Lab Studies Challenge Accepted Ideas on Heart-Tissue Embryonic Origins

November 23, 2006

November 23, 2006 (Boston, MA) — The range of embryonic stem cells that ultimately develop into the heart muscle and its conduction system and vasculature might be narrower in range than once believed, suggest two laboratory studies published online November 22, 2006 in Cell [1,2].

Each of the studies identified a single kind of progenitor cell that, at least in vitro, collectively differentiates into all of the major cardiac tissues, including myocardium, Purkinje fibers, vascular endothelium, and smooth muscle. The two progenitors belong to different embryonic cardiac-cell families, each believed responsible for the formation of the left and right side of the heart, respectively.

The research challenges a traditional view of the developmental origins of the heart's varied tissue types in which each is derived from a distinct precursor cell with different embryonic origins, according to the authors of both reports, which are slated for publication in the journal's December 15, 2006 issue. In place of the old view is the idea that all of the heart's tissue types are derived from no more than a few progenitor cell types.

The studies, if verified, point to potential ways around some current obstacles to using stem cells for cardiac-tissue regeneration to repair infarct-damaged myocardium or congenital defects. Although it has been suggested that embryonic stem cells are "a renewable source of cardiac-muscle cells for transplantation, this has been problematic, given the difficulty in generating sufficient amounts of homogenous cardiac myocytes and the dangers associated with the risk of teratomas," according to Dr Alessandra Moretti (Massachusetts General Hospital, Boston) and colleagues, authors of the right-sided progenitor-cell report [1]. Those problems, they write, might be overcome by the cloning and delivery of a few specific progenitor cells that might more easily and safely regenerate different heart tissues.

In a series of mouse and in vitro studies, Moretti et al traced the differentiation of a specific cardiac precursor cell characterized by the expression of the transcription factor islet-1 (isl1). They discovered that a subset of these "multipotent isl1+ cardiovascular progenitors" (MICPs) can differentiate into myocardial, conduction, endothelial, and smooth-muscle cell lineages.

"Since MICPs can be isolated and selectively expanded from a renewable embryonic-stem-cell-based source, the findings point to a new strategy for cardiovascular tissue regeneration via the directed differentiation of embryonic-stem-cell-based MICPs into discrete cardiac, pacemaker, smooth-muscle, and endothelial cell lineages," the group writes, "pointing to a new strategy for cardiovascular tissue regeneration."

Dr Sean M Wu (Children's Hospital, Boston, MA) and associates made similar observations and arrived at much the same conclusions after isolating cardiac-specific progenitor cells expressing the transcription factor Nkx2.5 from a mouse embryo, and following its developmental pathways [2]. A distinct subset of the Nkx2.5+ cells showed an unusual capacity in vitro for replication and differentiation into both myocardial and smooth-muscle cells. "With further differentiation, these precursor cells become atrial- or ventricular-specific myocytes or cells of the conduction system," they write. They appeared unable to differentiate into hematopoietic, neuronal, or skeletal muscle cells, "thus, they represent a population that is restricted with respect to other lineages.

According to Wu et al, their findings "support a new paradigm for cardiovascular development involving the divergence of myocardial and smooth-muscle-cell lineages from a common precursor."

In a press release on the two studies issued by Cell, lead investigator of the Wu et al study, Dr Stuart H Orkin (Children's Hospital), is quoted as saying the relationship between the two studies' key progenitor cells is unknown and a subject of continued research. "One may be the predecessor of the other, or they may be quite separate."

  1. Moretti A, Caron L, Nakano A, et al. Multipotent embryonic Isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 2006; doi:10.1016/j.cell.2006.10.029.

  2. Wu SM, Fujiwara Y, Cibulsky SM, et al. Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell 2006; doi:10.1016/j.cell.2006.10.028.

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