Does the adult heart contain a sizable population of dormant stem cells that can be roused to acts of regeneration in order to rebuild lost or damaged muscle? If this is the case, then regenerative treatments will be easier to construct, in the form of signaling to direct native stem cells. If not, then the road to such treatments is much less straightforward, requiring the delivery of cells capable of regeneration, as well as the instructions for those cells, or perhaps the conversion of scar tissue cells into heart muscle.
The research community is presently engaged in a debate of evidence and hypothesis over whether or not the claimed heart stem cell populations actually exist in adult individuals. This latest entry to this debate is a gloomy one, in which the researchers provide evidence for there to be no stem cells in the heart capable of regenerating heart muscle in response to damage.
Debates of this nature are actually fairly common in the field. Specific cell populations can be hard to isolate, and different groups may or may not be looking at the same cells as they argue with one another. One might look at the controversy over very small embryonic-like stem cells some years ago, for example. I hesitate to offer an opinion on the topic, save to note that firm answers will be established in the end – it is just a question of how long that takes.
During a myocardial infarction, commonly known as a heart attack, the blood supply to part of the heart muscle is cut off. As a consequence, part of the heart muscle dies. Most tissues of animals and humans contain stem cells that come to the rescue upon tissue damage: they rapidly produce large numbers of ‘daughter cells’ in order to replace lost tissue cells. For two decades researchers and clinicians have searched for cardiac stem cells, stem cells that should reside in the heart muscle and that could repair the heart muscle after a myocardial infarction. Multiple research groups have claimed the definitive identification of cardiac stem cells, yet none of these claims have held up.
To solve this debate, researchers focused on the broadest and most direct definition of stem cell function in the mouse heart: the ability of a cell to replace lost tissue by cell division. In the heart, this means that any cell that can produce new heart muscle cells after a heart attack would be termed a cardiac stem cell. The authors generated a ‘cell-by-cell’ map of all dividing cardiac cells before and after a myocardial infarction using advanced molecular and genetic technologies.
The study establishes that many types of cells divide upon damage of the heart, but that none of these are capable of generating new heart muscle. In fact, many of the ‘false leads’ of past studies can now be explained: cells that were previously named cardiac stem cells now turn out to produce blood vessels or immune cells, but never heart muscle. Thus, the sobering conclusion is drawn that heart stem cells do not exist. In other words, heart muscle that is lost due to a heart attack cannot be replaced. This finding – while disappointing – settles a long-standing controversy.
The authors make a second important observation. Connective tissue cells (also known as fibroblasts) that are intermingled with heart muscle cells respond vigorously to a myocardial infarction by undergoing multiple cell divisions. In doing so, they produce scar tissue that replaces the lost cardiac muscle. While this scar tissue contains no muscle and thus does not contribute to the pump function of the heart, the fibrotic scar ‘holds together’ the infarcted area. Indeed, when the formation of the scar tissue is blocked, the mice succumb to acute cardiac rupture. Thus, while scar formation is generally seen as a negative outcome of myocardial infarction, the authors stress the importance of the formation of scar tissue for maintaining the integrity of the heart.