A dual origin for blood vessels

Abstract

Standfirst: Contrary to previous assumptions, the cells that line blood vessels seem to be derived from more than one source. In addition to their known developmental path, they can arise from embryonic blood-cell progenitors.

Blood-cell lineages and the endothelial cells that line the interior of blood vessels have intertwined biology and interrelated embryonic origins. Our current knowledge indicates that endothelial cells arise from one of the three main cell layers of the early embryo (the mesoderm), and that a subset of endothelial cells subsequently gives rise to haematopoietic stem cells (HSCs)^1,2, from which all adult blood cells derive. In a paper in Nature, Plein and colleagues reveal a second origin for endothelial cells and refine our understanding of the relationship between the endothelial and blood lineages³.

Transient embryonic populations of red-blood and immune cells arise early in development, before the emergence of HSCs, from extraembryonic precursors called erythro-myeloid progenitors (EMPs). In line with the model that mesoderm gives rises to endothelium which in turn, gives rise to blood, EMPs originate from endothelial cells located in an extraembryonic structure called the yolk sac. Using a genetic-engineering approach to produce mouse embryos in which yolk-sac-derived EMPs and all their descendants were genetically labelled with a fluorescent protein, Plein and colleagues surprisingly found that these cells also contribute to the walls of blood vessels. Analysis of the labelled cells revealed that EMPs, actively migrate from the yolk sac into the embryo, and differentiate into endothelial cells — returning to their initial endothelial fate but now in an intraembryonic site (Fig. 1). Unlike mesoderm-derived endothelial cells, which form blood vessels through local proliferation, the authors found that EMP-derived endothelial cells contribute to the vasculature of several organs by incorporating themselves into existing vessels and interspersing with mesodermal-derived endothelium.

Figure 1 |. Two contributors to the vessel lining.

An embryonic tissue called mesoderm (not shown) gives rise to endothelial cells, which proliferate to form both the inner lining of blood vessels and the lining of a structure called the yolk sac that surrounds developing embryos. Yolk-sac endothelial cells in turn give rise to cells called erythro-myeloid progenitors (EMPs), which migrate into the embryo and are known to differentiate into embryonic blood-cell lineages. Plein et al.⁴ demonstrate in mice that migrating EMPs can return to an endothelial cell type. EMP-derived endothelial cells are incorporated into mesoderm-derived blood vessels in developing organs such as the brain, liver and lung, forming a mosaic pattern across the vessel lining.

In 2015, the very same genetic strategy was used to show that adult immune cells called tissue-resident macrophages are derived from yolk-sac EMPs⁴. This result surprised researchers in the field — until then, it had been thought that macrophages differentiated from circulating white-blood cells called monocytes. Thus, this EMP population constitutes a versatile group of cells. They have the potential to generate the primitive red blood cells and immune cells needed transiently during embryonic life, but can also generate tissue-resident macrophages and endothelial cells whose progeny persists in adults.

Plein et al. found that the percentage of endothelial cells in adult blood vessels that originated from EMPs ranged from about 30% in the brain to 60% in the liver. Importantly, high levels of Hoxa in EMP-derived endothelium appears to be required for normal brain development. Although deficiency of Hoxa also affected the microglia, making the conclusions not as clear-cut, the findings support an essential developmental requirement for EMP-derived endothelium in the brain. The authors also examined the gene-expression profiles of endothelial cells in vessels. They found that the EMP-derived cells had a transcriptional signature consistent with complete acquisition of an endothelial fate. However, there were some slight differences between these cells and neighbours of direct mesodermal descent. For example, the authors found overrepresentation of liver sinusoidal markers such as Oit3, Mrc1, Stab2 and Lyve1 and a lower representation of brain EC markers like Slc2a1.

Taken together, Plein and colleagues’ experiments showed that the vasculature of the embryo expands from two distinct lineages. Why does this matter? The origins of these cells are not only of intellectual interest, but might also have implications for physiology and disease. Although speculative at this point, it is conceivable that endothelial cells from different developmental origins could respond differently to the same stressor, as has been found for other lineages.

For example, vascular smooth-muscle cells, which form contractile layers of cells under the endothelium, originate from three distinct embryonic sources⁵. The sources affect the cells’ gene-expression profiles and responses to pathological states⁶. They are also thought to be the reason that different regions of the vasculature react differently when exposed to the same stimulus. Following kidney failure in mice, patterns of vessel calcification differ in different regions of the aorta (the body’s largest vessel), which have distinct embryonic origins⁷. Mutations in the gene NTSE in people result in vascular calcification exclusively in the limbs⁸. Finally, regional differences correlating with developmental origins and depending on the initiating insult were also reported for aneurisms⁹.

Could distinct lineage histories also cause differential endothelial-cell responses to stimuli? This remains an open question, but the idea raises the possibility that the endothelium might respond as a functional mosaic. Whereas large sections of vascular smooth muscle are derived from the same developmental source, it seems that EMP-derived endothelial cells interlace with cells of mesodermal origin (Fig. 1). As such, alternative responses to stimuli might occur in the same segment of endothelium.

Interestingly, the endothelial lining of the aorta houses cells that have different proliferative abilities — cells capable of regenerating adult vessels exist side by side with cells that have a lower proliferative potential⁹. Perhaps this variability relates to the origin of these cells. Extending this idea, maybe the high percentage of EMP-derived endothelial cells in the liver is a factor in the organ’s remarkable capacity for regeneration. Plein and colleagues’ work will most certainly inspire investigators to pursue new experiments that explore the relationship between the origin of endothelial cells and their function.

Going forward, the degree to which these findings apply to humans needs to be formally tested. Naturally, lineage tracing is not feasible in humans. An alternative strategy would be to identify evolutionarily conserved gene-expression patterns characteristic of the two types of endothelial-cell lineage in mice, and to identify cells that have each profile in humans. It would also be exciting to clarify whether these two lineages differentially contribute to vessel repair following damage.