Department of Cellular and Molecular Medicine
University of California, San Diego
Host: Judith Eisen
110 Willamette
A major goal of regenerative medicine is to instruct formation of multipotent, tissue-specific stem cells from pluripotent embryonic stem cells (ESCs) for cell
replacement therapies. Generation of
hematopoietic stem cells (HSCs) from ESCs is not currently possible, however,
necessitating a better understanding of how HSCs normally arise during
embryonic development. We previously
showed that hematopoiesis occurs through four
distinct waves during zebrafish development, with HSCs arising in the final
wave in close association with the dorsal aorta. Recent reports have suggested that murine HSCs derive from hemogenic
endothelial cells (ECs) lining the aortic floor. Additional in vitro studies have similarly
suggested that the hematopoietic progeny of ESCs arise through endothelial
intermediates. Using a permanent lineage
tracing strategy, we have demonstrated that all four waves of developmental hematopoiesis derive from shared endothelial precursors,
including the first HSCs that are the lineal founders of the adult
hematopoietic system. Utilizing
combinations of fluorescent reporter transgenes, we
have isolated the stepwise intermediates as hemogenic
endothelium transitions to nascent HSCs.
In addition, we have utilized the unique strengths of the zebrafish
embryo to image directly the birth of HSCs from the ventral wall of the dorsal
aorta. The genesis of HSCs from hemogenic endothelium is absolutely dependent upon the
Notch signaling pathway. In efforts to
identify the signaling elements genetically upstream of Notch signaling, we
have identified Wnt16, a non-canonical ligand of the Wnt signaling pathway that is required for HSC
specification. Generation of HSCs in
Wnt16 knock-down animals is rescued by enforced Notch expression, demonstrating
that Wnt16 regulates HSC formation in a Notch-dependent manner. Taken together, these studies have
demonstrated directly that HSCs are born from aortic endothelium, and have
begun to elucidate the genetic factors required to instruct HSC formation from mesodermal precursors.
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