Cell Findings Go to Heart of Heart Development

BOSTON, Nov. 22 -- Only two types of master cells are needed to build the heart, research teams here have found, apparently simplifying the challenge of using tissue engineering to repair congenital or acquired cardiac damage.

The stumbling block for such efforts has been to find ways to make all of the various tissue types in the heart grow together in the lab, before implanting new tissue in a patient. Researchers have assumed that several types of progenitor cells -- one for each tissue type -- must somehow be persuaded to develop together.

Now scientists at Children's Hospital Boston and Massachusetts General Hospital say that's not true.

In parallel papers published online today by Cell, two teams reported finding two types of master cells that differentiate into all of the major tissue types found in the heart, including the myocardium, smooth muscle, and endothelium.

One cell type, found by the Children's Hospital team, forms the tissues of the left side of the heart, which is the first to develop in mammals. The other cell type, identified by the Mass General scientists, develops into the tissues of the right side of the heart.

"It's a surprise that a single cell can give rise to all of these tissues and structures in the heart," said Kenneth Chien, M.D., Ph.D., who led the team from Mass General. Noting that hematopoietic stem cells give rise to all of the cell types found in blood, he said "the heart may look more like blood than we thought."

"This changes the way we think about organ development," said Stuart Orkin, M.D., who led the Children's Hospital Boston researchers. "Rather than different cell types coming together, the heart appears to develop from a common set of progenitors or stem cells."

It's a "simpler way of building the organ," Dr. Orkin said, "and because these cells can make multiple cell types, they could be more useful in repairing the heart than any single kind of cell."

Dr. Orkin and colleagues studied mouse embryonic stem cells, allowing them to differentiate enough so that the researchers could isolate a subtype that expressed a gene called Nkx2.5. Some of these cells, approximately 28% of the total, expressing an additional gene called c-kit, further differentiated into both myocardial and smooth-muscle cells.

Then, using genetic engineering techniques, the researchers showed that the same cells arise early in the embryonic development of mice and differentiate into both cell types.

Dr. Chien and colleagues had earlier found cardiac muscle progenitors called islet-1 (isl1⁺) cells in heart tissue from newborn rats, mice, and humans. For this study, they showed that these isl1⁺ progenitor cells produce not only cardiac muscle but also smooth muscle, endothelial, pacemaker, and other non-muscle cell lineages in the heart.

Also, they demonstrated that isl1⁺ cells can be obtained from embryonic stem cells.

Researchers from both labs are now collaborating to see how the two cell lines work together.

There is no immediate clinical application, Dr. Orkin cautioned -- the studies were done in mice, and it's not yet known what makes embryonic stem cells differentiate into cardiac progenitors, or what makes cardiac progenitors differentiate into more specialized heart cells.

That said, the findings are an advance, according to John Mayer, M.D., a cardiovascular surgeon at Children's Hospital Boston, who was not involved in the research.

"If you understand the process of how things develop from very primitive embryonic stem cells to fully differentiated tissue," he said in a statement, "you have the potential to duplicate that process in the lab and make a tissue that a patient might need."