# Determining themechanism of maternal IL-10 restriction of fetal emergency myelopoiesis to improve neonataloutcomes

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $414,026

## Abstract

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.

## Key facts

- **NIH application ID:** 10996651
- **Project number:** 1R01HD116402-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Amelie Collins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $414,026
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996651

## Citation

> US National Institutes of Health, RePORTER application 10996651, Determining themechanism of maternal IL-10 restriction of fetal emergency myelopoiesis to improve neonataloutcomes (1R01HD116402-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10996651. Licensed CC0.

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