Developmental Cell | De novo generation of macrophage from placenta-derived hemogenic endothelium

  • 胡小琛
  • Published: 2021-07-03
  • 104

Placenta is a critical organ for embryonic development in the uterus. During pregnancy, the placenta participates in the exchange of gases, nutrients and waste between mother and fetus, secretes hormones and growth factors needed for pregnancy, and protects the fetus from attack by the mother's immune system (Rossant and Cross, 2001). In addition to its role in maternal-fetal communication, placenta has been shown to serve as a source of hematopoietic stem cells during embryogenesis (Gekas et al., 2005; Ottersbach and Dzierzak, 2005). Furthermore, CD41+ hematopoietic cells were observed in the placenta of Ncx1 mutant embryos that lack blood circulation, implying that placenta could generate hematopoietic cells de novo (Rhodes et al., 2008). However, the lethality of Ncx1 mutant in embryos at E11.5 hinders further investigation of the biological function of placenta-resident hematopoietic cells (Koushik et al., 2001).

On June 30, 2021Professors Feng Liu (from Institute of Zoology, Chinese Academy of Sciences), Jing-Dong J. Han (from Peaking university), Hongmei Wang (from Institute of Zoology, Chinese Academy of Sciences) and Berthold Gottgens (from University of Cambridge) collaborate on a paper entitled “De novo generation of macrophage from placenta-derived hemogenic endothelium” in Developmental Cell journal. This work identifies and experimentally validates that a CD44+ subpopulation of placental endothelial cells (ECs) exhibits hemogenic potential. Importantly, lineage tracing using the newly-generated Hoxa13 reporter line shows that Hoxa13-labeled ECs can produce placental macrophages, named Hofbauer cell (HBC)-like cells.

They firstly performed 10× Genomics-based single cell RNA sequencing (scRNA-seq) of fetal placental cells and generated a placental cell atlas, including endothelial cells, hematopoietic cells, stromal cells, trophoblast cells and primitive endoderm. They also established an interactive website (, with all the data freely available to the community. When focused on placental ECs, all placental ECs were divided into three sub-clusters, annotated as EC1, EC2 and EC3. Among them, they found that EC2 highly expresses genes that are involved in HE specification. Combined with experimental validation, they identified that CD44 can be used to enrich placental HE cells. Transcriptional analysis indicated that Notch and inflammatory signaling are involved in placental HE specification, similar to their reported role in HE specification in aorta-gonad-mesonephros (AGM) region.

Furthermore, they performed scRNA-seq using ECs from yolk sac, AGM and placenta and identified that Hoxa13 is specifically expressed in placental ECs. Then, they established a tamoxifen (TAM)-inducible model (named as Hoxa13CreER) and crossed it with the Rosa26mT/mG reporter line. Lineage tracing using the newly-generated Hoxa13 reporter line showed that ECs give rise to macrophage through placental HE cells. Furthermore, cell-cell interaction analysis predicted the immune response and pro-angiogenic role of placental macrophages.

Taken together, this study generates the atlas of the fetal placenta and provides an important resource for placental biology. This work also extends the potential clinical value of placenta as a new source of HE cells and macrophages. This work was supported by grants from the National Key Research and Development Program of China, the Strategic Priority Research Program of the Chinese Academy of Sciences and the National Natural Science Foundation of China.


Gekas, C., Dieterlen-Lievre, F., Orkin, S.H., Mikkola, H.K., 2005. The placenta is a niche for hematopoietic stem cells. Dev Cell 8, 365-375.

Koushik, S.V., Wang, J., Rogers, R., Moskophidis, D., Lambert, N.A., Creazzo, T.L., Conway, S.J., 2001. Targeted inactivation of the sodium-calcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization. FASEB J 15, 1209-1211.

Ottersbach, K., Dzierzak, E., 2005. The murine placenta contains hematopoietic stem cells within the vascular labyrinth region. Dev Cell 8, 377-387.

Rhodes, K.E., Gekas, C., Wang, Y., Lux, C.T., Francis, C.S., Chan, D.N., Conway, S., Orkin, S.H., Yoder, M.C., Mikkola, H.K., 2008. The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation. Cell Stem Cell 2, 252-263.

Rossant, J., Cross, J.C., 2001. Placental development: lessons from mouse mutants. Nat Rev Genet 2, 538-548.