From origin to lifespan: Unravelling early human developmental haematopoiesis and macrophage heterogeneity

Abstract

This thesis explores early human developmental haematopoiesis, emphasising the integral roles of the extraembryonic yolk sac (YS) in generating the first blood and immune cells, including macrophages, and providing nutritional support to the embryo. Much of our current understanding of early haematopoiesis derives from pivotal studies in model systems. However, the application of single-cell genomics technologies have enabled this study to deliver a detailed multiomic characterisation of the multifunctional role the YS plays in early human development with temporal resolution. As part of the Human Cell Atlas, I co-led a collaborative, multi-site effort to construct a time-resolved multiomics atlas of the human YS from the 3rd to the 8th post-conception weeks. This atlas integrates protein and gene expression data and is augmented with existing scRNA-seq data from eleven other prenatal tissues, including crucial haematopoietic tissues like the liver, bone marrow, and Aorta-Gonad-Mesonephros (AGM). This integrative approach facilitated the mapping of human early immune and blood development. Our findings elucidate the unique spatiotemporal characteristics of YS haematopoiesis fundamental to the emergence of the first blood and immune cells. Our analyses reveal YS evolutionarily conserved roles in metabolism, coagulation, vascular development, and early haematopoietic regulation, with these functions gradually ceded as development progresses. We detailed the dynamic emergence and decline of YS Hematopoietic Stem and Progenitor Cells (HSPCs) which originate from YS hemogenic endothelium (HE), illustrating the earliest wave of haematopoiesis. We also identified a YS-specific macrophage production pathway, and a pre-specified, TREM2+ microglia-like macrophage subset across prenatal tissues. This work illuminates a previously obscure phase of human development, establishing the YS as a vital multifunctional organ. Building this map of early haematopoiesis offers valuable insights into cellular differentiation pathways specific to early life, paving the way for novel tissue engineering strategies and cellular therapeutic avenues.