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Open Access Publications from the University of California

Scholarly Works (4 results)

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UC Merced Electronic Theses and Dissertations (2022)

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.

    Cover page: Maternal inflammation directs fetal hematopoiesisCreative Commons 'BY-NC-ND' version 4.0 license
    • Article
    • Peer Reviewed
    UC Merced Previously Published Works (2020)
    Over the last century, the alarming surge in allergy and autoimmune disease has led to the hypothesis that decreasing exposure to microbes, which has accompanied industrialization and modern life in the Western world, has fundamentally altered the immune response. In its current iteration, the "hygiene hypothesis" suggests that reduced microbial exposures during early life restricts the production and differentiation of immune cells suited for immune regulation. Although it is now well-appreciated that the increase in hypersensitivity disorders represents a "perfect storm" of many contributing factors, we argue here that two important considerations have rarely been explored. First, the window of microbial exposure that impacts immune development is not limited to early childhood, but likely extends into the womb. Second, restricted microbial interactions by an expectant mother will bias the fetal immune system toward hypersensitivity. Here, we extend this discussion to hypothesize that the cell types sensing microbial exposures include fetal hematopoietic stem cells, which drive long-lasting changes to immunity.
      Cover page: Training the Fetal Immune System Through Maternal Inflammation—A Layered Hygiene Hypothesis
      • Article
      • Peer Reviewed
      UC Merced Previously Published Works (2023)
      Infection directly influences adult hematopoietic stem cell (HSC) function and differentiation, but the fetal hematopoietic response to infection during pregnancy is not well-studied. Here, we investigated the fetal hematopoietic response to maternal infection with Toxoplasma gondii (T. gondii), an intracellular parasite that elicits Type II IFNγ-mediated maternal immunity. While it is known that maternal infection without direct pathogen transmission can affect fetal immune development, the effects of maternal IFNγ on developing HSCs and the signals that mediate these interactions have not been investigated. Our investigation reveals that the fetal HSCs respond to T. gondii infection with virulence-dependent changes in proliferation, self-renewal potential, and lineage output. Furthermore, maternal IFNγ crosses the fetal-maternal interface, where it is perceived by fetal HSCs. By comparing the effects of maternal IFNγ injection with maternal T. gondii infection, we reveal that the effects of IFNγ treatment mimic some aspects of the fetal HSC response to infection. Moreover, our findings illuminate that the fetal HSC response to prenatal infection is distinct from the adult HSC response to IFNγ-induced inflammation. Altogether, our data disentangle the role of infection-induced inflammatory cytokines in driving the expansion of downstream hematopoietic progenitors.
        Cover page: Both maternal IFNγ exposure and acute prenatal infection with Toxoplasma gondii activate fetal hematopoietic stem cells.
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2023)
        Evolutionarily conserved, "natural" (n)IgM is broadly reactive to both self and foreign antigens. Its selective deficiency leads to increases in autoimmune diseases and infections. In mice, nIgM is secreted independent of microbial exposure to bone marrow (BM) and spleen B-1 cell-derived plasma cells (B-1PC), generating the majority of nIgM, or by B-1 cells that remain non-terminally differentiated (B-1sec). Thus, it has been assumed that the nIgM repertoire is broadly reflective of the repertoire of body cavity B-1 cells. Studies here reveal, however, that B-1PC generate a distinct, oligoclonal nIgM repertoire, characterized by short CDR3 variable immunoglobulin heavy chain regions, 7-8 amino acids in length, some public, many arising from convergent rearrangements, while specificities previously associated with nIgM were generated by a population of IgM-secreting B-1 (B-1sec). BM, but not spleen B-1PC, or B-1sec also required the presence of TCRαβ CD4 T cells for their development from fetal precursors. Together, the studies identify important previously unknown characteristics of the nIgM pool.
          Cover page: B-1 plasma cells require non-cognate CD4 T cell help to generate a unique repertoire of natural IgM
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