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One cell makes almost any heart tissue, study finds

Nov. 22, 2006
Courtesy Cell Press
and World Science staff

Re­search­ers have iden­ti­fied stem cells pos­sibly ca­p­able of pro­ducing all three ma­jor tis­sues of the heart. 

This, they said, could be a great stride in on­go­ing ef­forts to use stem cell­s—“mas­ter cells” able to mult­i­ply in­to a range of cell types—to re­build dis­eased or­gans. The or­gan in this case would be the heart, ill­nesses of which are the top kill­er in most in­dus­tri­al­ coun­tries.

The heart is a mus­cu­lar pump that cir­cu­lates blood car­ry­ing ox­y­gen and nu­tri­ents to, and wastes from, the bod­y’s cells. The right side of the heart cir­cu­lates blood to the lungs. The left side cir­cu­lates blood to the rest of the body and back to the heart. (Cour­te­sy or​gan​do​nor​.​gov)

“It’s a sur­prise that a sin­gle cell can give rise to all of these tis­sues and struc­tures in the heart,” said Ken­neth Chien of Mas­sa­chu­setts Gen­er­al Hos­pi­tal and Har­vard Med­i­cal School in Bos­ton. 

“The heart may look more like blood than we thought,” he added, re­fer­ring to the fact that sin­gle stem cells can give rise to all the cell types found in blood. Chien is co-author of a pa­per on the cells in the Nov. 22 ad­vance on­line edi­tion of the re­search jour­nal Cell.

“This changes the way we think about or­gan de­vel­op­ment,” said Stu­art Orkin of the How­ard Hughes Med­i­cal In­sti­tute in Chevy Chase, Md., co-author of a com­pan­ion pa­per in the jour­nal. 

“Rather than dif­fer­ent cell types com­ing to­geth­er, the heart ap­pears to de­vel­op from a com­mon set of pro­gen­i­tors or stem cells. This may be a more eco­nom­i­cal meth­od.”

But the cells come from em­bry­os, and em­bry­o­nic stem cell re­search has stirred heat­ed debate. Cri­tics say it’s wrong to ex­p­loit or kill hu­man em­b­ryos for med­i­cine.

Chien’s team fol­lowed the de­vel­opment of a group of cells called islet-1 cells in the hearts of mice. The cells are so called because they con­tain a pro­tein pf the same name. They found that the pre­cur­sors mul­tip­ly into heart-related tis­sues called car­di­ac mus­cle, smooth mus­cle, en­do­the­lial, pace­mak­er, and oth­er types. They al­so found that the cells were ob­tain­able from em­bryos.

Orkin and his col­leagues iso­lat­ed cells from a mouse em­bry­o in which a heart-specific gene, called Nkx2.5+, was ac­tive. They found that the these cells dif­fer­entiated main­ly in­to car­di­ac mus­cle cells and con­duc­tion sys­tem cells. The heart’s con­duc­tion sys­tem car­ries the elec­tri­cal im­pulses that al­low it to beat. 

The group then iso­lat­ed Nkx2.5 cells de­rived from em­bry­on­ic stem cells and found that some of the cells al­so ex­pressed a sec­ond gene, c-kit. Those with both genes could ex­pand and pro­duce both car­di­ac mus­cle and smooth mus­cle cells from a sin­gle cell. 

Smooth mus­cle is one of three types of mus­cles in the body: skele­tal, smooth and car­di­ac. Smooth mus­cle forms the sup­port­ing tis­sue of blood ves­sels and hol­low in­ter­nal or­gans, and is named for the ab­sence of mi­cro­scop­ic stripes seen in the oth­er two types. Car­di­ac mus­cle is the heart mus­cle ac­t­ual­ly res­pon­si­ble for pump­ing blood.

The re­search­ers said the cells stud­ied by Chien may give rise to those ex­am­ined by Orkin, but that re­mains a ques­tion for fu­ture stu­dy.

Past efforts to use em­bry­on­ic stem cells for heart re­gen­er­a­tion have fal­tered be­cause the cells tend to cause can­cers known as ter­a­to­mas, Chien said. The new­ly dis­cov­ered mas­ter cells might avoid that prob­lem, he added.

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Researchers have identified possible cardiac stem cells that can produce all three major tissues of the heart. That could be a major step forward in continuing efforts to use stem cells—”master cells” that can develop into various other types—to regenerate diseased organs, the researchers said. The organ in this case would be the heart. Heart disease in its various forms is the top killer in most industrialized countries. “It’s a surprise that a single cell can give rise to all of these tissues and structures in the heart,” said Kenneth Chien of Massachusetts General Hospital and Harvard Medical School in Boston. “The heart may look more like blood than we thought,” he added, referring to the fact that single stem cells can give rise to all the cell types found in blood. Chien is co-author of a paper on the cells in the Nov. 22 advance online edition of the research journal Cell. “This changes the way we think about organ development,” said Stuart Orkin of the Howard Hughes Medical Institute in Chevy Chase, Md., co-author of a companion paper in the journal. “Rather than different cell types coming together, the heart appears to develop from a common set of progenitors or stem cells. This may be a more economical method.” Chien’s team earlier found a group of cardiac muscle progenitors called islet-1 cells in heart tissue from newborn rats, mice, and humans. The cells are defined by the presence of a protein by the same name. In the new study, the researchers traced the development of these cells in the hearts of mice. They found that the precursors produce not only cardiac muscle but also heart-related tissues called smooth muscle, endothelial and pacemaker, as well as others. They also found that the cells were obtainable from embryonic stem cells. Orkin and his colleagues isolated cells from a mouse embryo in which a heart-specific gene, called Nkx2.5+, was active. They found that the these cells differentiated mainly into cardiac muscle cells and conduction system cells. The heart’s conduction system carries the electrical impulses that allow it to beat. The scientists then isolated Nkx2.5 cells derived from embryonic stem cells and found that some of the cells also expressed a second gene, c-kit. Those with both genes could expand and produce both cardiac muscle and smooth muscle cells from a single cell. Smooth muscle is one of three types of muscles in the body called skeletal, smooth and cardiac. Smooth muscle forms the supporting tissue of blood vessels and hollow internal organs, and is named for the absence of microscopic stripes seen in the other two types. The researchers said the cells studied by Chien may give rise to those examined by Orkin, but that remains a question for future study. In the past, it has been hard to use embryonic stem cells for heart regeneration because they tend to cause cancers known as teratomas, Chien said. But the newly discovered populations of master cells might avoid that problem, he added.