Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism

Augusto Zani, Mara Cananzi, Francesco Fascetti-Leon, Giuseppe Lauriti, Virpi V. Smith, Sveva Bollini, Marco Ghionzoli, Antonello D'Arrigo, Michela Pozzobon, Martina Piccoli, Amy Hicks, Jack Wells, Bernard Siow, Neil J. Sebire, Colin Bishop, Alberta Leon, Anthony Atala, Mark F. Lythgoe, Agostino Pierro, Simon EatonPaolo De Coppi

Research output: Contribution to journalArticle

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Abstract

Objective: Necrotising enterocolitis (NEC) remains one of the primary causes of morbidity and mortality in neonates and alternative strategies are needed. Stem cells have become a therapeutic option for other intestinal diseases, which share some features with NEC. We tested the hypothesis that amniotic fluid stem (AFS) cells exerted a beneficial effect in a neonatal rat model of NEC. Design: Rats intraperitoneally injected with AFS cells and their controls (bone marrow mesenchymal stem cells, myoblast) were analysed for survival, behaviour, bowel imaging (MRI scan), histology, bowel absorption and motility, immunofluorescence for AFS cell detection, degree of gut inflammation (myeloperoxidase and malondialdehyde), and enterocyte apoptosis and proliferation. Results: AFS cells integrated in the bowel wall and improved rat survival and clinical conditions, decreased NEC incidence and macroscopic gut damage, improved intestinal function, decreased bowel inflammation, increased enterocyte proliferation and reduced apoptosis. The beneficial effect was achieved via modulation of stromal cells expressing cyclooxygenase 2 in the lamina propria, as shown by survival studies using selective and non-selective cyclooxygenase 2 inhibitors. Interestingly, AFS cells differentially expressed genes of the Wnt/β-catenin pathway, which regulate intestinal epithelial stem cell function and cell migration and growth factors known to maintain gut epithelial integrity and reduce mucosal injury. Conclusions: We demonstrated here for the first time that AFS cells injected in an established model of NEC improve survival, clinical status, gut structure and function. Understanding the mechanism of this effect may help us to develop new cellular or pharmacological therapies for infants with NEC.

Original languageEnglish
Pages (from-to)300-309
Number of pages10
JournalGut
Volume63
Issue number2
DOIs
StatePublished - Feb 1 2014
Externally publishedYes

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Necrotizing Enterocolitis
Amniotic Fluid
Intestines
Cell Survival
Stem Cells
Enterocytes
Apoptosis
Inflammation
Catenins
Intestinal Diseases
Wnt Signaling Pathway
Myoblasts
Cyclooxygenase 2 Inhibitors
Cyclooxygenase 2
Stromal Cells
Malondialdehyde
Mesenchymal Stromal Cells
Peroxidase
Cell Movement
Fluorescent Antibody Technique

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Zani, A., Cananzi, M., Fascetti-Leon, F., Lauriti, G., Smith, V. V., Bollini, S., ... De Coppi, P. (2014). Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism. Gut, 63(2), 300-309. https://doi.org/10.1136/gutjnl-2012-303735

Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism. / Zani, Augusto; Cananzi, Mara; Fascetti-Leon, Francesco; Lauriti, Giuseppe; Smith, Virpi V.; Bollini, Sveva; Ghionzoli, Marco; D'Arrigo, Antonello; Pozzobon, Michela; Piccoli, Martina; Hicks, Amy; Wells, Jack; Siow, Bernard; Sebire, Neil J.; Bishop, Colin; Leon, Alberta; Atala, Anthony; Lythgoe, Mark F.; Pierro, Agostino; Eaton, Simon; De Coppi, Paolo.

In: Gut, Vol. 63, No. 2, 01.02.2014, p. 300-309.

Research output: Contribution to journalArticle

Zani, A, Cananzi, M, Fascetti-Leon, F, Lauriti, G, Smith, VV, Bollini, S, Ghionzoli, M, D'Arrigo, A, Pozzobon, M, Piccoli, M, Hicks, A, Wells, J, Siow, B, Sebire, NJ, Bishop, C, Leon, A, Atala, A, Lythgoe, MF, Pierro, A, Eaton, S & De Coppi, P 2014, 'Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism', Gut, vol. 63, no. 2, pp. 300-309. https://doi.org/10.1136/gutjnl-2012-303735
Zani, Augusto ; Cananzi, Mara ; Fascetti-Leon, Francesco ; Lauriti, Giuseppe ; Smith, Virpi V. ; Bollini, Sveva ; Ghionzoli, Marco ; D'Arrigo, Antonello ; Pozzobon, Michela ; Piccoli, Martina ; Hicks, Amy ; Wells, Jack ; Siow, Bernard ; Sebire, Neil J. ; Bishop, Colin ; Leon, Alberta ; Atala, Anthony ; Lythgoe, Mark F. ; Pierro, Agostino ; Eaton, Simon ; De Coppi, Paolo. / Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism. In: Gut. 2014 ; Vol. 63, No. 2. pp. 300-309.
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AU - Zani, Augusto

AU - Cananzi, Mara

AU - Fascetti-Leon, Francesco

AU - Lauriti, Giuseppe

AU - Smith, Virpi V.

AU - Bollini, Sveva

AU - Ghionzoli, Marco

AU - D'Arrigo, Antonello

AU - Pozzobon, Michela

AU - Piccoli, Martina

AU - Hicks, Amy

AU - Wells, Jack

AU - Siow, Bernard

AU - Sebire, Neil J.

AU - Bishop, Colin

AU - Leon, Alberta

AU - Atala, Anthony

AU - Lythgoe, Mark F.

AU - Pierro, Agostino

AU - Eaton, Simon

AU - De Coppi, Paolo

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N2 - Objective: Necrotising enterocolitis (NEC) remains one of the primary causes of morbidity and mortality in neonates and alternative strategies are needed. Stem cells have become a therapeutic option for other intestinal diseases, which share some features with NEC. We tested the hypothesis that amniotic fluid stem (AFS) cells exerted a beneficial effect in a neonatal rat model of NEC. Design: Rats intraperitoneally injected with AFS cells and their controls (bone marrow mesenchymal stem cells, myoblast) were analysed for survival, behaviour, bowel imaging (MRI scan), histology, bowel absorption and motility, immunofluorescence for AFS cell detection, degree of gut inflammation (myeloperoxidase and malondialdehyde), and enterocyte apoptosis and proliferation. Results: AFS cells integrated in the bowel wall and improved rat survival and clinical conditions, decreased NEC incidence and macroscopic gut damage, improved intestinal function, decreased bowel inflammation, increased enterocyte proliferation and reduced apoptosis. The beneficial effect was achieved via modulation of stromal cells expressing cyclooxygenase 2 in the lamina propria, as shown by survival studies using selective and non-selective cyclooxygenase 2 inhibitors. Interestingly, AFS cells differentially expressed genes of the Wnt/β-catenin pathway, which regulate intestinal epithelial stem cell function and cell migration and growth factors known to maintain gut epithelial integrity and reduce mucosal injury. Conclusions: We demonstrated here for the first time that AFS cells injected in an established model of NEC improve survival, clinical status, gut structure and function. Understanding the mechanism of this effect may help us to develop new cellular or pharmacological therapies for infants with NEC.

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