TY - JOUR

T1 - HOXB4 can enhance the differentiation of embryonic stem cells by modulating the hematopoietic niche

AU - Jackson, Melany

AU - Axton, Richard A

AU - Taylor, A Helen

AU - Wilson, Julie A

AU - Gordon-Keylock, Sabrina A M

AU - Kokkaliaris, Konstantinos D

AU - Brickman, Joshua M

AU - Schulz, Herbert

AU - Hummel, Oliver

AU - Hubner, Norbert

AU - Forrester, Lesley M

N1 - Copyright © 2011 AlphaMed Press.

PY - 2012/2

Y1 - 2012/2

N2 - Hematopoietic differentiation of embryonic stem cells (ESCs) in vitro has been used as a model to study early hematopoietic development, and it is well documented that hematopoietic differentiation can be enhanced by overexpression of HOXB4. HOXB4 is expressed in hematopoietic progenitor cells (HPCs) where it promotes self-renewal, but it is also expressed in the primitive streak of the gastrulating embryo. This led us to hypothesize that HOXB4 might modulate gene expression in prehematopoietic mesoderm and that this property might contribute to its prohematopoietic effect in differentiating ESCs. To test our hypothesis, we developed a conditionally activated HOXB4 expression system using the mutant estrogen receptor (ER(T2)) and showed that a pulse of HOXB4 prior to HPC emergence in differentiating ESCs led to an increase in hematopoietic differentiation. Expression profiling revealed an increase in the expression of genes associated with paraxial mesoderm that gives rise to the hematopoietic niche. Therefore, we considered that HOXB4 might modulate the formation of the hematopoietic niche as well as the production of hematopoietic cells per se. Cell mixing experiments supported this hypothesis demonstrating that HOXB4 activation can generate a paracrine as well as a cell autonomous effect on hematopoietic differentiation. We provide evidence to demonstrate that this activity is partly mediated by the secreted protein FRZB.

AB - Hematopoietic differentiation of embryonic stem cells (ESCs) in vitro has been used as a model to study early hematopoietic development, and it is well documented that hematopoietic differentiation can be enhanced by overexpression of HOXB4. HOXB4 is expressed in hematopoietic progenitor cells (HPCs) where it promotes self-renewal, but it is also expressed in the primitive streak of the gastrulating embryo. This led us to hypothesize that HOXB4 might modulate gene expression in prehematopoietic mesoderm and that this property might contribute to its prohematopoietic effect in differentiating ESCs. To test our hypothesis, we developed a conditionally activated HOXB4 expression system using the mutant estrogen receptor (ER(T2)) and showed that a pulse of HOXB4 prior to HPC emergence in differentiating ESCs led to an increase in hematopoietic differentiation. Expression profiling revealed an increase in the expression of genes associated with paraxial mesoderm that gives rise to the hematopoietic niche. Therefore, we considered that HOXB4 might modulate the formation of the hematopoietic niche as well as the production of hematopoietic cells per se. Cell mixing experiments supported this hypothesis demonstrating that HOXB4 activation can generate a paracrine as well as a cell autonomous effect on hematopoietic differentiation. We provide evidence to demonstrate that this activity is partly mediated by the secreted protein FRZB.

KW - Animals

KW - Cell Differentiation

KW - Cells, Cultured

KW - Embryo, Mammalian

KW - Embryonic Stem Cells

KW - Gene Expression

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Glycoproteins

KW - Hematopoiesis

KW - Hematopoietic Stem Cells

KW - Homeodomain Proteins

KW - Humans

KW - Mice

KW - NIH 3T3 Cells

KW - Oligonucleotide Array Sequence Analysis

KW - Paracrine Communication

KW - Stem Cell Niche

KW - Transcription Factors

KW - beta Catenin

U2 - 10.1002/stem.782

DO - 10.1002/stem.782

M3 - Journal article

C2 - 22084016

VL - 30

SP - 150

EP - 160

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 2

ER -