Regenerating the heart after a heart attack remains one of the Holy Grails of regenerative medicine. It is a daunting task. Even though text books may say, “the heart is just a pump,” this pump has a lot of tricks up its sleeve.
Stem cell treatments can certainly improve the structure and function of the heart after a heart attack, but getting the heart back to where it was before the heart attack is a whole different ball game. To truly regenerate, the heart, the organ or parts of it need to be reprogrammed to a time when the heart could regenerate itself. If that sounds difficult, it’s because it is. But some recent work suggests that it might at least partially possible.
Kenneth Chien and his colleagues from the Department of Stem Cell Biology and Regenerative Medicine at Harvard University have published a terrific paper in the journal Nature Biotechnology that tries to turn back to clock of the heart to augment its regenerative capabilities.
The outermost layer of the heart that surrounds the heart muscle is a layer called the “epicardium.”
In the epicardium are epicardial heart progenitors and these cells are activated within 48 hours after a heart attack in the mouse. In the fetal heart, epicardial heart progenitors migrate into the heart and differentiate into heart muscle, blood vessels and smooth muscles. In adults, these cells remain on the surface of the heart and differentiate largely into fibroblasts. When it comes to regenerative medicine, can we take adult epicardial cells and reprogram them to act like fetal epicardial heart progenitors?
A few experiments have suggested that we can. In 2011, Smart and others used a small peptide called thymosin β4 to reprogram epicardial cells in mice to form heart muscle and other heart-specific tissues. Even though the reprogramming was not terribly robust, Smart and others convincingly showed that it was real (Nature 474,640–644).
The Chien group used modified RNA molecules made with unusual nucleotides that encoded the protein vascular endothelial growth factor-A (VEGF-A) to reprogram the epicardium of mice. VEGF-A is very good and reprogramming the epicardium, and this modified RNA technique does not induce and immune response the way injecting DNA does and the RNA causes bursts of VEGF-A activity that efficiently reprograms the epicardium.
After giving mice heart attacks, Chien and others injected the VEGF-A modified RNAs into the border of the infarcted area of the heart. The modified RNAs induced new gene expression that is normally seen during the establishment of blood vessels. VEGF-A expression was elevated for up to 6 days after the injections, and animals that had their hearts injected with modified VEGF-A RNA had smaller scars in their hearts, less cell death, and greater tissue volume in their hearts than animals that received either injections of VEGF-A DNA, buffer, or modified RNA that expressed a glowing protein. Also, the effects of the modified VEGF-A RNA could be abrogated with co-administrating the drug Avastin, which is an antagonist of VEGF-A
Tests with cultured heart cells showed that VEGF-A modified RNA induced blood vessel-specific genes. These inductions were sensitive to drugs that blocked the VEGF-A receptor, which shows that it is indeed the VEGF-A protein that is inducing these trends. Finally, a heart muscle gene, Tnnt2 is also induced by the modified VEGF-A RNA. When the efficacy of the modified VEGF-A RNA was tested in living animals, if was clear that the most numerous cells induced by the modified VEGF-A RNA was endothelial cells, which line blood vessels, followed by smooth muscle cells, and then by heart muscle cells.
Thus, the growth factor VEGF-A can signal to epicardial heart progenitor cells to heal the heart after a heart attack in mice. It works through the VEGF-A receptor (KDR), and it induces epicardial derived cells (EPDCs) to differentiate into blood vessels, heart muscle cells, and smooth muscle cells, all of which are required to heal the heart. If VEGF-A signaling can be used to augment heart healing after a heart attack, it might provide a new strategy for healing the heart after a heart attack in a manner that helps the heart heal itself from the inside rather than placing something from the outside into it.