Humans and other mammals are unable to regenerate significant portions of muscles of the body or heart lost to trauma or ischemic injury, for example from motor vehicle accidents, surgery or heart attacks. Despite the fact that we know there are stem cells in our muscles, these do not suffice to replace the large amounts of tissue that can be lost in many types of injuries. Even more dramatically, in the heart, there is no significant ability to regenerate damaged tissue. Whereas humans may be said to have poor regenerative capacity, some animals have an extraordinary ability to replace damaged or lost body parts such as a limb, a jaw or a large part of the heart. Such regenerative vertebrates include urodele amphibians (salamanders and newts) or fish such as zebrafish. These animals excel at regeneration by utilizing mechanism that is distinct from classical stem cell based regeneration as we currently understand it in mammals. Regeneration in newts and zebrafish is based at least in part on dedifferentiation and proliferation of lineage-committed cells to regenerate skeletal muscle and the heart. Dedifferentiation is thought to provide large numbers of progenitor cells that proliferate at the site of an injury or an amputation and contribute to the regenerating structure. By contrast, resident stem cells that exist in humans and other mammals represent a small proportion of the total cells in a given tissue and it is easy to imagine how much proliferation would be required for these scarce cells to rebuild a complete organ such as the heart or a structure such as a limb. But what if we could recruit all of the cells at the site of an injury as our regenerative counterparts do? The overall goal of this proposal is to mimic the "regeneration by dedifferentiation" paradigm in human muscle cells and to enhance regeneration in vivo. While the basal growth control mechanisms in mammals such as ourselves are similar to those in regenerative organisms, we have added levels of complexity that, it is our hypothesis, contribute to suppressing regeneration. The goal of this proposal is to transiently target growth regulators that are present in mammals but conspicuously absent in regenerative organisms to induce differentiated cells such as cardiomyocytes to become progenitors that can expand at the site of an injury and then replace damaged tissue. This approach, if successful has the distinct advantage of mimicking a process that already exists in nature and as such may be readily transitioned to medical approaches in humans.
Statement of Benefit to California:
Humans are unable to regenerate significant portions of muscles of the body or heart lost to trauma or ischemic injury, for example from motor vehicle accidents and surgery or from heart attacks. Despite the fact that we know there are stem cells in our muscles, these do not suffice to replace the large amounts of tissue that can be lost from in many types of injuries. Even more dramatically, in the heart, there is no significant ability to regenerate damaged tissue. In California, as elsewhere, debilitating injuries and heart disease take a staggering toll on patients, their families and on health care spending. The research described in this proposal has significant potential to benefit Californians. First, and foremost, the experiments are aimed at improving our ability to regenerate skeletal muscle and heart. If this research is successful, Californians will directly benefit from the translation to therapy. The people of California will be the first benefactors of new solutions generated by this CIRM funded research.