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Maternal inflammation directs fetal hematopoiesis

Creative Commons 'BY-NC-ND' version 4.0 license

Infection in the adult organism drives cytokine-mediated inflammation that directly influences hematopoietic stem cell (HSC) function and differentiation within the bone marrow, but much less is known about the fetal hematopoietic response to maternal inflammation and infection during pregnancy. Here, we demonstrate that fetal hematopoietic stem and progenitor cells (HSPCs) respond to prenatal inflammation in utero and that the fetal response drives long-term changes to HSC function after transplantation. First, we modeled maternal immune activation (MIA) with the IFN-a stimulating viral mimetic, poly(I:C), and showed that fetal HSPCs exhibit changes in quiescence, expansion, and lineage-biased output in response to prenatal inflammation. Single-cell transcriptomic analysis of fetal HSPCs in response to MIA revealed specific upregulation of inflammatory gene profiles in discrete, transient HSC populations that propagated expansion of lymphoid-biased progenitors in the fetal liver.

Next, we investigated the fetal hematopoietic response to maternal Toxoplasma gondii infection. T. gondii is an intracellular parasite that elicits Type II, IFNγ-mediated maternal immunity to prevent vertical transmission and promote parasite clearance. The production of excessive IFNγ during congenital toxoplasmosis has dire consequences for the developing fetus, such as lowered birth weights and premature abortion, but the effects to the developing immune system and the signals that mediate these interactions have not been investigated previously. Our examination revealed that the fetal inflammatory repertoire is distinct from the maternal response and is directly influenced by parasite virulence. We show that maternal IFNy crossed the fetal-maternal interface and was perceived directly by fetal HSCs, and that the response of fetal HSCs was dependent on the fetal IFNy receptor. Functionally, the heterogenous fetal HSC pool responded to aberrant inflammation with virulence-dependent changes in proliferation, long-term multi-lineage reconstitution, and self-renewal potential. By directly comparing the effect of maternal IFNy injection with congenital T. gondii infection of varying virulence, our observations delineate both a direct effect of IFNy on fetal HSCs and illuminate the independent role of additional inflammatory cytokines in driving the expansion of downstream hematopoietic progenitors. Finally, in direct contrast to the adult hematopoietic response to infection and the fetal response to Type I interferon-mediated MIA, exposure to Type II interferon-mediated inflammation in utero did not impair fetal HSC function, even in response to severe infection. Our findings provide insight into the cues that direct fetal hematopoiesis in response to inflammation and begin to tease apart inflammatory cues that promote a beneficial hematopoietic response versus those that may ultimately be detrimental.

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