EpithelialMesenchymal interactions during embryonic development

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Epithelial-Mesenchymal interactions during
embryonic development

• Anna Means

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Epithelial-Mesenchymal interactions during
embryonic development
Outline

• Mesenchyme patterns endodermal epithelium
• Specification
• Outgrowth
• Differentiation
• Epithelium patterns mesenchyme

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Background

• Most endodermal epithelium does not develop
  correctly without mesenchyme
• Mounting evidence that stroma contributes to
  epithelial tumorigenesis
• Mostly, we dont know what the stroma does in
  tumorigenesis, but we know a lot about what it
  does in development

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Pancreatic cancer involves a massive stromal
expansion
Normal adult pancreas
Chronic pancreatitis
Embryonic pancreas
Pancreatic cancer
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All embryonic structures develop from 3 germ
layers
E4.5
E6.5
E7.5
ectoderm
mesoderm
blastocyst
epiblast
endoderm
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Endoderm starts as an epithelial sheet,
invaginates to form a tube, then
differentiates into different organs
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Splanchnic mesoderm stays in close apposition to
endoderm
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Mesenchyme/endoderm apposition
Kockel, 2006
Means, Wright
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Endoderm contacts many mesodermal structures
Le Douarin Fukuta-Taira
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Cardiac mesenchyme specifies liver vs. pancreas
Liver vs. pancreas
Zaret lab
Pdx1
Pdx1
Pdx1
Ventral endoderm cardiac mes. liver
Ventral endoderm alone pancreas
Ventral endoderm cardiac mes.
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FGF from cardiac mesenchyme is critical mediator
of liver induction
FGF2 liver
Untreated pancreas
Deutsch, 2001
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Mesenchyme can alter epithelial fate
Design isolate lung epithelium away from
mesenchyme and culture with homotypic or
heterotypic mesenchyme
lung
skin
intestine
Deimling, 2006
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Mesenchyme alters epithelial fate
E13 lung epithelium combined with
Lung mesenchyme
Intestinal mesenchyme
Skin mesenchyme
Intestinal morphology
Lung morphology
Skin morphology
Deimling, 2006
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Mesenchyme specifies stomach vs. intestinal
epithelium
Barx1 is a transcription factor in presumptive
stomach mesenchyme
Mesenchyme with Barx1
Mesenchyme without Barx1
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Mesenchyme specifies stomach vs. intestinal
epithelium
Barx1 is a transcription factor in presumptive
stomach mesenchyme
Mesenchyme with Barx1
Mesenchyme without Barx1
Barx1-/-
Stomach markers
Intestinal markers
Cdx2 (intestinal marker)
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Barx1 induces stomach by inhibiting Wnt signaling
Barx1 is required for sFRP expression
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Barx1 induces stomach by inhibiting Wnt signaling
Barx1 is required for sFRP expression
Addition of sFRP reestablished stomach development
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Barx1 induces stomach by inhibiting Wnt signaling
Barx1 is required for sFRP expression
Addition of sFRP reestablished stomach development
Other inhibitor of Wnt signaling also allows
stomach development
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Intestinal metaplasia is a precursor to stomach
cancer
Normal adult stomach
Intestinal metaplasia
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Permissive induction Mesenchyme in pancreas
development
Pancreatic endoderm requires surrounding
mesenchyme to develop but other mesenchyme can
substitute.
Golosow and Grobstein, 1962
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Mesenchyme affects outgrowth of lung epithelium
Bellusci, 1997
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Mesenchyme influences outgrowth
Mesenchyme is required for lung and tracheal
development Lung endoderm lung mesenchyme
branching Lung endoderm tracheal mesenchyme
no branching Tracheal endoderm lung mesenchyme
branching
endoderm
mesenchyme
no branching
branching
no branching
branching
Wessells
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FGF and BMP regulate lung branching
Epithelium FGF10 bead
Epi/Mes FGF10 bead
Epithelium FGF10 bead BMP4
24 hr
48 hr
96 hr
Weaver and Hogan
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Mesenchyme regulates pancreatic differentiation
All pancreatic cells form
Epithelium mesenchyme
Only ducts form
Epithelium alone
Gittes, 1996
Epithelium implanted under renal capsule
Only islets form
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The other direction mesenchyme development
depends on epithelial signals
BMP4
FGF10
Bellusci, 1997
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Wnt signals from epithelium affect mesenchymal
development
Wnt7b is expressed in lung epithelium
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Wnt signals from epithelium affect mesenchymal
development
Wnt7b is expressed in lung epithelium
Wnt7b knockout perturbs smooth muscle development
Less smooth muscle forms
Thickness of mesenchyme
Proliferation of mesenchyme
Shu, 2002
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Shh from epithelium is required for mesenchymal
development
Shh is expressed in lung epithelium
Shh signals to mesenchyme
Bellusci, 1997
Pepicelli, 1998
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Shh from epithelium is required for mesenchymal
development
Shh is expressed in lung epithelium
Shh signals to mesenchyme
Bellusci, 1997
Shh mutants lack smooth muscle
Pepicelli, 1998
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The unknown mesenchyme

• Epithelium probably affects more than smooth
  muscle development
• Many mesenchymal cell types dont have good
  markers
• Little is known about differences in stromal
  composition

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Permissive induction Who is talking to whom?
Does pancreatic epithelium require a ubiquitous
signal, or does the epithelium program the
mesenchymal signal?
Golosow and Grobstein, 1962