Contributions of Embryonic HSC-Independent Hematopoiesis to Organogenesis and the Adult Hematopoietic System

Abstract

During ontogeny, the establishment of the hematopoietic system takes place in several phases, separated both in time and location. The process is initiated extra-embryonically in the yolk sac (YS) and concludes in the main arteries of the embryo with the formation of hematopoietic stem cells (HSC). Initially, it was thought that HSC-independent hematopoietic YS cells were transient, and only required to bridge the gap to HSC activity. However, in recent years it has become clear that these cells also contribute to embryonic organogenesis, including the emergence of HSCs. Furthermore, some of these early HSC-independent YS cells persist into adulthood as distinct hematopoietic populations. These previously unrecognized abilities of embryonic HSC-independent hematopoietic cells constitute a new field of interest. Here, we aim to provide a succinct overview of the current knowledge regarding the contribution of YS-derived hematopoietic cells to the development of the embryo and the adult hematopoietic system.

Hlf Expression Marks Early Emergence of Hematopoietic Stem Cell Precursors With Adult Repopulating Potential and Fate

“…It is generally accepted that HSCs are derived from specialized endothelial cells termed hemogenic endothelial cells (HECs) through endothelial-to-hematopoietic transition in mid-gestational embryos ( Zovein et al, 2008 ; Chen et al, 2009 ; Dzierzak and Bigas, 2018 ; Neo et al, 2021 ). During this process, HECs bud from the dorsal aorta and then aggregate to form intra-aortic hematopoietic clusters (IAHCs) ( Boisset et al, 2010 ).…”

De-Novo Hematopoiesis From the Fetal Lung

“…The de-novo generation of blood in the fetal lung may act as an additional in-situ source of essential blood products for organogenesis. This is an important consideration when accounting for the role of macrophages and platelets in both organogenesis and angiogenesis [60][61][62][63] . Notably, the origins of many lung resident blood cells are not fully understood, but to date, the origins of resident macrophages are the most well studied.…”

Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors

“…Due to the tremendous clinical potential of HSC in numerous therapies, there has been until recently a much stronger emphasis on investigating and understanding AGM EHT. However, there is an increasing recognition that studying YS EHT would also generate a wealth of critical information 3 . First, a complete understanding of the EHT that gives rise to HSC is achievable only if we identify how AGM EHT differs from EHT in the YS.…”

“…First, a complete understanding of the EHT that gives rise to HSC is achievable only if we identify how AGM EHT differs from EHT in the YS. Secondly, there is increasing evidence that EMPs derived cells are not only sustaining early embryonic development but are also a significant source of hematopoietic cells in adults such as tissue-resident macrophages (Mφ) or subtype of NK cells 3 . Additionally, tumor-associated Mφ, which modulate the tumor microenvironment and contribute to therapy failure, have been proposed to originate from EMPs 39 .…”

“…Subsequently, the emergence of YS derived erythro-myeloid progenitors (EMPs) around E8.25 marks the onset of definitive hematopoiesis 1 , 2 . EMPs provide an essential source of erythroid and myeloid cells to sustain embryo development prior to the generation of multipotent and long-term self-renewing hematopoietic stem cells (HSCs) in the aorta–gonad–mesonephros (AGM), and their subsequent expansion in the fetal liver (FL) 3 . Defect in primitive hematopoiesis results in early lethality before E10.5 4 , a lack of EMP causes lethal embryonic anemia around E13.5, while the absence of HSC leads to perinatal lethality 5 – 7 .…”