Skip to main content
Top
Published in: Pediatric Surgery International 2/2016

01-02-2016 | Original Article

The role of the BMP signaling cascade in regulation of stem cell activity following massive small bowel resection in a rat

Authors: I. Sukhotnik, D. Berkowitz, T. Dorfman, Salim Halabi, Y. Pollak, J. Bejar, A. Bitterman, A. G. Coran

Published in: Pediatric Surgery International | Issue 2/2016

Login to get access

Abstract

Purpose

Bone morphogenetic proteins (BMPs) are a group of growth factors that are implicated in intestinal growth, morphogenesis, differentiation, and homeostasis. The role of the BMP signaling cascade in stimulation of cell proliferation after massive small bowel resection is unknown. The purpose of this study was to evaluate the role of BMP signaling during intestinal adaptation in a rat model of short bowel syndrome (SBS).

Methods

Male rats were divided into two groups: Sham rats underwent bowel transection and SBS rats underwent a 75 % bowel resection. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined 2 weeks after operation. Illumina’s Digital Gene Expression analysis was used to determine the BMP signaling gene expression profiling. BMP-related genes and protein expression were determined using real-time PCR, Western blotting and immunohistochemistry.

Results

From the total number of 20,000 probes, 8 genes related to BMP signaling were investigated. From these genes, five genes were found to be up-regulated in jejunum (BMP1–10 %, BMP2-twofold increase, BMP3–10 %, BMP2R–12 % and STAT3–28 %) and four genes to be up-regulated in ileum (BMP1–16 %, BMP2–27 %, BMP3–10 %, and STAT3–20 %) in SBS vs sham animals with a relative change in gene expression level of 10 % or more. SBS rats also demonstrated a significant increase in BMP2 and STAT3 mRNA and protein levels (determined by real-time PCR and Western blot) compared to control animals.

