In this issue of Blood, Myers and Krieg present an elegant series of experiments, which suggest that the hemangioblast may be a state of competence rather than a bipotential progenitor state that exists in vivo.1 

Is the hemangioblast a bipotential precursor state or a bipotential competence state, which reveals its latent developmental potential only under experimental conditions?

Is the hemangioblast a bipotential precursor state or a bipotential competence state, which reveals its latent developmental potential only under experimental conditions?

In the 1930s, following the careful observations of Murray in chick embryos and those of Sabin 2 decades earlier, Murray postulated that blood and endothelial lineages may share a common progenitor: the hemangioblast.2,3  Over the years, evidence has steadily accumulated in support of the hemangioblast. However, these confirmatory studies have been largely based on experiments that relied on the isolation, culture, and/or manipulation of cells in vitro.4-6  A recurring question has remained as to whether hemangioblast cells actually exist in vivo. In particular, various fate mapping studies in the mouse, chick, and zebrafish have led to contradictory conclusions.7-9 

In this paper, Myers and Krieg weigh into this controversy by performing a series of elegant experiments asking whether the ventral blood island (VBI) in the early frog embryo has cells consistent with the hypothetical hemangioblast. The VBI in amphibian embryos is analogous to the yolk sac in chick and mouse embryos, the site where hemangioblasts were first postulated to exist, and thus it provides a convenient complementary model system to tackle this question. Previously, it had already been shown that cells in the VBI of frog embryos express both hematopoietic and endothelial markers, consistent with the putative hemangioblasts. However the question had remained unresolved as to whether these cells represented bona fide hemangioblasts in vivo. To answer this question, they performed a series of experiments aimed at finally putting this issue to rest. First, they removed the VBI from early embryos and asked whether embryos lacking a VBI would go on to express both primitive blood and endothelial markers at later stages? The answer was that removal of the VBI resulted in a clear loss of primitive blood lineages, but the endothelial lineages remained intact. This finding suggested that the VBI is not a major source of endothelial cells in the early embryo. However, these findings did not exclude the possibility that some endothelial lineages may still arise from the VBI, albeit in smaller numbers. Thus, Myers and Krieg performed a series of classic specification assays. They isolated and cultured the VBI as explants, to ask whether this tissue could form both lineages when cultured in isolation? The answer was that the isolated VBI explants could only give rise to blood but not endothelial lineages. These results suggested that the VBI is specified only to give rise to blood cells. Finally Myers and Krieg performed a further set of fate mapping studies, using homotypic transplants, to ask whether the normal fate of the VBI was to give rise to both blood and endothelial lineages, or only blood, as suggested by their specification mapping studies. The results from these experiments showed that the VBI will normally only give rise to blood lineages and not endothelial lineages in vivo. Thus, they concluded that the VBI in early frog embryos does not contain bipotential precursor cells that give rise to both blood and endothelial lineages, and thus, that the this region does not contain what has been classically defined as hemangioblasts in vivo.

Myers and Krieg, however, performed a further series of experiments, which were especially revealing and may explain what the hemangioblast represents in developmental terms. The authors executed several experiments aimed at disrupting growth factor signaling or the erythroid specification program in the VBI and then assessed how these manipulations affected the development of blood vs endothelial lineages within the VBI. These experiments showed that inhibiting bone morphogenetic protein signaling or disrupting the erythroid program in the VBI largely eliminated red blood cells while allowing a preponderance of endothelial cells to form within this region. Thus, although the VBI is neither fated nor specified to give rise to endothelial cells, the VBI can, under experimental conditions, give rise to endothelial lineages. In other words, the VBI is competent to give rise to both primitive blood cells and endothelial cells, but the latter fate is only revealed under specific experimental conditions whereby either signaling or fate specification is disturbed. The definition of competence in embryology refers to the range of cell fates, which can be achieved by a cell or group of cells, given the appropriate conditions. A cell or tissue may be competent to give rise to many cell types that it would not normally be specified or fated to form. A clear example of this are the animal cap cells from blastula stage frog embryos, which, although they are specified and fated to give rise only to ectodermal tissues, are competent to form virtually any cell type in the embryo, given the appropriate signals.10  The findings from Myers and Krieg suggest that a similar scenario may explain what the hemangioblast is—a state of competence. This might help resolve many of the apparently controversial findings over the years. It is particularly notable that most of the experiments suggesting the existence of a bipotential precursor state for blood and endothelial cells have come from in vitro explant or cell culture studies, where the experimental manipulations may have been uncovering a latent competence state rather than an inherent precursor state.

If the hemangioblast is a state of competence, rather than a bona fide bipotential precursor state, should this affect their potential use in developmental biology or regenerative medicine? The short answer is no. These cells can still be used to help decipher the molecular mechanisms that drive both lineages, as well as how one developmental program might impact on the other. Furthermore, whether the hemangioblast is a state of competence or an actual precursor state should not have a significant impact in how these cells could be exploited to generate or expand either lineage for regenerative medicine purposes. Perhaps the greatest implication of these studies is that it may help explain away some of the controversies that have confounded this field in recent years.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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