Blood-cell lineages and the endothelial cells that line the interior of blood vessels have an intertwined biology and interrelated embryonic origins. Our current knowledge indicates that endothelial cells differentiate directly 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 adult blood cells derive. In a paper in Nature, Plein et al.3 reveal a second origin for endothelial cells, and refine our understanding of the relationship between the endothelial and blood lineages.
Transient embryonic populations of red blood and immune cells arise early in development, before the emergence of HSCs, from precursor cells 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 a structure called the yolk sac that surrounds the embryo. Using a genetic-engineering approach to produce mouse embryos in which yolk-sac-derived EMPs and all their descendants were labelled with a fluorescent protein, Plein and colleagues unexpectedly 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 — reverting to their initial endothelial fate but now in an intraembryonic site. 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 becoming incorporated into existing vessels and being interspersed in the mesoderm-derived endothelium, where they remain into adulthood (Fig. 1).
In 2015, the same genetic strategy was used to show4 that adult immune cells called tissue-resident macrophages are derived from yolk-sac EMPs. This result surprised researchers in the field — until then, it had been thought that macrophages differentiated only from circulating white blood cells called monocytes. Thus, this EMP population constitutes a versatile group of cells. It has 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 persist 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. They showed that EMP-derived endothelial cells expressed high levels of the gene Hoxa, and that loss of Hoxa expression altered vessel development in the brain. Loss of Hoxa also affected brain-specific immune cells called microglia, making it hard to say for certain that the defects were caused solely by changes in EMP-derived endothelial cells. Nonetheless, these findings suggest an essential developmental requirement for EMP-derived endothelium in the brain.
The authors also examined the gene-expression profiles of endothelial cells in blood vessels. They found that the EMP-derived cells had a transcriptional signature consistent with the 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 over-representation of genes characteristic of a type of liver vessel in EMP-derived cells, and a lower representation of brain-specific markers of endothelial cells.
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 could also have implications for physiology and disease. Although only speculation at this point, it is conceivable that endothelial cells from different developmental origins respond differently to the same stressor, as has been found for other lineages.
For example, vascular smooth-muscle cells, which form contractile muscle layers 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 regions of the aorta (the body’s largest blood vessel) that have distinct embryonic origins7. Mutations in a gene called NT5E in people result in vascular calcification exclusively in the limbs8. Finally, aneurysms, in which the blood-vessel wall weakens and bulges, seem to be triggered by different stressors in regions of blood vessels that have distinct origins9.
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 responds 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 direct mesodermal origin. 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 potential10. 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 that 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 search for 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.
Nature 562, 195-197 (2018)