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Enzyme inhibitor enhances transplanted stem cells' ability to treat heart failure

Durham, NC (August 13, 2020) – Stem cell replacement offers great potential for helping people recover from a heart attack by regenerating the damaged cardiac tissue. However, a critical barrier to the success of this promising therapy is the significant loss of transplanted stem cells due to inflammation in the host environment, which causes fibrosis (scarring) and the stem cells to die off. Today, a team of researchers report in STEM CELLS Translational Medicine that they have found a way to overcome this obstacle. Their discovery could lead to a potentially powerful class of compounds for treating heart failure.

The multi-institutional team of researchers is led by Nipavan Chiamvimonvat, M.D., Padmini Sirish, Ph.D., and Phung Thai, Ph.D. in the Division of Cardiovascular Medicine, and Bruce Hammock, Ph.D., in the Department of Entomology and Comprehensive Cancer Center, at the University of California, Davis. “A heart attack can result in a significant loss of more than a billion cardiomyocytes (heart muscle cells), which in turn leads to a decrease in heart function,” Dr. Chiamvimonvat said. “Current treatment regimen will help many patients recover over time, but unfortunately there is still a substantial number who do not improve, even with the best treatment available. For these people, heart failure remains a life-threatening disease with a five-year mortality rate of 45 to 60 percent.”

Currently, the only options for patients with end-stage heart failure are a surgically implanted mechanical pump known as a left ventricular assist device or, ideally, a heart transplant. But the limited availability of donor hearts leaves almost twice as many patients needing a transplantation each year as there are those receiving them. “This results in a compelling need to seek new options for treating heart failure,” Dr. Sirish said. 

Stem cell therapy represents one promising approach since it aims to generate new functional heart muscle and blood vessels. To date, various stem cells have been used in clinical trials with each cell type presenting several advantages and limitations. None of these have yet been able to fully restore the heart’s functions.

“This is because a high rate of transplanted stem cell loss — 90 percent — occurs within the first few days due to inflammation in the host environment,” Dr. Thai explained. “That’s why strategies for treating heart failure should focus on more than just replacing myocardial tissue. We also need to find ways to decrease inflammation so that we can give the transplanted stem cells a fighting chance of surviving in the harsh environment.”

In their study, the Chiamvimonvat/Sirish team focused on whether inhibiting an enzyme called soluble epoxide hydrolase (sEH) might be the answer. The enzyme converts epoxyeicosatrienoic acids, which are anti-inflammatory and cardioprotective, into byproducts that lose their anti-inflammatory activities. In previous studies, the team had demonstrated that treatment with sEH inhibitors led to a reduction in inflammation and cardiac fibrosis, as well as a decrease in irregular heartbeat (arrhythmia).

“This led us to hypothesize that the simultaneous reduction of inflammation due to the sEH inhibitor, in conjunction with stem cell transplantation, would enhance stem cell survival and engraftment and, thus, improve cardiac function,” Dr. Sirish said.

They tested their theory by inducing heart attacks in mice, then treating them with cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs-CMs) along with an sEH inhibitor called 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea, or TPPU. “TPPU was selected as the sEH inhibitor of choice after evaluating the pharmacokinetic and physiological properties of 11 different sEH inhibitors based on our prior publication,” Dr. Hammock said.

In total, the functional recovery of six groups of randomly assigned animals were tested. They were divided into the following groups:

  1. One that was treated with hiPSC-CMs
  2. One that was treated with TPPU
  3. One that was treated with a combination of hiPSC-CM/TPPU
  4. One that suffered a heart attack, but received no treatment
  5. A SHAM group that received no treatment. (SHAMS are used in clinical trials to help researchers determine the effectiveness of a drug or treatment. The researcher will go through the motions of a procedure or treatment – in this case, the inducement of a heart attack – without actually performing the procedure. Such groups ensure that those assessing the outcomes are “blinded” to the treatment assignment and, thus, not influenced by “wishful thinking.”
  6. A SHAM group treated with TPPUs 

“When we analyzed the results three weeks after the treatment, we saw a significant increase in the retention of transplanted stem cells, a decrease in fibrosis and an improvement in cardiac function in the hiPSC-CM/TPPU group,” Dr. Thai said. “We also observed that CRISPR/Cas9 gene editing of the sEH enzyme protects the hiPSC-CMs from undergoing apoptosis — that is, cell suicide.” 

“Taken together, our data suggests that conditioning hiPSC-CMs with sEH inhibitors may help the cells to better survive the harsh conditions in the muscle damaged by a heart attack. Granted, very little is known regarding this class of compounds in cell-based therapy,” Dr. Hammock added, “but there is consequently an opportunity to uncover a potentially powerful class of inhibitors for use in clinical settings.”

In closing, Dr. Chiamvimonvat concluded that, “Extensive work lies ahead to further translate these initial encouraging findings from preclinical models into the clinic.”

“This is an interesting study providing evidence of the potential for stem cell therapy for heart disease,” said Anthony Atala, MD, Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. “The finding is encouraging and sets the stage for further studies to uncover other anti-inflammatory agents that can be used clinically.”

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The full article, “Suppression of inflammation and fibrosis using soluble epoxide hydrolase inhibitors enhances cardiac stem cell-based therapy,” can be accessed at https://stemcellsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/sctm.20-0143.

About STEM CELLS Translational Medicine: STEM CELLS Translational Medicine (SCTM), co-published by AlphaMed Press and Wiley, is a monthly peer-reviewed publication dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and clinical trials, SCTM will help move applications of these critical investigations closer to accepted best practices. SCTM is the official journal partner of Regenerative Medicine Foundation.

About AlphaMed Press: Established in 1983, AlphaMed Press with offices in Durham, NC, San Francisco, CA, and Belfast, Northern Ireland, publishes two other internationally renowned peer-reviewed journals: STEM CELLS® (http://www.StemCells.com), celebrating its 38th year, is the world's first journal devoted to this fast paced field of research. The Oncologist® (http://www.TheOncologist.com), also a monthly peer-reviewed publication, entering its 25th year, is devoted to community and hospital-based oncologists and physicians entrusted with cancer patient care. All three journals are premier periodicals with globally recognized editorial boards dedicated to advancing knowledge and education in their focused disciplines. 

About Wiley: Wiley, a global company, helps people and organizations develop the skills and knowledge they need to succeed. Our online scientific, technical, medical and scholarly journals, combined with our digital learning, assessment and certification solutions, help universities, learned societies, businesses, governments and individuals increase the academic and professional impact of their work. For more than 200 years, we have delivered consistent performance to our stakeholders. The company's website can be accessed at http://www.wiley.com.

About Regenerative Medicine Foundation (RMF): The non-profit Regenerative Medicine Foundation fosters strategic collaborations to accelerate the development of regenerative medicine to improve health and deliver cures. RMF pursues its mission by producing its flagship World Stem Cell Summit, honouring leaders through the Stem Cell and Regenerative Medicine Action Awards, and promoting educational initiatives.