Accurate wound repair is a crucial step to

protect organisms from environmental

damage, for example infection and toxin

exposure. In this issue of The EMBO Journal,

Miyoshi et al (2017) have elucidated a

new mechanism underpinning this process

within the intestine where mesenchymal

prostaglandin E2 produced following

damage drives intestinal regeneration

Jackstadt, Rene

Sansom, Owen James

English

PubMed

Enlighten

News & ViewsThe Wae to repair: prostaglandin E2(PGE2) triggers intestinal wound repairRene Jackstadt & Owen James SansomAccurate wound repair is a crucial step toprotect organisms from environmentaldamage, for example infection and toxinexposure. In this issue of The EMBO Jour-nal, Miyoshi et al (2017) have elucidated anew mechanism underpinning this processwithin the intestine where mesenchymalprostaglandin E2 produced followingdamage drives intestinal regeneration.See also: H Miyoshi et al (January 2017)T he intestine requires an efficientlyorchestrated repair process given thecontents of the intestinal lumen andits primary function as an absorptive organ.Unless damage is repaired quickly, barrierfunction would be compromised whichwould rapidly lead to infection, sepsis andultimately death. After injury, the highlyreplicative nature of the intestine leads torapid wound closure, to minimize theexposure to luminal antigens and microor-ganisms (Peterson & Artis, 2014). However,given repair/wound healing often activatesmany pathways deregulated in cancer, forexample WNT and TGFb, uncontrolledrepair and loss of homoeostasis could lead tocarcinogenesis (Ashton et al, 2010). To guar-antee proper wound repair, a process termedepithelial restitution occurs in the intestineto rapidly reseal superficial injuries (Lacy,1988). The healing process is most likely tobe performed by a cell population that hastransient repair features, wound-associatedepithelial (WAE) cells, and the induction ofnon-canonical Wnt signalling is required(Stappenbeck & Miyoshi, 2009). WAE cells arecontrolled by an orchestra of growth factorsand chemokines. However, both upstreamactivators of WAE cells and downstreameffector pathways need to be elucidated.OrganoidsAB Stem media Differentiation mediaEP4• EP4 KO• iEP4REGENERATIONWAEscAMP/PKAGSK3ββ-cateninREGENERATIONcAMP/PKAGSK3ββ-cateninPGE2 containing mediumEP4 EP4EP4ISCs in cryptPGE2(mesenchyme)INJURYFigure 1. Mechanistic model describing the role of PGE2–EP4–PKA–ß-catenin signalling in intestinalwound repair.(A) During intestinal injury, PGE2 levels increase locally. This triggers a non-canonical Wnt signalling cascaderesulting in regeneration and wound repair. Pharmacological inhibition or genetic deletion of EP4 impairs thissignalling and the tissue remains refractory for regeneration and wound healing. (B) In vitro organoidpropagation using stem cell medium enables the culture of stem cell rich organoids. Growth factor-depleted butPGE2-containing medium leads to WAE cell differentiation if cells are EP4 proficient; those cells resemble theirin vivo analogue. EP4 deficiency or pharmacological inhibition of EP4 (iEP4) leads to enterocyte differentiationand a reduced regenerative capacity.CRUK Beatson Institute, University of Glasgow, Glasgow, UK. E-mail: o.sansom@beatson.gla.ac.ukDOI 10.15252/embj.201695973 | Published online 8 December 2016ª 2016 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license The EMBO Journal Vol 36 | No 1 | 2017 3Published online: December 8, 2016 In an elegant study, Miyoshi et al (2017)used a series of models to address thisimportant question: mouse, organoid andhuman cell lines. Transcriptomic profilingrevealed that postmitotic properties of WAEcells can be generated by growth factordepletion of intestinal organoids. Thisresembles an atypical differentiation state ofWAE cells that has been previouslydescribed during the process of epithelialreconstitution (Lacy, 1988; Stappenbeck &Miyoshi, 2009). Importantly, this differentia-tion state was prostaglandin E2 (PGE2)dependent. Using a genetically engineeredmodel for Ptger4 (encoding for the prosta-glandin E receptor 4, EP4) deletion, theauthors show that PGE2 triggered WAE celldifferentiation is transmitted by EP4 in vitroand in vivo. In an array of elegant in vitroassays, the authors could show that