‘Granting’ a heart’s desire

LOUISVILLE, Ky.—In September, The University of Louisville (UofL) received one of the largest grants for medical research in the school’s history, a $13.8-million award from the National Institutes of Health (NIH) to study a promising new type of adult cardiac stem cell. The latest round of funding comes after Dr. Roberto Bolli and his colleagues discovered a new population of cardiac mesenchymal cells (CMCs) in the heart three years ago.

The announcement was made by Dr. Gregory Postel, interim president of UofL, and the study’s principal investigator, Bolli, director of UofL’s Institute of Molecular Cardiology. Bolli also serves as scientific director of the Cardiovascular Innovation Institute at UofL and as a professor and chief of the Division of Cardiovascular Medicine at the School of Medicine.

“This is a prestigious grant reflecting the magnitude of the work being conducted here,” Postel said. “Being awarded this grant is a huge, huge accomplishment.” Postel noted that the NIH didn’t just approve UofL’s grant application—a long, multistep process involving more than a dozen reviewers who are experts in the field—it funded the project with a perfect score and rare high praise. The committee reviewing the application concluded Bolli’s program was “exceptional, [with] significant translational impact, an exceptional leader and investigative team and an exceptional environment.”

Bolli and his team want to find out what CMCs will do when transplanted into a diseased heart in mice and pigs, ultimately laying the groundwork for clinical trials in patients.

“CMCs seem to be more effective,” Bolli said. “In addition to showing more promise than those we have used in the past, these cells also offer several advantages in that they can be produced more easily, faster, more consistently and in larger numbers than other adult stem cells, which have proven tricky.” This would make them easier to apply for widespread use, as specialized labs to isolate the cells would not be needed as with other types of adult stem cells.

According to the April 2017 study “Myocardial Reparative Properties of Cardiac Mesenchymal Cells Isolated on the Basis of Adherence” in the Journal of the American College of Cardiology, “Our results demonstrated that a simple method based on differential adhesion to plastic is effective in isolating reparative CMCs. This method offers several advantages. Because it does not require surface marker-based sorting with antibodies, it enables isolation of slowly adhering (SA) CMCs from virtually any species. Indeed[…]we have used this method to isolate and characterize porcine SA CMCs that are phenotypically similar to murine SA CMCs (Online Figure 7), which indicates that these cells are not unique to the mouse.

“Additionally, we have conducted preliminary studies in which we isolated a similar cell population from rat and human tissue. This method was particularly advantageous when isolating cells from small tissue samples (e.g., EMBs); because the sorting step is omitted, larger amounts of cells can be grown in a shorter period, which reduces the cost of cell production and the number of passages, resulting in the use of younger, potentially more efficacious cells. Indeed, our studies with porcine EMBs demonstrated that clinically relevant cell numbers (~1 × 108) can be generated by passage 4 from only ~50 mg of tissue.”

The NIH grant is a continuation of a Program Project Grant (PPG) that Bolli and his team were originally awarded in 2005, entitled Protection of Ischemic Myocardium. A PPG is a cluster of several projects with a common focus relating to one theme—in this case, the use of adult stem cells to repair the heart. It involves a collaboration among different investigators working as a team, a collaboration that otherwise might not be able to occur without funding. The overall goal of Bolli et. al.’s PPG is the use of stem cells to repair the damage caused by myocardial infarction by regenerating heart muscle in the area that died, replacing scar tissue with new muscle and helping make the heart stronger.

The most recent grant extension (http://grantome.com/grant/NIH/P01-HL078825-11) by Bolli reads as follows: “We will focus on cardiac mesenchymal cells (CMCs), a promising new population of heart-derived cells that we have recently discovered and that appears to be particularly suitable for clinical translation. Four closely inter-related and inter-dependent Projects will address different facets of this theme. These Projects will be supported by four Cores that will provide expertise in mouse and pig surgery, cell transplantation, CMC culture and phenotyping, pathology, flow cytometry and cell sorting.”

“[The team] will carefully evaluate the use of repeated treatments to maximize therapeutic benefit, including translational studies in a preclinical porcine model. The central hypothesis is that repeated administrations of CMCs dramatically increase the beneficial effects of cell therapy via repetitive bursts of extracellular vesicle (EV) release. The pig studies will lay the groundwork for translational investigations of CMC therapy in patients with HF. This PPG may generate disruptive new knowledge, including two new therapeutic paradigms (repeated treatments and use of cell-free EV products), either of which, in itself, would revolutionize cell therapy,” the grant continues. “The overall objective of this renewal application is to advance our understanding of the mechanism of action of CMCs and to develop strategies that optimize their efficacy for treating heart failure caused by myocardial infarction. The results of these studies will lay the groundwork for first-in-human clinical trials of CMCs.”

Bolli thanked the National Heart, Lung and Blood Institute and the NIH for their support. “It is critical that we have this type of support for the important research programs that we carry out, which can help patients around the world,” he said. “We are continually striving for new and better ways to treat heart disease. I’m confident we are not that far from a cure.”