Erythro-myeloid progenitor origin of Hofbauer cells in the early mouse placenta.

Hofbauer cells (HBCs) are tissue macrophages of the placenta thought to be important for fetoplacental vascular development and innate immune protection. The developmental origins of HBCs remain unresolved and could implicate functional diversity of HBCs in placenta development and disease. In this study, we used flow cytometry and paternally inherited reporters to phenotype placenta macrophages and to identify fetal-derived HBCs and placenta-associated maternal macrophages in the mouse. In vivo pulse-labeling traced the ontogeny of HBCs from yolk sac-derived erythro-myeloid progenitors, with a minor contribution from fetal hematopoietic stem cells later on. Single-cell RNA-sequencing revealed transcriptional similarities between placenta macrophages and erythro-myeloid progenitor-derived fetal liver macrophages and microglia. As with other fetal tissue macrophages, HBCs were dependent on the transcription factor Pu.1, the loss-of-function of which in embryos disrupted fetoplacental labyrinth morphology, supporting a role for HBC in labyrinth angiogenesis and/or remodeling. HBC were also sensitive to Pu.1 (Spi1) haploinsufficiency, which caused an initial deficiency in the numbers of macrophages in the early mouse placenta. These results provide groundwork for future investigation into the relationship between HBC ontogeny and function in placenta pathophysiology.

Megakaryocyte production is sustained by direct differentiation from erythromyeloid progenitors in the yolk sac until midgestation.

The extra-embryonic yolk sac contains the first definitive multipotent hematopoietic cells, denominated erythromyeloid progenitors. They originate in situ prior to the emergence of hematopoietic stem cells and give rise to erythroid, monocytes, granulocytes, mast cells and macrophages, the latter in a Myb transcription factor-independent manner. We uncovered here the heterogeneity of yolk sac erythromyeloid progenitors, at the single cell level, and discriminated multipotent from committed progenitors, prior to fetal liver colonization. We identified two temporally distinct megakaryocyte differentiation pathways. The first occurs in the yolk sac, bypasses intermediate bipotent megakaryocyte-erythroid progenitors and, similar to the differentiation of macrophages, is Myb-independent. By contrast, the second originates later, from Myb-dependent bipotent progenitors expressing Csf2rb and colonize the fetal liver, where they give rise to megakaryocytes and to large numbers of erythrocytes. Understanding megakaryocyte development is crucial as they play key functions during vascular development, in particular in separating blood and lymphatic networks.