By Bekah McBride

For the nearly one million Americans who have a heart attack each year, receiving care in the first 90 minutes is a critical step towards restoring blood flow to the jeopardized heart muscle. Unfortunately, many patients do not receive care in this window, so a portion of their functioning heart muscle dies. Researchers have turned to stem cells as they aim to help these individuals regenerate heart muscle cells, but previous studies have shown an increased risk of life-threatening heart arrhythmias following this intervention. A new study from the University of Wisconsin–Madison is helping to remove this roadblock by advancing a different, safer approach to heart muscle regeneration.

“The goal of the project was to see if we can repair infarcted hearts with cell therapy using cells derived from human pluripotent potent stem cells,” says Tim Kamp, the Craig T. January Professor of Medicine and Director of the Stem Cell and Regenerative Medicine Center. “After a patient has a heart attack, a fair amount of muscle, up to a billion cells, can be lost and replaced by fibrous scar tissue, and that fibrous scar is unable to contract, which can start a downward spiral of heart failure that ultimately can lead to early death. Our goal is to intervene in that process, block the progression to heart failure, and ideally remuscularize the heart.”

The intervention begins by using committed cardiac progenitor cells that can be injected into the patient using a catheter. Committed cardiac progenitor cells are generated from induced pluripotent stem cells (iPSCs) and can mature into beating cardiomyocytes, which are the heart cells responsible for contracting to help pump blood throughout the body. The cells are commercially available from FUJIFILM Cellular Dynamics who provided support for the project along with the NIH Regenerative Medicine Innovation Program.

These committed cardiac progenitor cells are delivered into the damaged heart via a minimally invasive catheter, with the delivery targeted by an electroanatomic mapping system to ensure injections of the cell clusters are localized to the damaged zones of the tissue.

The concept is pretty straightforward, we put cells in that will create new heart muscle that can integrate into the existing injured heart and replace the area of damage with functional muscle, but in practice, it’s turned out not to be so simple,” says Kamp. “It is not so easy to get cells there and to get them to perfectly integrate and do things in a safe fashion. Although there have been a number of studies using iPSC cardiomyocytes, oftentimes they’ve been complicated by the presence of bad heart rhythms, called ventricular arrhythmias, that can be life threatening.”

To address this concern, Kamp in partnership with Amish Raval MD, FACC, FAHA, FSCAI, a Professor of Medicine and affiliate in Biomedical Engineering, began testing a cell product generated from human induced pluripotent stem cells called iPSC committed cardiac progenitor cells from FUJIFILM Cellular Dynamics. Unlike the cells used in most previous studies, these cells potentially can continue to grow once they enter the heart and integrate more gradually to form replacement heart tissue. They also co-injected the cells with a novel cardiac fibroblast-derived extracellular matrix (a mix of proteins, carbohydrates, and minerals that contribute to cell structure and function) designed to boost cell retention from Cellular Logistics. Ultimately, the plan was successful.

“For the first time, we observed human cell grafts of apparently integrated cardiomyocyte clusters in scarred myocardium without causing ventricular arrhythmias,” says Raval. “We also saw that minimally invasive transendocardial catheter delivery was safe and permitted numerous cell and retention matrix injections without plugging the catheter and without any complications. This delivery approach is far superior to the surgical open chest approach, in terms of clinical applicability.”

The testing is currently taking place in large animal models and showing signs of success. The team says the next step will be to fine tune the technology in hopes of moving this intervention from the lab to the clinic.

“We saw that the treated hearts responded more vigorously, consistent with an improvement in their ability to respond to stress. So that was encouraging, but the response was not quite as much as we had anticipated with the current experimental approaches,” says Kamp. “The real takeaway is that this method showed no induced ventricular arrhythmias. Most previous studies using cardiomyocytes have been plagued by these ventricular arrhythmias, so it suggests that we may have a safer road to therapy, which is an exciting result.”

There are plans in place to continue to study this technology and bring it to the clinic, but Kamp emphasized the barriers that exist in moving research forward.

“These studies are expensive and the animals are precious, so we need to carefully design the studies and identify funding mechanisms to support the next steps,” says Kamp. “The emphasis is always on making safe therapies for people and the large animal models provide the complexity that is relevant to the clinical situation and is not available currently through in-vitro or culture-based systems. This study has shown us an improvement in a safety signal with this model, which is encouraging for next steps and getting this to patient applications.”

One avenue for supporting this work has been connecting with industry partners such as FUJIFILM Cellular Dynamics and Cellular Logistics. Collaborations on such projects by multiple parties can help researchers to translate some of their basic research into clinical applications.

“It’s important to work with industry, and that’s one of the goals of the Stem Cell and Regenerative Medicine Center, to make these connections and help transition some of these potential therapies out into clinical practice,” says Kamp.

Chad Koonce, senior director of iPSC Platform at FUJIFILM Cellular Dynamics added, “One of the major challenges in translating iPSC-derived cell therapies is bridging the gap between promising biology and a cell product that can be manufactured reproducibly and at a clinically relevant scale. We spent years translating our cardiac differentiation expertise into a fully GMP-compliant process capable of producing a unique cell product that is cryopreserved at a defined stage that when thawed it will subsequently further develop into cardiomyocytes. Working with Drs. Kamp and Raval and the UW–Madison teams have allowed us to put that manufacturing platform to the test in a rigorous large-animal model. The resulting preclinical data are an important demonstration of what can be achieved when scalable iPSC manufacturing and innovative delivery approaches are developed together.”

While there is additional funding and research needed, Raval and Kamp are thrilled that this study has helped them to overcome a major barrier in stem cell therapy by showcasing the safety of this new approach.

“This type of important, translational research is critical to the advancement of novel solutions for everyday problems,” says Raval.

Kamp added, “We’re on the verge of meaningful clinical translation, where some of these therapies will get into patients more broadly. The burden of heart failure is so great in our country and around the world, and for advanced heart failure, as would be addressed by this study, the potential broad impact on patients could be significant.”