thePGE2–EP4 axis irreversibly leads to WAE celldifferentiation, while inhibition of the PGE2–EP4 axis leads to enterocyte differentiation.Mechanistically, the authors describe thatEP4 signalling acts via cAMP–PKA–GSK3bcascade that controls b-catenin stabilization(Wnt signalling activity) and eventually dif-ferentiation to WAE cells. Notably, theauthors demonstrated a concentration-dependent differentiation into WAE cells,which may explain the spatial–temporalappearance of WAE cells during healing. Tonote, mesenchymal cells as source for PGE2have been described by the authors previ-ously (Manieri et al, 2015).Cancer has been suggested to be a “woundthat cannot heal” so it is notable that many ofthe pathways described here have beensuggested to be important in colorectalcarcinogenesis. Stromal COX2 has beenshown to be important for growth of adeno-mas in Apc+/ mice, and COX2 producesProstaglandin H2 of which Prostaglandin E2is a downstream metabolite. Loss of EP2 andEP4 was shown to suppress tumorigenesis inApc+/ mice (Sonoshita et al, 2001, 2002)and, recently, a PGE2–EP4 axis was suggestedto control colon cancer stem cell expansionand metastasis (Wang et al, 2015).Taken together, this study using a sophis-ticated in vitro tool to study wound repairhas generated important new findings intothis process. This in vitro system may alsobe able to define many more novel regula-tors of wound repair. Importantly, trialshave already been performed using EP4agonist in inflammatory bowel disease(Nakase et al, 2010). It would be interestingto assess whether these patients had moreWAE cells and whether they showedincreased wound repair. Conversely, furtherwork examining the inhibition of the Prosta-glandin E2–EP4 axis in both the initiationand progression of colorectal cancer shouldprovide key insights into the hijacking ofrepair processes by cancer cells.ReferencesAshton GH, Morton JP, Myant K, Phesse TJ,Ridgway RA, Marsh V, Wilkins JA, Athineos D,Muncan V, Kemp R, Neufeld K, Clevers H,Brunton V, Winton DJ, Wang X, Sears RC,Clarke AR, Frame MC, Sansom OJ (2010)Focal adhesion kinase is required forintestinal regeneration and tumorigenesisdownstream of Wnt/c-Myc signaling. Dev Cell19: 259 – 269Lacy ER (1988) Epithelial restitution in thegastrointestinal tract. J Clin Gastroenterol 10(Suppl. 1): S72 – S77Manieri NA, Mack MR, Himmelrich MD, WorthleyDL, Hanson EM, Eckmann L, Wang TC,Stappenbeck TS (2015) Mucosally transplantedmesenchymal stem cells stimulate intestinalhealing by promoting angiogenesis. J Clin Invest125: 3606 – 3618Miyoshi H, VanDussen KL, Malvin NP, Ryu SH,Wang Y, Sonnek NM, Lai CW, Stappenbeck TS(2017) Prostaglandin E2 promotes intestinalrepair through an adaptive cellular response ofthe epithelium. EMBO J 36: 5 – 24Nakase H, Fujiyama Y, Oshitani N, Oga T,Nonomura K, Matsuoka T, Esaki Y, MurayamaT, Teramukai S, Chiba T, Narumiya S (2010)Effect of EP4 agonist (ONO-4819CD) forpatients with mild to moderate ulcerativecolitis refractory to 5-aminosalicylates: arandomized phase II, placebo-controlled trial.Inflamm Bowel Dis 16: 731 – 733Peterson LW, Artis D (2014) Intestinal epithelialcells: regulators of barrier function andimmune homeostasis. Nat Rev Immunol 14:141 – 153Sonoshita M, Takaku K, Sasaki N, Sugimoto Y,Ushikubi F, Narumiya S, Oshima M, Taketo MM(2001) Acceleration of intestinal polyposisthrough prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. Nat Med 7:1048 – 1051Sonoshita M, Takaku K, Oshima M, Sugihara K,Taketo MM (2002) Cyclooxygenase-2 expressionin fibroblasts and endothelial cells of intestinalpolyps. Cancer Res 62: 6846 – 6849Stappenbeck TS, Miyoshi H (2009) The role ofstromal stem cells in tissue regeneration andwound repair. Science 324: 1666 – 1669Wang D, Fu L, Sun H, Guo L, DuBois RN(2015) Prostaglandin E2 promotes colorectalcancer stem cell expansion and metastasisin mice. Gastroenterology 149: 1884 –1895License: This is an open access article under theterms of the Creative Commons Attribution 4.0License, which permits use, distribution and repro-duction in any medium, provided the original workis properly cited.The EMBO Journal Vol 36 | No 1 | 2017 ª 2016 Cancer Research UK Beatson InstituteThe EMBO Journal PGE2 triggers wound repair Rene Jackstadt & Owen James Sansom4Published online: December 8, 2016 

