Today we return our interest to human development, focusing on a special blood cell: the macrophage. Produced in multiple, stem cell-independent waves, macrophages colonize the developing foetus early on, forming several tissue-resident populations. This includes the microglia which are essential for brain and spinal cord development. In this paper, the authors looked into macrophage development in the human embryo, drawing parallels to the better-known mouse and zebrafish models.
First of all, they performed single-cell RNA sequencing on blood cells sampled from 8 human embryos across different Carnegie stages (11 to 23). They sampled the yolk sac (where the first macrophage wave arose), head, liver, blood, skin, and lungs; all sites successively colonized by macrophages. The first round of sequencing was performed with STRT-seq and analysed 1231 cells, from which 15 populations could be identified. This included a yolk-sac derived progenitor group (YSMPs) that strongly resembled the established signature for mouse multipotent cells called erythro-myeloid progenitors (EMPs). Notably, YSMPs were almost completely biased toward the myeloid cell fate, as confirmed by in vitro studies. The second round of sequencing using 10x Genomics confirmed the previous results in more than 11,000 cells. The combined STRT-seq and 10x data were used to define developmental trajectories, in order to understand the origin of the tissue-resident macrophage populations. Interestingly, several of these populations seemed to have already initiated their tissue residency genetic programs, as has been observed in the mouse. Although not a lineage tracing study, the authors described a major contribution of yolk sac-derived macrophages to microglia development. Conversely, YSMPs seem to play a secondary role in microglia formation, a result consistent with mouse development.
In summary, this work confirms the high degree of conservation between species, creating a roadmap for macrophage differentiation. Moreover, it is a testament to the maturity of the single-cell transcriptomic field and the accompanying data analysis.