Mouse placenta fetal macrophages arise from endothelial cells outside the placenta

•New Hoxa13Cre knockin mice specifically target all placenta endothelial cells •Mouse placenta fetal macrophages do not arise from placental endothelium •Mouse placenta fetal macrophages are tissue resident macrophages from the yolk sac •Mouse placental fetal macrophages share a common origin as human Hofbauer cells Placental fetal macrophages (fMacs) are the only immune cells on the fetal side of the placental barrier. Mouse models have not been used to test their function because they have previously been found to have distinct cellular origins and functions in mice and humans. Here, we test the ontogeny of mouse placental fMacs. Using a new Hoxa13Cre allele that labels all placental endothelial cells (ECs), we demonstrate that mouse placenta fMacs do not arise from placental endothelium. Instead, lineage tracing studies using Tie2-Cre and Cx3cr1CreERT2 alleles demonstrate that mouse placental fMacs arise from yolk sac endothelium. Administration of blocking antibodies against CSF1R at E6.5 and E7.5 results in depletion of placental fMacs throughout pregnancy, and this suggests a yolk sac origin, similar to that in human fMacs. This Matters Arising paper is in response to Liang et al., published in Developmental Cell. A response by Liang and Liu is published in this issue. Placental fetal macrophages (fMacs) are the only immune cells on the fetal side of the placental barrier. Mouse models have not been used to test their function because they have previously been found to have distinct cellular origins and functions in mice and humans. Here, we test the ontogeny of mouse placental fMacs. Using a new Hoxa13Cre allele that labels all placental endothelial cells (ECs), we demonstrate that mouse placenta fMacs do not arise from placental endothelium. Instead, lineage tracing studies using Tie2-Cre and Cx3cr1CreERT2 alleles demonstrate that mouse placental fMacs arise from yolk sac endothelium. Administration of blocking antibodies against CSF1R at E6.5 and E7.5 results in depletion of placental fMacs throughout pregnancy, and this suggests a yolk sac origin, similar to that in human fMacs. This Matters Arising paper is in response to Liang et al., published in Developmental Cell. A response by Liang and Liu is published in this issue. Response to Matters Arising: Characterization of placental fetal macrophagesLiang et al.Developmental CellDecember 05, 2022In BriefUsing single-cell RNA sequencing, Liang et al. identified a placental fetal macrophage subpopulation expressing CD31 and revealed that placental fetal macrophages are heterogenous in mid-gestion during mouse pregnancy. Full-Text PDF