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Yolk sac hematopoiesis: does it contribute to the adult hematopoietic system?

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Abstract

In most vertebrates, the yolk sac (YS) represents the very first tissue where blood cells are detected. Therefore, it was thought for a long time that it generated all the blood cells present in the embryo. This model was challenged using different animal models, and we now know that YS hematopoietic precursors are mostly transient although their contribution to the adult system cannot be excluded. In this review, we aim at properly define the different waves of blood progenitors that are produced by the YS and address the fate of each of them. Indeed, in the last decade, many evidences have emphasized the role of the YS in the emergence of several myeloid tissue-resident adult subsets. We will focus on the development of microglia, the resident macrophages in the central nervous system, and try to untangle the recent controversy about their origin.

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Acknowledgements

V.W. is an investigator of WELBIO and is also supported by grants from the Fonds National de la Recherche Scientifique (FNRS) and The Minerve Foundation. J.Y.B. is funded by the swiss national fund (#310030_184814).

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Correspondence to Julien Y. Bertrand.

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Appendices

Box 1: a few definitions about developmental hematopoiesis

Monopotent blood progenitor: blood precursor endowed with a single differentiation capacity.

Multipotent blood progenitor: blood progenitor that can give rise to multiple lineages after differentiation.

Hematopoietic stem cells: multipotent self-renewable hematopoietic precursors. They are the only ones with the ability to reconstitute all blood lineages after transplantation. In the adult animal they are located mainly in the bone marrow, whereas their niche is the fetal liver during embryogenesis in mammals. These cells are specified during a very short time window during embryogenesis from the main arteries, through a process called endothelial-to-hematopoiesis transition (EHT).

Hemogenic endothelium: it consists of a limited number of endothelial cells that undergo EHT to give rise to hematopoietic progenitors.

Hemangioblast: mesoderm-derived precursor endowed with endothelial and hematopoietic potential at the single-cell level.

Primitive hematopoiesis: historically, represents the very first wave of hematopoiesis in the embryo. The blood cells produced from this wave are specified from mesoderm immediately after gastrulation. This wave does not originate from hematopoietic stem cells.

Definitive hematopoiesis: historically, represents the process that generates blood cells in the adult, and by extension all hematopoietic phenomena that concern HSCs.

Box2: time to revisit nomenclature in developmental hematopoiesis?

EMPs are referred to as transient definitive progenitors. However, using the term “definitive” similarly between HSCs and EMPs could be misleading, as it may imply that those progenitors are not transient and remain throughout life. Since it is widely accepted that HSCs are truly definitive (they seed the bone marrow prior to birth and regenerate immune cells throughout life), limiting the use of “definitive” for cells that are indeed derived from HSCs may thus better reflect the biology. As a consequence, mono- or bi- (i.e., mesoderm/hemangioblastderived cells) versus multi-potency (hemogenic endotheliumderived progenitors) could be addressed separately from the term “primitive”. Such approach would also leave room for additional progenitors that may be identified in the future, as well as for the transient lymphoid-primed progenitors that emerge from the hemogenic endothelium before the HSCs. However, perhaps the most appropriate designation would be to describe hematopoiesis as pre- (independent of) HSCs and post- (dependent of) HSCs, with the HSC-independent hematopoiesis compartment including monopotent (mesoderm/hemangioblast-derived) progenitors in the blood island and later multi-potent progenitors derived from the hemogenic endothelium. While these ideas can certainly serve as a starting point for discussion, deciding on a revised terminology will however require a large community effort.

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Wittamer, V., Bertrand, J.Y. Yolk sac hematopoiesis: does it contribute to the adult hematopoietic system?. Cell. Mol. Life Sci. 77, 4081–4091 (2020). https://doi.org/10.1007/s00018-020-03527-6

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