IFNγ and acute prenatal infection withToxoplasma gondiiactivate fetal hematopoietic stem cells

Abstract

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 infection during pregnancy. Here, we investigated the fetal hematopoietic response to maternal infection with Toxoplasma gondii (T. gondii). 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 maternal infection with T. gondii has dire consequences for the developing fetus, such as reduced birth weights and premature abortion, but the effects on developing hematopoietic cells and the signals that mediate these interactions have not been investigated. Our investigation reveals that the heterogenous fetal HSC pool responds to T. gondii infection with virulence-dependent changes in proliferation, self-renewal potential, and lineage output. We demonstrate that maternal IFNγ crosses the fetal-maternal interface and is perceived directly by fetal HSCs. By directly comparing the effects of maternal IFNγ injection with maternal T. gondii infection, our observations reveal that IFNγ mimics several aspects of the fetal HSC response to infection. Moreover, our data disentangle the role of additional infection-induced inflammatory cytokines in driving the expansion of independent downstream hematopoietic progenitors. Together, our findings illuminate the robust response of fetal hematopoietic stem cells to prenatal infection, and demonstrate that this response is distinct from the adult HSC response to IFNγ-induced inflammation.

Maternal IL-10 restricts fetal emergency myelopoiesis

“…Employing a second model of demandadapted myelopoiesis by depleting granulocytes with α-Ly6G antibody, we followed the kinetics of this response across the perinatal period, showing that the lack of EM engagement in fetal HSPCs translated into absence of the burst of mature myeloid cells characteristic of EM activation in the adult. While some of our observations are in contrast to two recent studies demonstrating transient expansion and activation of a subset of fetal HSCs as well as MPP4 leading to persistence of fetal-like lymphoid cells in the neonate 68,69 , it is likely that differences in the types of inflammatory stimuli, embryonic timing of exposure, and route of administration will account for these discrepancies. This emphasizes the need for continued investigations of fetal hematopoiesis in situ, and for further integration of the results obtained from different challenges.…”

Metabolomics of Mouse Embryonic CSF Following Maternal Immune Activation

“…MIA imparts systemic embryonic stress, with impact on the brain and the hematopoietic system (López et al , 2023; Tseng & Beaudin, 2023). At both E12.5 and E14.5, the developing embryonic hematopoietic system is located in the liver.…”

The fulfilled promise and unmet potential of umbilical cord blood

“…Zhu et al [36 ▪ ] reviewed the impact of birth trends, delivery methods and pregnancy conditions impacting maternal and fetal health on banking of stem cells from gestational tissues. Other factors that have been proposed to impact CB potency include gestational diabetes [37,38 ▪ ], caffeine consumption and smoking [46], infections during pregnancy [39,40] and folic acid levels in maternal diet [41 ▪ ]. To improve the accumulation of banked CBUs with the required potency to be effective for clinical utility, collections from donors with noted health considerations may be best utilized as research units.…”