In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of ...blood cells while also preventing HSC exhaustion. All putative niche cells suggested thus far have a nonhematopoietic origin. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation. Here we show that megakaryocytes (MKs) can directly regulate HSC pool size in mice. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to MKs in a nonrandom fashion. Selective in vivo depletion of MKs resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that MKs are the source of chemokine C-X-C motif ligand 4 (CXCL4, also named platelet factor 4 or PF4) in the bone marrow, and we found that CXCL4 regulates HSC cell cycle activity. CXCL4 injection into mice resulted in a reduced number of HSCs because of their increased quiescence. By contrast, Cxcl4(-/-) mice exhibited an increased number of HSCs and increased HSC proliferation. Combined use of whole-mount imaging and computational modeling was highly suggestive of a megakaryocytic niche capable of independently influencing HSC maintenance by regulating quiescence. These results indicate that a terminally differentiated cell type derived from HSCs contributes to the HSC niche, directly regulating HSC behavior.
The erythroblastic island (EI), formed by a central macrophage and developing erythroblasts (EBs), was first described decades ago and was recently shown to play an in vivo role in homeostatic and ...pathological erythropoiesis. The exact molecular mechanisms, however, mediating the interactions between macrophages and EBs remain unclear. Macrophage-EB attacher (Maea) has previously been suggested to mediate homophilic adhesion bounds bridging macrophages and EBs. Maea-deficient mice die perinatally with anemia and defective erythrocyte enucleation, suggesting a critical role in fetal erythropoiesis. Here, we generated conditional knockout mouse models of Maea to assess its cellular and postnatal contributions. Deletion of Maea in macrophages using Csf1r-Cre or CD169-Cre caused severe reductions of bone marrow (BM) macrophages, EBs, and in vivo island formation, whereas its deletion in the erythroid lineage using Epor-Cre had no such phenotype, suggesting a dominant role of Maea in the macrophage for BM erythropoiesis. Interestingly, Maea deletion in spleen macrophages did not alter their numbers or functions. Postnatal Maea deletion using Mx1-Cre or function inhibition using a novel monoclonal antibody also impaired BM erythropoiesis. These results indicate that Maea contributes to adult BM erythropoiesis by regulating the maintenance of macrophages and their interaction with EBs via an as-yet-unidentified EB receptor.
•Maea, but not Vcam1, is required for adult BM macrophage development and EI function in vivo.•Deletion of Maea expressed by macrophages, but not by EBs, impairs BM EI formation.
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Whereas the cellular basis of the hematopoietic stem cell (HSC) niche in the bone marrow has been characterized, the nature of the fetal liver niche is not yet elucidated. We show that Nestin⁺NG2⁺ ...pericytes associate with portal vessels, forming a niche promoting HSC expansion. Nestin⁺NG2⁺ cells and HSCs scale during development with the fractal branching patterns of portal vessels, tributaries of the umbilical vein. After closure of the umbilical inlet at birth, portal vessels undergo a transition from Neuropilin-1⁺Ephrin-B2⁺ artery to EphB4⁺ vein phenotype, associated with a loss of periportal Nestin⁺NG2⁺ cells and emigration of HSCs away from portal vessels. These data support a model in which HSCs are titrated against a periportal vascular niche with a fractal-like organization enabled by placental circulation.
A role for macrophages in erythropoiesis was suggested several decades ago when erythroblastic islands in the bone marrow, composed of a central macrophage surrounded by developing erythroblasts, ...were described. However, the in vivo role of macrophages in erythropoiesis under homeostatic conditions or in disease remains unclear. We found that specific depletion of CD169(+) macrophages markedly reduced the number of erythroblasts in the bone marrow but did not result in overt anemia under homeostatic conditions, probably because of concomitant alterations in red blood cell clearance. However, CD169(+) macrophage depletion significantly impaired erythropoietic recovery from hemolytic anemia, acute blood loss and myeloablation. Furthermore, macrophage depletion normalized the erythroid compartment in a JAK2(V617F)-driven mouse model of polycythemia vera, suggesting that erythropoiesis in polycythemia vera remains under the control of macrophages in the bone marrow and splenic microenvironments. These results indicate that CD169(+) macrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders.
Research into the extra-skeletal functions of vitamin D has been expanding in recent years. During pregnancy, maternal vitamin D status may be of concern because of the key role of this vitamin in ...fetal skeletal development and due to the association between hypovitaminosis D and adverse maternal–fetal outcomes. Therefore, the objective of this manuscript was to review the maternal–fetal impact of gestational vitamin D deficiency and the benefits of vitamin D supplementation during pregnancy. A literature search was performed in PubMed and Embase employing the following keywords: vitamin D deficiency, pregnancy, 25-hydroxyvitamin D, and hypovitaminosis D. All relevant articles in English language published since 1980 were analysed by the two authors. Neonatal complications derived from vitamin D deficiency include low birth weight, growth restriction, and respiratory tract infection. In the mother, vitamin D deficiency has been associated with altered glucose homeostasis and increased incidence of gestational diabetes mellitus, pre-eclampsia, and bacterial vaginosis. However, the current state of the evidence is controversial for some other endpoints and the actual benefit of vitamin D supplementation in pregnancy remains unclear. Additional longitudinal studies may clarify the actual impact of vitamin D deficiency during pregnancy, and randomised trials are required to define the benefits of vitamin D supplementation in reducing the incidence of adverse outcomes in the mother and infant.
A single hematopoietic stem cell (HSC) is capable of reconstituting hematopoiesis and maintaining homeostasis by balancing self-renewal and cell differentiation. The mechanisms of HSC division ...balance, however, are not yet defined. Here we demonstrate, by characterizing at the single-cell level a purified and minimally heterogeneous murine Tie2⁺ HSC population, that these top hierarchical HSCs preferentially undergo symmetric divisions. The induction of mitophagy, a quality control process in mitochondria, plays an essential role in self-renewing expansion of Tie2⁺ HSCs. Activation of the PPAR (peroxisome proliferator-activated receptor)-fatty acid oxidation pathway promotes expansion of Tie2⁺ HSCs through enhanced Parkin recruitment in mitochondria. These metabolic pathways are conserved in human TIE2⁺ HSCs. Our data thus identify mitophagy as a key mechanism of HSC expansion and suggest potential methods of cell-fate manipulation through metabolic pathways.
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