Different Kinds of Stem Cells in the Heart


For almost a century, the sciences of human physiology, cardiology, and medicine have believed that the heart is a terminally differentiated organ whose cells do not undergo further cell division. Essentially however many heart cells you were born with persisted throughout your own personal lifespan. Any increases in the size of the heart were thought to result from expansion of the size of the heart muscle cells .

Work from several labs over the last 15 years have shown that this dogma does not stand further scrutiny. In 1995, Peiro Anversa and his colleagues at New York Medical College in Valhalla, NY examined the differences in heart size between men and women at various ages and found that heart mass was stable in women, but in men, loss of heart mass was due to cell loss and not a decrease in cell size. Also, cell size was stable in women, but tended to increase in men. This increase in cell volume compensated for the loss of heart muscle cells and kept the thickness of the heart walls the same in older and younger men. However, the mass of the heart still decreased in men as they age. This finding does not support the assumption that heart muscle cells are born during development and stay with you throughout your life (for this study see Giorgio Olivetti, et al., Gender Differences and Aging: Effects on the Human Heart. JACC Vol. 26, No. 4 (1995): 1068-79).

Other work that contradicted the commonly accepted dogma examined hearts of people who had experienced “acromegalic cardiomyopathy.”  In a nutshell, individuals with acromegalic cardiomyopathy had a problem with too much growth hormone.  This growth hormone imbalance caused the patient to be really tall, and suffer from bone abnormalities.  This also causes enlargement of the heart.  This patient died at the age of 65, and had a heart that weighed 800 grams.  This is six times the weight of a normal heart.  However, when the size of the heart muscle cells from the man who had died of acromegaly were compared with that of a 99-year old women who had died of pneumonia, the volume of their cells was similar (Leri, Kajstura and Anversa, Role of Cardiac Stem Cells in Cardiac Pathophysiology: A Paradigm SHift in Human Myocardial Biology. Circulation Research 109 (2011): 941-61).  This strongly calls into question the notion that heart enlargement is due to an increase in cell size.

Why was the acromegalic heart larger?  The answer seems to be that it contained far more cells, and recent work has demonstrated that hearts have a stem cell population that can divide and generate new heart cells.  At all ages, the heart contains heart muscle cells that are dividing and expressing a host of genes found only in dividing cells (CDC6, Ki67, MCM5, Phospho-H3, aurora B kinase).  When the heart enlarges for pathological reasons, the proportion of heart muscle cells that expresses these genes increases (see Levi P, Kajstura J and Anversa P, Cardiac Stem Cells and Mechanisms of Myocardial Regeneration. Physio Rev 85 (2005): 1373-1416).

There is not one population of heart stem cells, but four of them, and they all possess different characteristics, and, possibly, different embryological origins.  The first group is “side population cells.”  Side population cells (SPCs) are identified by their ability to expel toxic compounds and dyes (Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEBS Lett.2002 Oct 23;530(1-3):239-43).  SPCs have a membrane protein that pumps such molecules from the cell, and when cultured in a semisolid medium, they will differentiate into heart muscle cells.  The exact genes expressed by SPCs is uncertain, since there seem to be, at least in rodents, a few subclasses of SPCs.  In mice, 2% of all heart cells are SPCs, and they have an expression pattern that looks like this: Sca1[high], c-kit[low], CD34[low], and CD45[low].  Cells that express Sca1 normally form blood vessels, but SPCs do not seem to form blood vessels.  This is the conclusion of cell tracing experiments that marks cells and then places them into damaged hearts.  Once the stem cells have divided and integrated into the heart, the animals are sacrificed and their hearts are stained for the marker that characteristic of the implanted stem cells.  Such experiments show that SPCs do not make blood vessels in mice (Tara L. Rasmussen, et al., Getting to the Heart of Myocardial Stem Cells and Cell Therapy. Circulation. 2011; 123: 1771-1779).

In rats, the data is less clearly interpretable, because rat SPCs express a gene called Bcpr1, but the Bcpr1-positive cells either express CD31 and can form blood vessels or do not express CD31 and cannot form blood vessels.  It appears that only the Sca-1[positive] CD31[negative] cells have a pronounced ability to form heart muscle cells.  SCPs might come from neural crest cells, and this hypothesis comes from their behavior in culture (Oyama et al., Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo.  J Cell Biol 176 (2007): 329-41).

The second population of cardiac stem cells is the Sca-1 cells.  Sca1 cells do not possess the functional properties of stem cells, but they represent 2% of all heart cells.  While they can be grown in culture, only a very small percentage of the cells express any heart muscle-specific proteins (3%-4%), and when delivered to a damaged heart, Sca1 cells will fuse with existing cells to modestly improve heart function (Matsuura K., et al., JBC 279 (2004): 11384-91).  When injected into damaged hearts, Sca1 cells form blood vessels but their ability to survive in the heart is very poor (Li Z., et al., JACC 53 (2009): 1229-40).  Also, Sca1 cells seem to secrete molecules that help the heart and its other stem cell populations to work better.  Most of the heart muscle turnover seems to result from c-kit[positive] cells and the role of SPCs and Sca1 cells is, to date, uncertain.

On the cardiac surface, a third heart stem cells exists, the epicardial progenitors.  There are several different subtypes of epicardial progenitors; Flk1-expressing cells form blood vessels, WT1- and Tbx18-expressing cells make heart muscle (Zhou B., et al., Nature 454 (2008): 109-13 and Cai CL., et al., Nature 454 (2008): 104-108).  There is also a pool of c-kit[positive] cells in the human heart that can differentiate into heart muscle cells and blood vessels (Castaldo C, et al., Stem Cells 26(7), 2008: 1723-31).

The final heart stem cell population is the cardiosphere derived cell (CDC) population.  “Cardiospheres” are balls of cells formed by CDCs in culture.  While in these spheres, a variety of cells form around a core of primitive, c-kit[positive] cells.  Cardiospheres do not consist of a uniform mass of cells, but a pastiche of cells.  Some of these cells have gap junction proteins that are found in mature heart muscle cells that allow them to connect with each other and pass ions from one cell to another.  Others are highly uncommitted and have tremendous growth potential.  These cells express c-kit at high levels.  CDCs are the stem cells that have been used in the recent CADUCEUS and SCIPIO clinical trials.  They are capable of forming heart muscle cells and blood vessels.  They are also easily extracted from hearts by biopsies that are out-patient procedures.

Thus even though there are several different types of heart stem cells, they play a role in repair, and pathology.  They can also be exploited to heal hearts, shrink heart scars, and make a denser collection of blood vessels in the heart.  Further work on them will increase the ability of cardiologists to heal the hearts of patients with failing hearts.