My O'Myeloid, a tale of two lineages.

B lood giving rise to endothelium, evidence of which is described by Bailey et al. (1) in this issue of PNAS, has been a hot-button topic in the adult hematopoietic vascular literature. Paradigms of hematopoietic and endothelial shared origins are well established in the embryo. However, the demonstration that this phenomenon occurs in the adult has been significantly more controversial. Part of the controversy centers on the issues of ‘‘stemness’’ and plasticity, both concepts fully accepted in the developing embryo but thought to be lost and or diminished in most adult lineages (2). Within the embryo, there exist two major developmental time points where the hematopoietic and endothelial lineages cohabitate. The first is in the early yolk sac, where both blood cells and endothelium emerge simultaneously, thus giving rise to the theory of a common predecessor, the hemangioblast (3–5) (Fig. 1). However, the blood derived from this early ancestor is thought to be of ‘‘primitive’’ origin and thus does not continue to support the adult hematopoietic system (for a full review, see ref. 6). Later in development, the aorta-gonado-mesonephros region in conjunction with the vitelline and umbilical arteries exhibits clusters of hematopoietic cells capable of imparting adult hematopoiesis that are in physical contact with the endothelium (6, 7). This appearance of ‘‘budding’’ hematopoietic cells in contact with the vasculature has led some to term this endothelium ‘‘hemogenic,’’ i.e., the vasculature giving rise to the hematopoietic system (Fig. 1) (8). Now, whether this is indeed the case or whether cells of mesodermal origin are migrating through the endothelium remains to be established (9). Nonetheless, during development, at least two paradigms exist: first is the hemangioblast, a common predecessor to both systems, and second is the endothelium differentiating into, giving rise to, or supporting the hematopoietic system. For a period of time, it was thought that once these two systems were parted in the embryo, they would be forever separated in the adult. This no longer seems to be the case. An explosion of literature evaluating the plasticity of the adult hematopoietic stem cell (HSC) has suggested that bone marrow-derived stem cells could give rise to neurons, cardiac cells, muscle cells, liver, and blood vessels (reviewed in ref. 2). Unfortunately, much of the initial excitement of HSC plasticity has been extinguished with later investigations noting that although these cells migrated to different organs, their later ‘‘transdifferentiation’’ was more likely due to fusion events, or upon closer analysis, the HSC progeny remained in injured tissue but maintained their hematopoietic identity (2, 10). However, one potential offspring from the HSC still remained in the game: the vasculature. Once one takes the developmental history of these two lineages into account, it is not surprising that there would be a continued connection throughout adulthood. Yet, the nature of that connection remains a controversial issue.