The Wae to repair: prostaglandin E2 (PGE2) triggers intestinal wound repair

Enlighten: Publications

News & Views
The Wae to repair: prostaglandin E2
(PGE2) triggers intestinal wound repair
Rene Jackstadt & Owen James Sansom
Accurate wound repair is a crucial step to
protect organisms from environmental
damage, for example infection and toxin
exposure. In this issue of The EMBO Jour-
nal, Miyoshi et al (2017) have elucidated a
new mechanism underpinning this process
within the intestine where mesenchymal
prostaglandin E2 produced following
damage drives intestinal regeneration.
See also: H Miyoshi et al (January 2017)
T he intestine requires an efficientlyorchestrated repair process given thecontents of the intestinal lumen and
its primary function as an absorptive organ.
Unless damage is repaired quickly, barrier
function would be compromised which
would rapidly lead to infection, sepsis and
ultimately death. After injury, the highly
replicative nature of the intestine leads to
rapid wound closure, to minimize the
exposure to luminal antigens and microor-
ganisms (Peterson & Artis, 2014). However,
given repair/wound healing often activates
many pathways deregulated in cancer, for
example WNT and TGFb, uncontrolled
repair and loss of homoeostasis could lead to
carcinogenesis (Ashton et al, 2010). To guar-
antee proper wound repair, a process termed
epithelial restitution occurs in the intestine
to rapidly reseal superficial injuries (Lacy,
1988). The healing process is most likely to
be performed by a cell population that has
transient repair features, wound-associated
epithelial (WAE) cells, and the induction of
non-canonical Wnt signalling is required
(Stappenbeck & Miyoshi, 2009). WAE cells are
controlled by an orchestra of growth factors
and chemokines. However, both upstream
activators of WAE cells and downstream
effector pathways need to be elucidated.
Organoids
A
B Stem media Differentiation media
EP4
• EP4 KO
• iEP4
REGENERATION
WAEs
cAMP/PKA
GSK3β
β-catenin
REGENERATION
cAMP/PKA
GSK3β
β-catenin
PGE2 containing medium
EP4 EP4
EP4
ISCs in crypt
PGE2
(mesenchyme)
INJURY
Figure 1. Mechanistic model describing the role of PGE2–EP4–PKA–ß-catenin signalling in intestinal
wound repair.
(A) During intestinal injury, PGE2 levels increase locally. This triggers a non-canonical Wnt signalling cascade
resulting in regeneration and wound repair. Pharmacological inhibition or genetic deletion of EP4 impairs this
signalling and the tissue remains refractory for regeneration and wound healing. (B) In vitro organoid
propagation using stem cell medium enables the culture of stem cell rich organoids. Growth factor-depleted but
PGE2-containing medium leads to WAE cell differentiation if cells are EP4 proficient; those cells resemble their
in vivo analogue. EP4 deficiency or pharmacological inhibition of EP4 (iEP4) leads to enterocyte differentiation
and a reduced regenerative capacity.
CRUK Beatson Institute, University of Glasgow, Glasgow, UK. E-mail: o.sansom@beatson.gla.ac.uk
DOI 10.15252/embj.201695973 | Published online 8 December 2016
ª 2016 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license The EMBO Journal Vol 36 | No 1 | 2017 3
Published online: December 8, 2016 
In an elegant study, Miyoshi et al (2017)
used a series of models to address this
important question: mouse, organoid and
human cell lines. Transcriptomic profiling
revealed that postmitotic properties of WAE
cells can be generated by growth factor
depletion of intestinal organoids. This
resembles an atypical differentiation state of
WAE cells that has been previously
described during the process of epithelial
reconstitution (Lacy, 1988; Stappenbeck &
Miyoshi, 2009). Importantly, this differentia-
tion state was prostaglandin E2 (PGE2)
dependent. Using a genetically engineered
model for Ptger4 (encoding for the prosta-
glandin E receptor 4, EP4) deletion, the
authors show that PGE2 triggered WAE cell
differentiation is transmitted by EP4 in vitro
and in vivo. In an array of elegant in vitro
assays, the authors could show that the
PGE2–EP4 axis irreversibly leads to WAE cell
differentiation, while inhibition of the PGE2–
EP4 axis leads to enterocyte differentiation.
Mechanistically, the authors describe that
EP4 signalling acts via cAMP–PKA–GSK3b
cascade that controls b-catenin stabilization
