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Circulation. 2003;107:2638-2639
doi: 10.1161/01.CIR.0000074240.87740.BE
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(Circulation. 2003;107:2638.)
© 2003 American Heart Association, Inc.

Editorials

The Way to a Human’s Heart Is Through the Stomach

Visceral Endoderm-Like Cells Drive Human Embryonic Stem Cells to a Cardiac Fate

Teruya Nakamura, MD, PhD; Michael D. Schneider, MD

From the Center for Cardiovascular Development, Departments of Medicine, Molecular and Cellular Biology, and Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Tex.

Correspondence to Dr Michael D. Schneider, Center for Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza, Rm 506D, Houston, TX 77030. E-mail michaels{at}bcm.tmc.edu


Key Words: Editorials • stem cells • cells, visceral • myocytes

Heart failure due to myocardial infarction is the leading cause of morbidity and mortality in developed countries.1 While that point needs no reiteration for the Circulation audience, its corollary does: that heart failure, in essence, is a myocyte-deficiency disease. Cell death, whether from acute infarction alone or from sustained sporadic losses in chronic heart failure, is not matched by sufficient cell replacement. Adult cardiac muscle cells have long lost much if not all of their capacity for proliferative growth, and differences in interpretation hinge on shadings between "none" and "almost none."2,3 What cell replacement does occur occurs by other means, including the recruitment of undifferentiated progenitor cells—eg, from their niche in bone marrow through the circulation to the injured myocardium.4

See p 2733

Advances in fundamental molecular and cellular biology have paved the way for development of tissue engineering and regenerative medicine as a new therapeutic paradigm, in effect, the Regeneration Superhighway. Among such advances, so-called stem cells have been greeted with greatest enthusiasm, as well as religious and political alarm. Replacing dead cardiac muscle cells with living ones to preserve pump function is a goal of indisputable merit. But which cells have this capacity to transform from something that isn’t a cardiac myocyte into something that is? Among the potential sources, why has controversy arisen for some? Which can be propagated and expanded best in tissue culture? How faithful is their differentiation, compared with "real" cardiac muscle cells? And, what governs their conversion?

The concept of "stemness" embraces two properties, which much coexist for a cell to be a stem cell. The first is long-term self-renewal, the ability to divide indefinitely, without senescing. The second is pluripotency, the ability to generate multiple, disparate cell types. Clinically and historically, hematopoietic stem cells are the most familiar of adult stem cells,5 with a capacity to create not merely each of the various blood lineages, but also other cell types including cardiac muscle, vascular smooth muscle, and endothelium,4 albeit not all cells.6 To a varying extent, evidence for analogous plasticity has been adduced in just the past few years for progenitor cells from other adult sources, including skeletal muscle,7 adipose tissue,8 and, less accessibly, brain.9 A more nuanced or, at least, jaundiced view of such reports has also emerged10: Claims of adult stem cell plasticity can be deceived for many reasons—mixed starting populations, contaminating blood-borne cells, and cell-to-cell fusion among them.

Totipotency, the ability to generate all cell types, not just many, has been shown best for those cells that have this task ordinarily: embryonic stem cells (ES cells). Derived from the blastocyst just a few days after conception, when the embryo is just a hollow ball of cells with none of the later cell layers (endoderm, mesoderm, ectoderm) and not of the later differentiated cell types, ES cells from mice—and the animals generated from them—have been instrumental to the emergence of "knockouts" lacking one gene or another as the current "gold standard" of mammalian gene function. In addition, mouse ES cells grown in tissue culture have been useful for gaining clues into the very earliest steps for cardiac differentiation.11

