Early hematopoiesis and macrophage development

Abstract

The paradigm that all blood cells are derived from hematopoietic stem cells (HSCs) has been challenged by two findings. First, there are tissue-resident hematopoietic cells, including subsets of macrophages that are not replenished by adult HSCs, but instead are maintained by self-renewal of fetal-derived cells. Second, during embryogenesis, there is a conserved program of HSC-independent hematopoiesis that precedes HSC function and is required for embryonic survival. The presence of waves of HSC-independent hematopoiesis as well as fetal HSCs raises questions about the origin of fetal-derived adult tissue-resident macrophages. In the murine embryo, historical examination of embryonic macrophage and monocyte populations combined with recent reports utilizing genetic lineage-tracing approaches has led to a model of macrophage ontogeny that can be integrated with existing models of hematopoietic ontogeny. The first wave of hematopoiesis contains primitive erythroid, megakaryocyte and macrophage progenitors that arise in the yolk sac, and these macrophage progenitors are the source of early macrophages throughout the embryo, including the liver. A second wave of multipotential erythro-myeloid progenitors (EMPs) also arises in the yolk sac . EMPs colonize the fetal liver, initiating myelopoiesis and forming macrophages. Lineage tracing indicates that this second wave of macrophages are distributed in most fetal tissues, although not appreciably in the brain. Thus, fetal-derived adult tissue-resident macrophages, other than microglia, appear to predominately derive from EMPs. While HSCs emerge at midgestation and colonize the fetal liver, the relative contribution of fetal HSCs to tissue macrophages at later stages of development is unclear. The inclusion of macrophage potential in multiple waves of hematopoiesis is consistent with reports of their functional roles throughout development in innate immunity, phagocytosis, and tissue morphogenesis and remodeling. Understanding the influences of developmental origin, as well as local tissue-specific signals, will be necessary to fully decode the diverse functions and responses of tissue-resident macrophages.

Contribution of Extra‐Cardiac Cells in Murine Heart Valves is Age‐Dependent

“…Here, we used C57 / Bl6 WT mice to show that CD45‐positive cells are detected in endocardial cushions of primitive aortic valves at embryonic day 14.5, and reactivity is also observed in the mitral position, but the percentage of cells is significantly lower (Figure A). It is not known whether these cells are embryonic hematopoietic stem cells derived from primitive or definitive hematopoiesis, or tissue‐resident hematopoietic cells . Similar percentages of CD45‐positive cells are observed at postnatal stages in both valve sets (≈1.2% aortic, ≈2.6% mitral), but the percent significantly increases by 4 months (≈8.0% aortic, ≈6.7% mitral) and 16 months (≈10.9% aortic, ≈10.5% mitral) of age (Figure A).…”

TET2‐Mediated Spatiotemporal Changes of 5‐Hydroxymethylcytosine During Organogenesis in the Late Mouse Fetus

“…TET2 and TET3 were such as to participate in demethylation of liver development in the late Kunming mouse fetus. TET‐mediated oxidation of 5mC to 5hmC, 5fC, or 5caC is considered to be the main force for fetal liver differentiation (Lewis et al, ; McGrath et al, ). In the late stage of Kunming fetus, the expression of 5hmC was significantly associated with the formation of liver tissue and TET2 was strongly positive, which suggested that TET2 is related to the development of hepatocytes.…”

Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes

“…Recent studies have demonstrated that some tissue-resident macrophage populations (such as microglia in the brain) arise in the yolk sac during early embryogenesis and populate the tissues of the developing embryo, where they can be maintained by self-renewal for long periods (even throughout life) (Hashimoto et al, 2013; Schulz et al, 2012). Other tissue-resident macrophage populations arise from circulating monocytes produced by hematopoietic stem cells (HSCs), initially in the fetal liver and subsequently in the bone marrow (Geissmann and Mass, 2015; McGrath et al, 2015). Neutrophils and DCs are also derived from HSCs.…”