In this study, we characterise CD34 +CD43 + progenitors in human placental villi. However, the identity of these progenitors and the cells they generate are poorly defined. Previous work by others has identified CD34 +CD43 + haematopoietic progenitors in pre-circulation human placental villi 15. Therefore, we sought to determine if HBC are generated de novo in the placenta. Vitelline vessels of the yolk sac do not connect directly with the placenta, and foetal blood flow to the placenta via the umbilical cord is not established until ~10 post-conception weeks (PCW) 16, 17. However, HBC are not likely to be generated in the yolk sac, as they have been identified in the placenta prior to the commencement of embryonic blood circulation 14 and vascularisation of the placental mesenchyme 15. Previously, we observed that the transcriptome of HBC is very similar to that of yolk sac macrophages 2. Murine fate mapping models have established that the first embryonic macrophages are generated from EMPs in the yolk sac 10, 11, 12, and it is widely accepted that the yolk sac is the sole site of primitive haematopoiesis 13. Later in gestation, transient definitive ‘late’ EMPs and haematopoietic stem cells (HSCs) give rise to ‘definitive’ macrophages via a monocyte stage 5, 6, 7, 8, 9, 10. These first macrophages are commonly termed ‘primitive’ macrophages. The first primitive haematopoietic wave generates macrophages from a population of ‘early’ erythro-myeloid progenitors (EMPs), independently of a monocyte intermediate. Hence, primary human tissue must be used to develop our understanding of HBC ontogeny and function, and, consequently, HBC precursors remain poorly described 4.ĭuring gestation, haematopoiesis occurs in successive waves in different anatomical sites. HBC are unique amongst all tissue-resident macrophages, as equivalent cells are not found in the murine placenta 2, 3. Throughout pregnancy, HBC remain the only significant foetal-derived immune cell population of the human placenta. They rapidly proliferate and are highly abundant within first-trimester placental villi, the functional units of the placenta. Placental macrophages, termed Hofbauer cells (HBC), first appear at ~18 days post conception 1. The placenta starts to form 5 days after conception and continues to grow and develop throughout pregnancy, up to birth. It is the site of transfer of oxygen and nutrients to the foetus and acts as an important barrier against pathogens, amongst other functions. The human placenta is a major organ that regulates the health of both the mother and foetus during pregnancy. These findings establish the human placenta as an additional site of primitive haematopoiesis. We find the absence of HLA-DR in primitive macrophages is mediated via epigenetic silencing of class II transactivator, CIITA, the master regulator of HLA class II gene expression. Using in vitro culture experiments we demonstrate that PEMP generate HBC-like cells lacking HLA-DR expression. Here, we identify a population of placental erythro-myeloid progenitors (PEMPs) in the early human placenta that have conserved features of primitive yolk sac EMPs, including the lack of HLF expression. Human foetal placental macrophages, or Hofbauer cells (HBC), arise during the primitive haematopoietic wave ~18 days post conception and lack expression of human leukocyte antigen (HLA) class II. Although this process is thought to be spatially restricted to the yolk sac in the mouse, in humans, it remains poorly understood. The earliest macrophages are generated during embryonic development from erythro-myeloid progenitors (EMPs) via primitive haematopoiesis.

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