Hematopoietic stem cell development is dependent on blood flow.
During vertebrate embryogenesis, hematopoietic stem cells (HSCs) arise in the aorta-gonads-mesonephros (AGM) region. We report here that blood flow is a conserved regulator of HSC formation. In zebrafish, chemical blood flow modulators regulated HSC development, and silent heart (sih) embryos, lacking a heartbeat and blood circulation, exhibited severely reduced HSCs. Flow-modifying compounds primarily affected HSC induction after the onset of heartbeat; however, nitric oxide (NO) donors regulated HSC number even when treatment occurred before the initiation of circulation, and rescued HSCs in sih mutants. Morpholino knockdown of nos1 (nnos/enos) blocked HSC development, and its requirement was shown to be cell autonomous. In the mouse, Nos3 (eNos) was expressed in HSCs in the AGM. Intrauterine Nos inhibition or embryonic Nos3 deficiency resulted in a reduction of hematopoietic clusters and transplantable murine HSCs. This work links blood flow to AGM hematopoiesis and identifies NO as a conserved downstream regulator of HSC development.
North
Trista E
TE
Stem Cell Program and Hematology/Oncology, Children's Hospital, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
Goessling
Wolfram
W
Peeters
Marian
M
Li
Pulin
P
Ceol
Craig
C
Lord
Allegra M
AM
Weber
Gerhard J
GJ
Harris
James
J
Cutting
Claire C
CC
Huang
Paul
P
Dzierzak
Elaine
E
Zon
Leonard I
LI
D000818:Animals; D001790:Blood Physiological Phenomena; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015027:Zebrafish
D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III