Hierarchical organization of developing HSPC in the human embryonic liver

Abstract

SUMMARY STATEMENTWe uncover the phenotypic and functional hematopoietic hierarchy operating in the early human embryo. It will bring insights into the mechanisms driving hematopoietic stem cell self-renewal for future cell therapies. ABSTRACTDespite advances to engineer transplantable hematopoietic stem and progenitor cells (HSPCs) for research and therapy, an in depth characterization of the developing human hematopoietic system is still lacking. The human embryonic liver is at the crossroad of several hematopoietic sites and harbours a complex hematopoietic hierarchy including the first, actively dividing, HSPCs that will further seed the definitive hematopoietic organs. However few is known about the hierarchical phenotypic and functional hematopoietic organization operating at these stages of development.Here, by using a combination of four endothelial and hematopoietic surface markers i.e. the endothelial-specific marker VE-cadherin, the pan-leukocyte antigen CD45, the hemato-endothelial marker CD34 and the Angiotensin-Converting Enzyme (ACE, CD143), encompassing all early human HSPCs, we identified a hematopoietic hierarchy and, among it, a population co-expressing the four markers that uniquely harbored a proliferation and differentiation potential both ex vivo and in vivo. Moreover, we traced back this population to the yolk sac and AGM sites of hematopoietic emergence. Taken together, our data will help to identify human HSPC self-renewal and amplification mechanisms for future cell therapies.