The area of cardiac regeneration in general and of cardiac stem cell biology in particular, is an area that has attracted a lot of interest from both scientists and physicians. While a number of studies have moved aggressively ahead in clinical studies by the transplantation or mobilization of currently available stem cells from a variety of organ systems (myoblasts, mesenchymal stem cells, bone marrow stem cells, neupogen mobilization, etc.), the most recent clinical and experimental data suggests that these may not be the optimal cell types to achieve cardiac muscle regeneration.

“The discovery of a new heart cell in the mammalian myocardium is probably the most important aspect of the work.”

In short, the ideal cell type for cardiac regeneration has not been identified. Our study describes the discovery of a new cardiac stem cell in the post-natal hearts of humans and other mammalian species. A genetic approach is utilized to show their developmental origins as being related to the precursors that form the embryonic heart itself, so there is a strong developmental underpinning for these cells.

The fact that they can be renewed and expanded while maintaining their potentiality, and their robust conversion to a fully differentiated cardiac phenotype, makes a case for their utility as a model system for studying cardiogenic signaling pathways, which in turn might uncover ways to capitalize on this knowledge to guide new strategies for cardiac regeneration over the long term.

The combined relevance to developmental biology, physiology, and disease, forms the basis for the interest in the work.

The discovery of a new heart cell in the mammalian myocardium is probably the most important aspect of the work. At the same time, the use of a conditional Cre-mediated strategy utilized to achieve the temporal and cell-type-restricted islet-1 cardiac progenitor fate-mapping in the post-natal heart is novel. This should be a useful tool for the cardiovascular field, and the approach is generalizable for the discovery of other adult tissue progenitors that may have developmental origins.

Its significance lies in the discovery of a new, rare, human cardiac stem cell that can be isolated from the post-natal heart, and that can also be expanded from the few hundred cells in the post-natal heart to millions of cells.

There were many problems, and also several surprises. We initially did not expect to find cardiac stem cells in the post-natal heart, but in early studies had strong evidence for a cardiac progenitor activity in long-term cultures of non-myocardial cells. Only later did we make the connection that these cells could be identified with islet-1 as a marker based on the expression of this gene early in cardiac development, which was a serendipitous event.

This led to the ability to unravel the origins of these cells back to the earliest steps of cardiogenesis in the secondary heart field, which has important implications for the discovery of the renewal pathways that expand the stem cell population, and the molecules that trigger their differentiation into a myriad of diverse cardiovascular cell types.

It also was a key, unsuspected finding that the cardiac mesenchymal cells would provide signals that would allow the massive renewal of the rare islet progenitor cell population, and finding the basis for this activity will be a key to the whole story in the future. It should be fun sorting these out over the next few years and identifying the cellular hierarchy that governs cardiogenesis.

The studies suggest that there is value in studying both post-natal and embryonic stem cell approaches to cardiac regeneration. My own view is that human embryonic stem cells will be the most viable path forward to achieve real cardiac muscle regeneration, particularly if the islet progenitors can be successfully isolated from human ES cells and expanded on a clonal level while maintaining pluripotentcy.

At the same time there will have to be the capability of triggering their differentiation into specific progeny of interest, i.e., vascular cells, working cardiac muscle cells, or pacemaker cells, depending on the therapeutic goal. I envision that the path to achieving this goal will rest not so much on our own work, but on fundamental advances in the biology of human embryonic stem cells and approaches to high-efficiency reprogramming during human somatic cell nuclear transfer.