Human ES cells evoke especially intense scientific interest, given their unsurpassed capacity to renew themselves and give rise to specialized human cells,5,12 thereby providing clues into our origins and potential tools for our repair. A suppositional linkage with abortion fuels ethical, legal, and public debates, despite the fact that these cells are retrieved from Fallopian tubes well before implantation and, consequently, before the stage blocked by intrauterine contraception.13 Current White House policy speaks to this issue by permitting no new human ES cell lines to be made with federal funds, and restricting the ones allowable for study with National Institutes of Health support to those already in creation as of 9 PM EDT, August 9, 2001. Despite the potentially worrisome limitation that this compromise entails, the crucial and innovative finding that human ES cells indeed can form heart muscle in vitro14 has now been confirmed independently for multiple ES cell lines.15 Cardiac myocytes derived from human ES cells and their potential suitability for clinical grafting in vivo have been recently reviewed.16 One outstanding question remains, specifically what cues and signals pass on to transcription factor networks in the nucleus, to drive human ES cells to a cardiac destiny.

It has long been thought, on the basis of developmental studies of amphibian and avian embryos, that cardiac progenitor cells require an instructive, inductive interaction with anterior endoderm for their specification as cardiac myocytes to occur.17,18 This also seems to be the case in mice19: If explanted 7.25 days after conception, mouse mesodermal tissue that lacks cardiac-specific markers (the right molecules and beating) can turn into beating myocardium if cultured together with an explant of visceral endoderm, the normally subjacent tissue.19 A cardiogenic inductive effect of visceral endoderm-like cells (VE cells) has also been shown in coculture with mouse ES cells,20 and endogenous paracrine factors secreted by the new parietal endoderm contribute to cardiomyogenesis even when mouse ES cells are cultured on their own.21 Taken together, these discoveries imply the generalizable notion that heart formation in these many diverse systems invariably requires some communication from underlying endoderm, most likely in the form of a secreted local signal. Nothing was known, though, about such signals for cardiac muscle formation by human ES cells.

In the present issue of Circulation, Mummery et al22,23 report dramatic and conclusive results for one such deterministic interaction. The authors’ findings will unquestionably provoke accelerated work on molecular mechanisms of human cardiogenesis, and likely will lead to practical benefits, as well, for the utility of human ES cells in cardiac cell transplantation. Using a human ES cell line that (unlike several others) does not initiate beating spontaneously, these investigators demonstrated that cultivation together with VE cells provided the missing trigger for differentiation into cardiomyocytes. Within 10 days of coculture, 35% of the surface contained beating regions. Beating was maintained over 6 weeks, and beating clusters could be collected individually, cultured sequentially, and even cryopreserved and thawed.

The distinguishing features of cardiomyocytes documented in this study were unusually comprehensive: expression of sarcomeric proteins, atrial natriuretic peptide, cardiac ion channel genes, and phospholamban; ventricular action potentials; chronotropic responses to phenylephrine, isoproterenol, and carbachol; dye-coupling, indicative of gap junctions; and repetitive intracellular calcium oscillations. In addition, this report demonstrates rational, physiologically driven ways to surface-label (and, hence, perhaps to sort) the cardiac cells emerging in human ES cell cultures, including antibody to the L-type calcium channel dihydropyridine receptor.

The crux of the study, though, is its direct evidence for the presence of paracrine factors derived from VE cells, which function on human ES cells as extrinsic stimuli for cardiac differentiation. The authors did not specify which molecules are responsible for the signal but note a few candidates that are especially well posed, such as bone morphogenetic proteins24 and fibroblast growth factors,25 neither of which appeared to work, and repression of signaling by a third class of factors, Wnts, that are suspected inhibitors of cardiogenesis.26 Because of precedents for synergy among these pathways, an important experiment will be whether various combinations of these factors can mimic the effect of visceral endoderm, perhaps with others that have been described. Of course, factors still unknown may play the trump card.

For human cardiac regeneration, the magnitude of the task ahead is enormous, but the potential benefits are even greater. Many may find it of concern that the American Heart Association declines to support any work at all on human ES cells, even within the federally sanctioned constraints, which constitute a prudent and responsible middle ground.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

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Related Article:

Differentiation of Human Embryonic Stem Cells to Cardiomyocytes: Role of Coculture With Visceral Endoderm-Like Cells
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