Project 1: Identify how fetal HSPCs are restricted from engaging in robust emergency myelopoiesis by cell-extrinsic factors.
Our work identifying maternal IL-10 restriction of fetal emergency myelopoiesis suggests that the immunoregulatory mechanisms necessary to maintain a healthy pregnancy to term also have the bystander consequences of limiting fetal immune responses that may otherwise be beneficial in the face of infection. If the fetal emergency myelopoiesis-restricting effects of maternal IL-10 could be separated from its pregnancy-protecting effects, this might yield novel therapeutic strategies that could be targeted to boost neonatal myeloid cell production without compromising maternal or fetal health.
As such, a better understanding of the mechanism by which maternal IL-10 restricts fetal emergency myelopoiesis is crucial. Our preliminary data show that while IL-10 levels in maternal serum increase significantly in response to lipopolysaccharide (LPS), fetal systemic IL-10 levels are low and remain unchanged in response to maternal LPS exposure, suggesting that maternal IL-10 does not modulate fetal HSPCs directly. Altered placental function is widely viewed as the critical central mediator linking the effects of maternal inflammation on adverse outcomes in the offspring.
We hypothesize 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 dysfunction in response to inflammation, releasing soluble mediators into the fetal circulation that go to the fetal liver where they regulate fetal HSPCs in either a direct or indirect manner. Such a cascade would likely yield several potential targets that could be investigated for therapeutic purposes.
To test this hypothesis, we are using genetically modified mice in which we can conditionally delete the IL-10 receptor alpha chain from specific maternal vs fetal compartments using tissue and cell-specific Cre transgenic mice, RNA sequencing and metabolomics, extensive immunophenotyping of the fetal HSPC compartment using multi-parameter flow cytometry and high dimensional flow cytometry, and in vitro and in vivo functional assays of HSPC function.
These studies will help elucidate the network of systemic factors that contribute to impaired neonatal myelopoiesis, paving the way for novel therapeutic opportunities in neonatal sepsis.
