Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis

Abstract

During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.

Hemogenic endothelium of the vitelline and umbilical arteries is the major contributor to mouse fetal lympho-myelopoiesis

“…For a long time, the FL was thought to be an intermediate reservoir for HSC expansion after their initial generation in the AGM, in preparation to their lifelong residency in the BM. Several recent work revolutionized this concept and showed that FL is in fact a complex hub in which distinct waves of progenitors differentiate, expand and might even mature with mechanisms still largely unknown 33,34,38,63,[79][80][81] . Indeed, ours and others' data imply that fetalrestricted HSPC and adult-type HSCs coexist in the FL, where they undergo different processes leading respectively to differentiation and self-renewal.…”