Master Cardiac Stem Cell May Progress Regenerative Heart Therapy
27 Nov, 2006 06:25 pm
The core finding of this study and of a companion study by the laboratory of Stuart Orkin at Children's Hospital essentially points to a paradigm for generating multiple different cell types in the heart from a stem cell-based model, as opposed to a model where all these different heart cell lineages come from distinct locations in separate embryonic precursors. There is a master cardiovascular progenitor cell with the function to form the three different cell types of the heart. It is essentially the ancestor of the previously reported islet progenitor that exists in the neo-natal heart of mice, rats, and humans.
Basically, the study  and a companion study done by the laboratory of Stuart Orkin at Children's Hospital  is designed to uncover the basis of how the heart designs these different cell types. In many cases one can see the diversity of the cells in the heart are as diverse as the cells in blood; there is working muscle and atrium ventricle cells—and even in the ventricle, there are different types of cells with different action potentials. The atrium [cells] are different from the ventricle cells. There are conduction system cells that are modified cardiac muscle cells and it’s been clear for many years that these actually come from a common precursor with working muscles. There is some point in development that has not been clear, where there is a branching and the common precursor can give rise to either the conduction system, which is made of specialized cells that have pacemaker activity, or working muscle cells. In addition, there are smooth muscle cells, that are non-striated, located in the vasculature, large vessels, the aorta pulmonary arteries, and also in the coronary arteries. Finally, there are endothelial cells that line the heart. In a nutshell, our study shows that a single cell, in the secondary heart field, can give rise to all these three major lineages. Using lineage tracing based upon genetic tagging, we have been able to show that, in vivo, the islet + cells and their descendants contribute to over 2/3 of the cells in the heart, including these three major cell types and all the major regional compartments in the heart, with the exception of the left ventricle.
How did you come to this conclusion?
The approach is entirely based on studies done on mice and there are multiple independent approaches. Earlier in a paper in Nature 2005, we had shown that islet marks are a very rare progenitor population in the neo-natal heart that can go into a fully differentiated cardiac myocyte genotype, that being a sort of cardio blastocyte which will be analogous to the satellite cells present in the neo-natal heart. This established that islet could mark a progenitor population specific cell type. Now, it had been known earlier that islet marks a secondary heart field and that this can give rise to a number of different tissues, so it became natural to examine whether or not islet precursors could give rise to other cell types beyond cardiac muscle. That was the beginning of looking at this in the adult heart where we could trace back, viewing that even though these individual tissues no longer express islet, they actually are derived from and descendants of the very earliest origins of the heart. They can be traced back to the islet progenitors, to a family of islet progenitors, that we describe in the paper. We went on knowing that to ask the question, “If islet + cells can give rise to all these tissues, is there the possibility that a single islet cell could make the decision to become anyone of these?” The ability of islet to mark a specific set of master cardiovascular progenitors, which could go in any one of three directions, would essentially define how these lineages are formed. We then moved to embryonic stem cells where you can study events in cardio-genesis, identifying and cloning this islet + master cardiovascular progenitor cell that is essentially the ancestor of the previously reported islet progenitor that exists in the neo-natal heart of mice, rats, and humans. Going earlier in development, we used ES cells as a system, to later confirm that these cells actually existed in the embryo. There is both in vitro and in vivo evidence that these cells exist and have authentic function to form these three different cell types of the heart.
Does this study hold promise for cardiac stem cell therapies?
I think those are the precise terms: “hold promise.” These cells are not in a state to be considered by us, or others, to be injected into patients with heart attacks, or for cardiac repair. What this represents for us is the beginning of an alternative strategy to most of the strategies which are currently being used which are based on adult stem cells—many of which are not from the heart and whose function normally is not to form the heart or is not clear of what their function is relative to heart development. It’s almost like asking a stem cell that wants to form blood, when put into the heart, to change its mind and form the heart. [Having that happen] has been the hope. The clinical studies to date have been ambiguous. Two have been negative; these have been randomized, large-scale, double-blind placebo controlled trials. One was transiently positive, then negative, and two were marginally positive. The jury’s still out, but the bulk of the evidence suggests that the cells, in the way that their being delivered, are not regenerating cardiac muscle. With ES cells, we’ve known for 15 years or more, that they can give rise to beating cardiac muscle. It’s been difficult to harness this because the ES stem cells go in multiple different directions, creating multiple different cell types, including heart cells, but they are only a minority of the cells that are created. The idea is to isolate this work and the work done by the Orkin lab, representing the beginning of a new strategy where you could isolate progenitors from ES cells and go forward with these progenitors, directing their differentiation into specific cell types that are of therapeutic interests for different reasons. The cells from the islet family that you want to regenerate the coronary artery are going to be different from those which are used to generate a pacemaker tissue, versus those which are used to generate heart muscle. The nice thing about this is that these cells, we know, are the cells that perform this function in vitro and in vivo and they’re programmed to do it. It represents a step forward to be able to purify cells that have been able to already take this step forward to the cardiovascular progenitor state, then to use that as a starting point, so I view this as a beginning of a new approach, certainly not the end.
Interviewee’s Final Note: Human embryonic stem cell work has been controversial. There have been 2 schools of camp with regard to regenerative medicine. There is one school that believes that adult stem cells are the best way forward for a variety of different reasons, all of which are cogent, including ethical, regulatory, and the ability to obtain the cells, autologous cells which have been available—all of these have driven the underpinnings of current clinical trials for stem cell therapy for heart repair. At the same time, I think it’s very clear now, our studies make a compelling case, that the time has come to begin to unlock the potential of human embryonic stem cells also for heart repair. While this is at an earlier stage, I also believe this holds great long term promise and deserves an opportunity to move forward. Patients suffering from heart disease, among other problems, should be able to know and say, “This can benefit me, too.”
 Moretti et al.: "Multipotent Embryonic Isl1+ Progenitor Cells Lead to Cardiac, Smooth Muscle, and Endothelial Cell Diversification." Publishing online 22 November; Scheduled for the 15 December 2006 issue of Cell.
 Wu et al.: "Developmental Origin of a Bipotential Myocardial and Smooth Muscle Cell Precursor in the Mammalian Heart." Publishing online 22 November; Scheduled for the 15 December 2006 issue of Cell.
Related Article by Kattman et al.: "Multipotent Flk-1+ Cardiovascular Progenitor Cells Give Rise to the Cardiomyocyte, Endothelial, and Vascular Smooth Muscle Lineages."
Dr. Chien is a researcher at the Massachusetts General Hospital.
Interviewed by: Thanh-Tam Candice Vu