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The stepwise specification of embryonic stem cells to hematopoietic fate is driven by sequential exposure to Bmp4, activin A, bFGF and VEGF
Georges Lacaud, and
Cancer Research UK, Paterson Institute for Cancer Research, Manchester
University, Wilmslow Road, M20 4BX, Manchester, UK.
Author for correspondence (e-mail:
Accepted for publication 15 February 2008.
The differentiation of embryonic stem (ES) cells offers a powerfulapproach
to study mechanisms implicated in cell fate decision.A major hurdle, however,
is to promote the directed and efficientdifferentiation of ES cells toward a
specific lineage. Here,we define in serum-free media the minimal factor
requirementcontrolling each step of the differentiation process, resultingin
the production of highly enriched hematopoietic progenitors.Four factors -
Bmp4, activin A, bFGF (Fgf2) and VEGF (VegfA)- are sufficient to drive the
selective and efficient differentiationof mouse ES cells to hematopoiesis.
Each of these factors appearsto regulate a step of the process: Bmp4 promotes
the very efficientformation of mesoderm; bFGF and activin A induce the
differentiationof these mesodermal precursors to the hemangioblast fate; and
VEGFis required for the production of fully committed hematopoietic
progenitors.The stimulation of mesodermal precursors by bFGF and activinA
switches on very rapidly the hematopoietic program, allowingus to dissect the
molecular events leading to the formationof the hemangioblast. Runx1,
Scl (Tal1) and Hhex expressionis upregulated within 3
hours of stimulation, whereas upregulationof Lmo2 and Fli1
is observed later. Interestingly, increasedexpression levels of genes such as
cMyb, Pu.1 (Sfpi1), Gata1and Gata2 are
not observed at the onset of hemangioblast commitment.This stepwise control
of differentiation is extremely efficient,giving rise to a very high
frequency of hematopoietic precursors,and provides an optimal system for
understanding the molecularmachineries involved in blood progenitor