gain nothing,” said Mahmood Khan, a cardiovascular scientist at the Davis Heart and Lung Research Institute at The Ohio State University Wexner Medical Center. “We still don’t know exactly how stem cells work to heal the heart. We do know 90 percent of stem cells die or disappear within the first four days of transplant, so their potential is probably not being fully realized.”

As scientists push forward with clinical trials to identify a cardiac stem cell regimen that can gain FDA approval, Khan and Dr. Mark Angelos, Vice Chair of Research in Ohio State’s Department of Emergency Medicine, are taking a different approach: helping stem cells survive the inhospitable micro environment of a scarred heart. 

“A damaged heart has areas of poor oxygenation and blood flow. It’s not a friendly place for stem cells to thrive,” Angelos said. “By developing techniques that improve stem cell delivery and survival, we’re hopeful the therapy can yield more consistent and greater benefits.” 

Within hours and days after a heart attack, oxygen-deprived tissue dies and chemical messengers instruct damaged heart cells to self-destruct. It’s believed this is the optimal window for delivering stem cell based therapies, when stem cells might have a chance to short circuit the remodeling process and prevent scarring which ultimately leads to heart failure. 

“It’s probably the best and worst time to deliver stem cell therapies. We’re sending them into a battlefield where there is minimal oxygen and genes are telling cells to self-destruct,” Khan said.

Khan says 30% of all mammalian protein-encoding genes are regulated by microRNAs (miRNAs), single-stranded RNA molecules. Research has shown that miRNAs have great potential as a therapeutic target for treating many conditions including cardiovascular disease. Altered expression of miRNAs such as miR-1, miR-133, miR-21 and miR-208 has been shown to contribute to the development of heart disease. The researchers focused on miR-133a which plays a role in slowing fibrosis and cardiac remodeling. Levels of miR-133a are reduced in people who have suffered a heart attack. 

The team hypothesized that if they could increase miR-133a in stem cells as they are cultured, they might be able to pre-program the cells to survive. Supported by a pilot grant from the Ohio State Center for Clinical and Translational Science (CCTS), the team bioengineered a molecule to induce mesenchymal stem cells (MSCs) to produce miRNA-133a. When transplanted into an animal model of cardiac ischemia, the pre-treated MSCs showed improved survival over non-treated MSCs. 

“The pre-treated MSCs did a better job of decreasing the global damage to the heart and improving the left-ventricular wall thickness compared to the untreated MSCs,” Angelos said. “MSCs are a commonly used cell type in current heart failure studies, so our findings are relevant to that work.”

The team’s results were published recently in the Journal of Cardiovascular Pharmacology.

While working on ways to increase stem cell survival, the researchers also tackled another issue facing stem cells – how to help them seamlessly function alongside existing heart tissue.

Most stem cells are grown on a flat culture plate and either injected directly into heart scar tissue or infused into the heart via an artery. While most of these stem cells either die or diffuse throughout the body, successfully transplanted stem cells sometimes inadvertently interrupt heart function. 

“The heart is a constantly moving, connected matrix of muscle fibers working together to make the heart pump in sync,” Angelos said.  “Transplanted stem cells may not align with native tissue, potentially disrupting or attenuating signals that keep a steady heartbeat.  There’s evidence this could contribute to arrhythmias.”

To create a more secure environment in which stem cells can engraft – and one that more closely resembles healthy heart tissue, Khan and Angelos have used a biodegradeable nanofiber “patch” seeded with human inducible pluripotent stem cell derived cardiomyocytes (hiPSC-CMs).  Researchers used hiPSC-CMs because they’re patient-derived and could be used for disease remodeling and autologous stem cell transplantation in patients with failing hearts. 

The aligned nanofiber patch and standard culture plate were both seeded with hiPSC-CMs, and then both were compared for calcium signaling and synchronous beating.  Within two weeks, both stem cell cultures were spontaneously beating like a miniature heart. 

“The cardiomyocytes cultured on a flat plate are scattered and disorganized. Cardiomyocytes grown on the nanofiber scaffolding look more like healthy heart cells, beat more strongly and in greater synchronicity than cells from the flat plate,” Khan said. “Next, we hope to use what we’ve learned from this study to develop a thicker, multi-layer patch that could help restore thin and weakened heart walls.”

Khan and Angelos see great potential for future clinical applications to treat patients with heart failure by bandaging the damaged heart muscle with the nanofiber cardiac patch. They believe it’s also possible to someday combine the microRNA pre-treatment and the patch to give stem cells a survival boost along with a protective structure to improve outcomes.

The nanofiber patch research published in the May 19 PLoS ONE

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The Ohio State University Center for Clinical and Translational Science (CCTS) is funded by the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program (UL1TR001070, KL2TR001068, TL1TR001069) The CTSA program is led by the NIH’s National Center for Advancing Translational Sciences (NCATS). The content of this release is solely the responsibility of the CCTS and does not necessarily represent the official views of the NIH.