Heart failure – when the heart muscle cannot pump blood as well as it needs to – is often due to an irreversible loss of heart muscle cells. Stem cell-based therapies offer a promising way to regenerate damaged heart tissue, but a key obstacle stands in the way: immune rejection. With a new Igniting Interdisciplinary Innovation (I3) award from the Office of the Vice Chancellor for Research (OVCR) and the Wisconsin Alumni Research Foundation, Division of Transplantation Assistant Professor Matthew E. Brown, PhD and a team of multi-disciplinary experts from the Departments of Medicine, Chemical and Biological Engineering, and Pathology and Laboratory Medicine will be coming up with a way to work around the human body’s main defense system.
“Our immune system is designed to protect us – it interprets anything that it doesn’t recognize as ‘self’ as something that is potentially harmful and that needs to be fought and destroyed,” explained Brown. “The problem is that the immune system can’t distinguish between something that is truly harmful, like viruses, bacteria, and cancer cells, and something that is actually good for us, like organ transplants or medications that are created from donor stem cells.”
Brown is collaborating with lead investigator Dr. Tim Kamp and co-leads Dr. Sean Palecek and Dr. Igor Slukvin to overcome the barrier that is the human immune system by developing a new, human-relevant animal system in which stem cell-based therapies can be tested using innovative strategies to promote immune acceptance of these medications.
“New drugs are routinely tested on animal models to establish their safety before we can start to test them in humans, but the animal immune system is different from the human system. My lab developed a mouse model that actually has a human immune system, and we’ll be using these mice to study how stem cell-derived heart tissues that have been transplanted are recognized and rejected by human immune cells,” said Brown. “Once we understand how rejection happens in this model, we can then develop ways to teach the body to tolerate transplanted donor cells and also genetically engineer them to evade detection by the immune system.”
This project will provide the research team with the preliminary data and understanding needed to support transitioning the testing of stem cell-based therapies for heart failure into large animal models. Their long-term goal is to advance new therapies that can enable long-lasting, functional heart repair without the need for harmful immunosuppressive drugs. Importantly, the results could also provide valuable insight into the development and clinical application of regenerative therapies for a wide variety of human diseases.