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Macrophage Diversity in the First Trimester Human Placenta: Phenotypes, Functions and Developmental Origins


Type

Thesis

Change log

Authors

Thomas, Jake 

Abstract

The placenta is the fetal-derived organ that forms the interface between mother and child during pregnancy and is essential for maintaining fetal and maternal health throughout gestation. The human placenta contains a population of tissue-resident macrophages called Hofbauer cells (HBC), however the functions and developmental origins of these cells remain poorly defined. Our attempts to profile HBC in the first trimester human placenta revealed the presence of maternally-derived cells in placental digests. We established reliable gating strategies for the isolation of HBC and placenta-associated maternal macrophages/monocytes (PAMM), allowing us to profile their functions at the steady state and in response to inflammatory stimuli. Our data suggest that HBC have roles in angiogenesis and tissue remodelling, whilst PAMM are involved in the repair of the placental surface. We also determined that HBC have the capacity to play a defensive role in protecting the fetus from pathogens, as they are responsive to Toll-like receptor stimulation and display microbicidal activity in vitro. Through transcriptomic analyses we show that HBC are likely derived from the first primitive wave of haematopoiesis in development, and analysis of publicly available datasets revealed that macrophages derived from primitive haematopoiesis can be specifically identified by a lack of HLA Class II expression. Finally, we identify a population of haematopoietic progenitors in the early first trimester placenta which display features of primitive erythro- myeloid progenitors. Using in vitro single cell culture experiments we show that these progenitors generate HBC-like cells which lack HLA-DR expression. These findings indicate that HBC are derived locally within the placenta via primitive haematopoiesis. Together this research provides a new framework for human placental immunology. By increasing our understanding of placental macrophages new insights will emerge about human placental development and how this underpins pregnancy disorders.

Description

Date

2022-04-27

Advisors

McGovern, Naomi

Keywords

Placenta, Macrophage, Hofbauer cells, Fetal Immunology

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge