Reducing Heart Attack Scars in the Heart – Skip the Stem Cells

Two research groups have independently discovered that the heart scar that forms after a heart attack can be regenerated without stem cell treatments. Li Qian in the laboratory of Deepak Srivastava at the Gladstone Institute, and Victor Dzau’s team at Duke University have shown that the use of various molecules can trigger the conversion of scar tissue into heart muscle.

Dzau’s lab worked in mice and delivered microRNAs into fibroblasts, which are the cells that form the scar tissue in the heart. When these engineered fibroblasts took up the microRNAs, they became heart muscle cells.

MicroRNAs (miRNAs) are found inside cells are usually about 22 nucleotides long. These very small RNA molecules play important regulatory roles in animals and plants by targeting messenger RNAs (mRNAs) for cleavage or translational repression. Thus, miRNAs act as master regulatory molecules for gene expression (See Bartel DP. Cell. 2004;116(2):281-97).

“This is a significant finding with many therapeutic implications,” said Victor J. Dzau, MD, a senior author on the study who is James B. Duke professor of medicine and chancellor of health affairs at Duke University. “If you can do this in the heart, you can do it in the brain, the kidneys, and other tissues. This is a whole new way of regenerating tissue.”

After their experiments in tissue culture, Dzau’s lab showed that this conversion can also occur inside a living animal. Maria Mirotsou, PhD, assistant professor of cardiology at Duke and a senior author of the study commented, “This is one of the exciting things about our study. We were able to achieve this tissue conversion in the heart with these microRNAs, which may be more practical for direct delivery into cells and allow for possible development of therapies without using genetic methods or transplantation of stem cells.”

Since stem cells have proven difficult to manage inside the body, this mode of therapy has distinct advantages over stem cell-based treatments. Notably, the microRNA process eliminates technical problems such as genetic alterations, and also avoids the ethical dilemmas posed by the use of some stem cells.

“It’s an exciting stage for reprogramming science,” said Tilanthi M. Jayawardena, PhD, first author of the study. “It’s a very young field, and we’re all learning what it means to switch a cell’s fate. We believe we’ve uncovered a way for it to be done, and that it has a lot of potential.”

The next step is to test this approach in larger experimental animals. Dzau said therapies could be developed within a decade if additional studies advance in larger animals and humans.

“We have proven the concept,” Dzau said. “This is the very early stage, and we have only shown that is it doable in an animal model. Although that’s a very big step, we’re not there yet for humans.”

Gladstone researchers took a very different approach.  They delivered a cocktail of three genes that are known to direct cells to form heart muscle during embryonic development.  These three genes, Gata4, Mef2c and Tbx5, which are collectively called GMT, were placed into cells at the site of a heart attack.  Srivastava’s group engineered viruses to infect the heart tissue, and after inducing a heart attack, the engineered viruses were injected into the heart, at the site of the heart attack.

The heart contains several resident cell types that are not involved in contraction.  One of these resident populations is the fibroblast, which seems to be able to differentiate into heart muscle cells if properly coaxed.  The GMT-bearing viruses infected the resident fibroblasts and the infected cells differentiated into heart muscle cells that beat, formed connections with existing heart muscle cells, and contracted in synchrony.  The hearts that had suffered heart attacks came roaring back, functionally speaking, and were as good as new.

Dr. Qian, first author on this article, who is also a California Institute for Regenerative Medicine postdoctoral scholar and a Roddenberry Fellow. said, “These findings could have a significant impact on heart-failure patients—whose damaged hearts make it difficult for them to engage in normal activities like walking up a flight of stairs.  This research may result in a much-needed alternative to heart transplants—for which donors are extremely limited. And because we are reprogramming cells directly in the heart, we eliminate the need to surgically implant cells that were created in a petri dish.”

Dr. Srivastava noted, “Our next goal is to replicate these experiments and test their safety in larger mammals, such as pigs, before considering clinical trials in humans.  We hope that our research will lay the foundation for initiating cardiac repair soon after a heart attack—perhaps even when the patient arrives in the emergency room.”  Dr. Srivastava, is also a professor at the University of California, San Francisco (UCSF), with which Gladstone is affiliated.