(Wnt signalling activity) and eventually dif-
ferentiation to WAE cells. Notably, the
authors demonstrated a concentration-
dependent differentiation into WAE cells,
which may explain the spatial–temporal
appearance of WAE cells during healing. To
note, mesenchymal cells as source for PGE2
have been described by the authors previ-
ously (Manieri et al, 2015).
Cancer has been suggested to be a “wound
that cannot heal” so it is notable that many of
the pathways described here have been
suggested to be important in colorectal
carcinogenesis. Stromal COX2 has been
shown to be important for growth of adeno-
mas in Apc+/ mice, and COX2 produces
Prostaglandin H2 of which Prostaglandin E2
is a downstream metabolite. Loss of EP2 and
EP4 was shown to suppress tumorigenesis in
Apc+/ mice (Sonoshita et al, 2001, 2002)
and, recently, a PGE2–EP4 axis was suggested
to control colon cancer stem cell expansion
and metastasis (Wang et al, 2015).
Taken together, this study using a sophis-
ticated in vitro tool to study wound repair
has generated important new findings into
this process. This in vitro system may also
be able to define many more novel regula-
tors of wound repair. Importantly, trials
have already been performed using EP4
agonist in inflammatory bowel disease
(Nakase et al, 2010). It would be interesting
to assess whether these patients had more
WAE cells and whether they showed
increased wound repair. Conversely, further
work examining the inhibition of the Prosta-
glandin E2–EP4 axis in both the initiation
and progression of colorectal cancer should
provide key insights into the hijacking of
repair processes by cancer cells.
References
Ashton GH, Morton JP, Myant K, Phesse TJ,
Ridgway RA, Marsh V, Wilkins JA, Athineos D,
Muncan V, Kemp R, Neufeld K, Clevers H,
Brunton V, Winton DJ, Wang X, Sears RC,
Clarke AR, Frame MC, Sansom OJ (2010)
Focal adhesion kinase is required for
intestinal regeneration and tumorigenesis
downstream of Wnt/c-Myc signaling. Dev Cell
19: 259 – 269
Lacy ER (1988) Epithelial restitution in the
gastrointestinal tract. J Clin Gastroenterol 10
(Suppl. 1): S72 – S77
Manieri NA, Mack MR, Himmelrich MD, Worthley
DL, Hanson EM, Eckmann L, Wang TC,
Stappenbeck TS (2015) Mucosally transplanted
mesenchymal stem cells stimulate intestinal
healing by promoting angiogenesis. J Clin Invest
125: 3606 – 3618
Miyoshi H, VanDussen KL, Malvin NP, Ryu SH,
Wang Y, Sonnek NM, Lai CW, Stappenbeck TS
(2017) Prostaglandin E2 promotes intestinal
repair through an adaptive cellular response of
the epithelium. EMBO J 36: 5 – 24
Nakase H, Fujiyama Y, Oshitani N, Oga T,
Nonomura K, Matsuoka T, Esaki Y, Murayama
T, Teramukai S, Chiba T, Narumiya S (2010)
Effect of EP4 agonist (ONO-4819CD) for
patients with mild to moderate ulcerative
colitis refractory to 5-aminosalicylates: a
randomized phase II, placebo-controlled trial.
Inflamm Bowel Dis 16: 731 – 733
Peterson LW, Artis D (2014) Intestinal epithelial
cells: regulators of barrier function and
immune homeostasis. Nat Rev Immunol 14:
141 – 153
Sonoshita M, Takaku K, Sasaki N, Sugimoto Y,
Ushikubi F, Narumiya S, Oshima M, Taketo MM
(2001) Acceleration of intestinal polyposis
through prostaglandin receptor EP2 in Apc
(Delta 716) knockout mice. Nat Med 7:
1048 – 1051
Sonoshita M, Takaku K, Oshima M, Sugihara K,
Taketo MM (2002) Cyclooxygenase-2 expression
in fibroblasts and endothelial cells of intestinal
polyps. Cancer Res 62: 6846 – 6849
Stappenbeck TS, Miyoshi H (2009) The role of
stromal stem cells in tissue regeneration and
wound repair. Science 324: 1666 – 1669
Wang D, Fu L, Sun H, Guo L, DuBois RN
(2015) Prostaglandin E2 promotes colorectal
cancer stem cell expansion and metastasis
in mice. Gastroenterology 149: 1884 –
1895
License: This is an open access article under the
terms of the Creative Commons Attribution 4.0
License, which permits use, distribution and repro-
duction in any medium, provided the original work
is properly cited.
The EMBO Journal Vol 36 | No 1 | 2017 ª 2016 Cancer Research UK Beatson Institute
The EMBO Journal PGE2 triggers wound repair Rene Jackstadt & Owen James Sansom
4
Published online: December 8, 2016 


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The Wae to repair: prostaglandin E2 (PGE2) triggers intestinal wound repair

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