652 - Maternal inflammatory response restricts fetal emergency myelopoiesis.

Poster Number: 652
Publication Number: 652.24

Amelie Collins, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States; James Swann, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States; Melissa A. Proven, Columbia University, New York, NY, United States; Emmanuelle Passegué, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States

Background: Neonates are uniquely susceptible to infection, and infection is a leading cause of neonatal mortality. Neutropenia is a cardinal feature of the neonatal immune response that contributes to mortality. Neonatal neutropenia is commonly attributed to a lack of regenerative potential in the hematopoietic progenitor compartment, although which progenitor cells are responsible and how this occurs is underexplored. In adults, the process of rapidly generating large numbers of neutrophils in response to demand, called emergency myelopoiesis (EM), has been well studied. In response to both direct and indirect signals, quiescent adult hematopoietic stem cells (HSC) become activated, shifting the production of downstream progenitors to favor amplification of myeloid progenitors that support increased neutrophil production.

Objective: To investigate the ability of fetal and neonatal HSCs to activate emergency myelopoiesis.

Design/Methods: In vivo mouse models of inflammation that recapitulate neonatal neutropenia, including lipopolysaccharide (LPS) injection and anti-Ly6G antibody mediated granulocyte depletion.

Results: We found that fetal hematopoietic stem and progenitor cells (HSPC) fail to activate EM pathways in vivo. The fetal HSPC compartment responds to inflammation with a prolonged depletion of HSCs and multipotent progenitors (MPPs), in contrast to the transient depletion of HSCs and expansion of myeloid-biased MPPs seen in adults. While fetal HSPCs display cell intrinsic deficits in the production of myeloid cells at steady-state, we found that these cell intrinsic deficits can be overcome by strong inflammatory stimuli ex vivo. To explore cell extrinsic mechanisms limiting fetal EM, we manipulated inflammatory mediators in genetically mixed mother-fetal dyads. We found that maternal, not fetal, cytokines drive the fetal HSPC response, with maternal TNFa required for fetal HSPC depletion. We used interleukin (IL)-10-deficient pregnant mice, in which inflammation triggers an exaggerated response including significantly increased TNFa production, and found that deletion of maternal IL-10 partially restores the ability of fetal HSPCs to engage in EM.

Conclusion(s): We have identified the lack of EM activation in fetal HSPCs as a key contributor to neonatal neutropenia. This restriction is largely cell extrinsic and driven by the maternal inflammatory response. These studies will help to elucidate strategies by which fetal EM could be enhanced to counteract neonatal neutropenia, leading to improved outcomes for infected neonates.