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

Melany Jackson; Richard A Axton; A Helen Taylor; Julie A Wilson; Sabrina A M Gordon-Keylock; Konstantinos D Kokkaliaris; Joshua M Brickman; Herbert Schulz; Oliver Hummel; Norbert Hubner; Lesley M Forrester

doi:10.1002/stem.782

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

Melany Jackson, Richard A Axton, A Helen Taylor, Julie A Wilson, Sabrina A M Gordon-Keylock, Konstantinos D Kokkaliaris, Joshua M Brickman, Herbert Schulz, Oliver Hummel, Norbert Hubner, Lesley M Forrester

24 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Stem Cells
Volume	30
Issue number	2
Pages (from-to)	150-60
Number of pages	11
ISSN	1066-5099
DOIs	https://doi.org/10.1002/stem.782
Publication status	Published - Feb 2012
Externally published	Yes

Keywords

Animals
Cell Differentiation
Cells, Cultured
Embryo, Mammalian
Embryonic Stem Cells
Gene Expression
Gene Expression Profiling
Gene Expression Regulation
Glycoproteins
Hematopoiesis
Hematopoietic Stem Cells
Homeodomain Proteins
Humans
Mice
NIH 3T3 Cells
Oligonucleotide Array Sequence Analysis
Paracrine Communication
Stem Cell Niche
Transcription Factors
beta Catenin

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10.1002/stem.782

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@article{6406f0561b9647f18d15b9ed3313cacf,

title = "HOXB4 can enhance the differentiation of embryonic stem cells by modulating the hematopoietic niche",

abstract = "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.",

keywords = "Animals, Cell Differentiation, Cells, Cultured, Embryo, Mammalian, Embryonic Stem Cells, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Glycoproteins, Hematopoiesis, Hematopoietic Stem Cells, Homeodomain Proteins, Humans, Mice, NIH 3T3 Cells, Oligonucleotide Array Sequence Analysis, Paracrine Communication, Stem Cell Niche, Transcription Factors, beta Catenin",

author = "Melany Jackson and Axton, {Richard A} and Taylor, {A Helen} and Wilson, {Julie A} and Gordon-Keylock, {Sabrina A M} and Kokkaliaris, {Konstantinos D} and Brickman, {Joshua M} and Herbert Schulz and Oliver Hummel and Norbert Hubner and Forrester, {Lesley M}",

note = "Copyright {\textcopyright} 2011 AlphaMed Press.",

year = "2012",

month = feb,

doi = "10.1002/stem.782",

language = "English",

volume = "30",

pages = "150--60",

journal = "Stem Cells",

issn = "1066-5099",

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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

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

SN - 1066-5099

VL - 30

SP - 150

EP - 160

JO - Stem Cells

JF - Stem Cells

IS - 2

ER -

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

Abstract

Keywords

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