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Abstract
Human pluripotent stem cells (hPSCs) have been suggested as a potential source for
the de novo production of blood cells for transfusion, immunotherapies, and transplantation.
However, even with advanced hematopoietic differentiation methods, the primitive and
myeloid-restricted waves of hematopoiesis dominate in hPSC differentiation cultures,
whereas cell surface markers to distinguish these waves of hematopoiesis from lympho-myeloid
hematopoiesis remain unknown. In the embryo, hematopoietic stem cells (HSCs) arise
from hemogenic endothelium (HE) lining arteries, but not veins. This observation led
to a long-standing hypothesis that arterial specification is an essential prerequisite
to initiate the HSC program. It has also been established that lymphoid potential
in the yolk sac and extraembryonic vasculature is mostly confined to arteries, whereas
myeloid-restricted hematopoiesis is not specific to arterial vessels. Here, we review
how the link between arterialization and the subsequent definitive multilineage hematopoietic
program can be exploited to identify HE enriched in lymphoid progenitors and aid in
in vitro approaches to enhance the production of lymphoid cells and potentially HSCs
from hPSCs. We also discuss alternative models of hematopoietic specification at arterial
sites and recent advances in our understanding of hematopoietic development and the
production of engraftable hematopoietic cells from hPSCs.