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Principal Investigator: Amelie Collins
Organization: CINCINNATI CHILDRENS HOSP MED CTR
Fiscal Year: 2024
Award: $414,026
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY/ABSTRACT
Maternal infections during pregnancy lead to adverse outcomes for the offspring, including short-term
outcomes such as intrauterine fetal demise, preterm delivery and neonatal sepsis, and long-term sequelae
such as neurodevelopmental impairment. A key factor contributing to fetal/neonatal susceptibility to infection is
the failure to robustly produce innate immune cells such as neutrophils that form a first line of defense against
infection. We recently made the novel observation that fetal hematopoietic stem and progenitor cells (HSPCs)
are extrinsically restricted from activating the pathways that would lead to rapid production of neutrophils,
termed emergency myelopoiesis (EM), by maternal interleukin-10 (IL-10), although how maternal IL-10
restricts fetal EM is unknown. Altered placental function is proposed to be the critical central mediator linking
the effects of maternal inflammation on adverse outcomes in the offspring. In particular, maternal inflammation
increases placental synthesis of serotonin that is released into the fetal circulation, reaching the fetal brain and
disrupting the growth of serotonergic axons. We have found that fetal HSPCs express serotonin receptors and
their proliferation is suppressed in vitro by serotonin, supporting the hypothesis that placental serotonin may
also regulate fetal hematopoiesis. This proposal will test the hypothesis that maternal IL-10 restricts fetal
emergency myelopoiesis via a multi-layered cascade of events involving a network of maternal
decidual immune cells that trigger placental serotonin synthesis which is then released into the fetal
circulation and reaches the fetal liver where it regulates fetal HSPCs in either a direct manner or
indirectly by regulating the stromal and mature hematopoietic cells of the fetal liver niche. Our
approach will be to 1) identify the IL-10-responsive cell in the maternal-fetal milieu and determine the function
of that cell that results in restriction of fetal emergency myelopoiesis, and 2) determine how maternal
inflammation is sensed in the fetal liver microenvironment and whether this signal, which we predict to be
serotonin, regulates fetal HSPC function directly or indirectly. We predict that maternal IL-10 restricts fetal EM
via its baseline function of establishing a tolerogenic profile in maternal decidual macrophages and that in its
absence, the exaggerated inflammatory response of alternatively-primed macrophages negatively impacts
placental function resulting in increased synthesis of serotonin that regulates fetal HSPCs directly and
indirectly. This project will systematically identify the mechanisms by which maternal inflammation is translated
across the placenta and sensed in the fetal liver to modulate fetal HSPC emergency myelopoiesis, uncovering
potential nodes along the cascade that might be amenable to therapeutic targeting, and ultimately boosting
neonatal immune function and improving neonatal outcomes.
Terms: <21+ years old><5-HT><5-HT Receptors><5-Hydroxytryptamine><5-Hydroxytryptamine Receptors><5HT><Address><Adult><Adult Human><Axon><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Precursor Cell><Blood Serum><Body Tissues><Brain><Brain Nervous System><CSIF><CSIF-10><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cells Placenta-Tissue><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Circulation><Communication><Cytokine Synthesis Inhibitory Factor><Decidua><Decidua Graviditas><Dysfunction><Emergencies><Emergency Situation><Encephalon><Endothelium><Ensure><Enteramine><Event><Failure><Fetal Liver><Fetus><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Generalized Growth><Generations><Gestation><Growth><Hematopoiesis><Hematopoietic><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hippophaine><IL-10><IL-10 receptor><IL10><IL10A><Immune><Immunes><In Vitro><Infection><Inflammation><Inflammatory><Inflammatory Response><Innate Immune System><Interleukin 10 Precursor><Interleukin-10><Intracellular Communication and Signaling><Lead><Link><Liver Cells><Macrophage><Marrow Neutrophil><Mediator><Mice><Mice Mammals><Murine><Mus><Myeloid Cells><Myelopoiesis><Mφ><Neonatal><Neonatal Mortality><Neurodevelopmental Impairment><Neutropenia><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Normal Placentoma><Outcome><Pathway interactions><Pb element><Physiopathology><Placenta><Placenta Embryonic Tissue><Placentome><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Predisposition><Pregnancy><Premature Birth><Prematurely delivering><Preterm Birth><Process><Production><Progenitor Cells><Proliferating><R-Series Research Projects><R01 Mechanism><R01 Program><Receptor Signaling><Regulation><Research Grants><Research Project Grants><Research Projects><Serotonin><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Subcellular Process><Supporting Cell><Survey Instrument><Surveys><Susceptibility><Testing><Therapeutic Intervention><Tissue Growth><Tissues><Transgenic Mice><Translating><Validation><adulthood><adverse consequence><adverse outcome><biological signal transduction><blood cell formation><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><cell type><combat><cytokine><death among neonates><death among newborns><death in neonates><death in newborn><fetal><fetal cell><fetus cell><flow cytophotometry><heavy metal Pb><heavy metal lead><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><high dimensionality><immune function><improved><in vivo><interleukin-10 receptor><intervention therapy><long-term sequelae><metabolism measurement><metabolomics><metabonomics><mortality among neonates><mortality among newborns><mortality in neonates><mortality in newborns><neonatal death><neonatal demise><neonatal immune system><neonatal morbidity><neonatal outcome><neonatal sepsis><neutrophil><newborn death><newborn morbidity><newborn mortality><novel><offspring><ontogeny><pathophysiology><pathway><premature childbirth><premature delivery><preterm delivery><prevent><preventing><progenitor cell function><progenitor function><response><scRNA-seq><serotonin receptor><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><stem and progenitor cell function><stem and progenitor function><stem cell function><stem cells><therapeutic target><transcriptomics><validations>