Regenerative strategies for cardiac repair

The heart is a marvelous machine which in adult humans propagates 8000 liters of blood through our body every day. This achievement is even more impressive considering the adult human heart muscle cells (cardiomyocytes) hardly ever divide, thus cannot create new cells in case of problems with the machine. In light of this, it is hardly surprising that cardiovascular diseases, including heart attacks, are the leading cause of death in the western world. Unlike adult mammals, neonatal mice can regenerate their hearts after injury however this ability is lost 7 days after birth. In contrast, some superhero organisms such as Zebrafish and the Salamander, Ambystoma Mexicanum (Axolotl) retain robust regenerative capabilities throughout their lives enabling healing of gills, limbs, spinal cord, and hearts. Much work has been taking place in recent years to understand why adult mice cannot heal their hearts and attempts were made to induce healing by utilizing cellular cues from neonatal mice. Although these works progressed our understanding on the difference between regenerating and non-regenerating systems, to date no cardiac regenerative treatment successfully completed clinical trials. The heart possesses other cell types apart from the cardiomyocytes, these include fibroblasts, endothelial cells, and immune cells. After injury all of these cells work in concert to promote healing however very limited studies were conducted on understanding how they work in axolotls to achieve regeneration and even less studies attempted to compare between axolotls and mammalian regenerat ion. In this project we will use newly developed tools to dissect the different heart cell types and understand how they communicate with each other in the axolotl. We will then see if similar interactions also occur in regenerating neonatal mice and do not occur in non- regenerat ing adult mice. By doing these comparisons we could identify a new pro- regenerative cell type or process which could be important for cardiac regenerat ion. To test that we will perform two types of experiments: loss of function in which we will inhibit the process in axolotls and assess whether regenerat ion is impaired. The second is gain of function in which we will induce the pro-regenerative process in injured adult mice hearts and see if indeed regeneration occurs. Along with this project significant basic research value, also comes an overall goal of promoting cardiac healing and paving the way for future clinical development