Conclusion

Two weeks following massive bowel resection in rats, the BMP signaling pathway is stimulated. BMP signaling may serve as an important mediator of reciprocal interactions between the epithelium and the underlying mesenchymal stroma during intestinal adaptation following massive bowel resection in a rat.
Literature
1.
go back to reference Martin GR, Wallace LE, Hartmann B, Holst JJ, Demchyshyn L, Toney K, Sigalet DL (2005) Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome. Am J Physiol Gastrointest Liver Physiol 288:G431–G438CrossRefPubMed Martin GR, Wallace LE, Hartmann B, Holst JJ, Demchyshyn L, Toney K, Sigalet DL (2005) Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome. Am J Physiol Gastrointest Liver Physiol 288:G431–G438CrossRefPubMed
2.
go back to reference O’Brien DP, Nelson LA, Huang FS, Warner BW (2001) Intestinal adaptation: structure, function, and regulation. Sem Pediatr Surg 10:55–64 O’Brien DP, Nelson LA, Huang FS, Warner BW (2001) Intestinal adaptation: structure, function, and regulation. Sem Pediatr Surg 10:55–64
3.
go back to reference De Santa BarbaraP, van den Brink GR, Roberts DJ (2003) Development and differentiation of the intestinal epithelium. Cell Mol Life Sci 2003(60):1322–1323 De Santa BarbaraP, van den Brink GR, Roberts DJ (2003) Development and differentiation of the intestinal epithelium. Cell Mol Life Sci 2003(60):1322–1323
4.
go back to reference Hogan BL (1996) Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 10:1580–1594CrossRefPubMed Hogan BL (1996) Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 10:1580–1594CrossRefPubMed
5.
go back to reference Bandyopadhyay A, Yadav PS, Prashar P (2013) BMP signaling in development and diseases: a pharmacological perspective. Biochem Pharmacol 85:857–864CrossRefPubMed Bandyopadhyay A, Yadav PS, Prashar P (2013) BMP signaling in development and diseases: a pharmacological perspective. Biochem Pharmacol 85:857–864CrossRefPubMed
6.
go back to reference Shroyer NF, Wong MH (2007) BMP signaling in the intestine: cross-talk is key. Gastroenterology 133:1035–1038CrossRefPubMed Shroyer NF, Wong MH (2007) BMP signaling in the intestine: cross-talk is key. Gastroenterology 133:1035–1038CrossRefPubMed
7.
go back to reference Hardwick JCH, van den Brink GR, Bleuming SA, Ballester I, van den Brande JMH, Keller JJ, Offerhaus GJA, van Deventer JH, Peppelenbosch MP (2004) Bone morphogenetic protein 2 is expressed by, and acts upon mature epithelial cells in the colon. Gastroenterology 126:111–121CrossRefPubMed Hardwick JCH, van den Brink GR, Bleuming SA, Ballester I, van den Brande JMH, Keller JJ, Offerhaus GJA, van Deventer JH, Peppelenbosch MP (2004) Bone morphogenetic protein 2 is expressed by, and acts upon mature epithelial cells in the colon. Gastroenterology 126:111–121CrossRefPubMed
8.
9.
go back to reference Katoh M, Katoh M (2007) WNT signaling pathway and stem cell signaling network. Clin Cancer Res 13:4042–4045CrossRefPubMed Katoh M, Katoh M (2007) WNT signaling pathway and stem cell signaling network. Clin Cancer Res 13:4042–4045CrossRefPubMed
10.
go back to reference Turashvili G, Bouchal J, Burkadze G, Kolar Z (2006) Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology 73:213–223CrossRefPubMed Turashvili G, Bouchal J, Burkadze G, Kolar Z (2006) Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology 73:213–223CrossRefPubMed
11.
go back to reference Sukhotnik I, Roitburt A, Pollak Y, Dorfman T, Matter I, Mogilner JG, Bejar J, Coran AG (2014) Wnt/β-catenin signaling cascade down-regulation following massive small bowel resection in a rat. Pediatr Surg Int 30:173–180CrossRefPubMed Sukhotnik I, Roitburt A, Pollak Y, Dorfman T, Matter I, Mogilner JG, Bejar J, Coran AG (2014) Wnt/β-catenin signaling cascade down-regulation following massive small bowel resection in a rat. Pediatr Surg Int 30:173–180CrossRefPubMed
12.
go back to reference He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, Tian Q, Zeng X, He X, Wiedemann LM, Mishina Y, Li L (2004) BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 36:1117–1121CrossRefPubMed He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, Tian Q, Zeng X, He X, Wiedemann LM, Mishina Y, Li L (2004) BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 36:1117–1121CrossRefPubMed
13.
go back to reference Sampath TK, Maliakal JC, Hauschka PV, Jones WK, Sasak H, Tucker RF (1992) Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. J Biol Chem 267:20352–20362PubMed Sampath TK, Maliakal JC, Hauschka PV, Jones WK, Sasak H, Tucker RF (1992) Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. J Biol Chem 267:20352–20362PubMed
14.
go back to reference Hogan BL (1996) Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 10:1580–1594CrossRefPubMed Hogan BL (1996) Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 10:1580–1594CrossRefPubMed
15.
go back to reference Tang Y, Swietlicki EA, Jiang S, Buhman KK, Davidson NO, Burkly LC, Levin MS, Rubin DC (2006) Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection. Am J Physiol Gastrointest Liver Physiol 290(6):G1280–G1288CrossRefPubMed Tang Y, Swietlicki EA, Jiang S, Buhman KK, Davidson NO, Burkly LC, Levin MS, Rubin DC (2006) Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection. Am J Physiol Gastrointest Liver Physiol 290(6):G1280–G1288CrossRefPubMed
16.
go back to reference Ge C, Yang Q, Zhao G, Yu H, Kirkwood KL, Franceschi RT (2012) Interactions between extracellular signal-regulated kinase 1/2 and p38 MAP kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity. J Bone Miner Res 27:538–551PubMedCentralCrossRefPubMed Ge C, Yang Q, Zhao G, Yu H, Kirkwood KL, Franceschi RT (2012) Interactions between extracellular signal-regulated kinase 1/2 and p38 MAP kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity. J Bone Miner Res 27:538–551PubMedCentralCrossRefPubMed
17.
go back to reference Kosinski C, Li VS, Chan AS, Zhang J, Ho C, Tsui WY, Chan TL, Mifflin RC, Powell DW, Yuen ST, Leung SY, Chen X (2007) Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A 104:15418–15423PubMedCentralCrossRefPubMed Kosinski C, Li VS, Chan AS, Zhang J, Ho C, Tsui WY, Chan TL, Mifflin RC, Powell DW, Yuen ST, Leung SY, Chen X (2007) Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A 104:15418–15423PubMedCentralCrossRefPubMed
Metadata
Title
The role of the BMP signaling cascade in regulation of stem cell activity following massive small bowel resection in a rat
Authors
I. Sukhotnik
D. Berkowitz
T. Dorfman
Salim Halabi
Y. Pollak
J. Bejar
A. Bitterman
A. G. Coran
Publication date
01-02-2016
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Surgery International / Issue 2/2016
Print ISSN: 0179-0358
Electronic ISSN: 1437-9813
DOI
https://doi.org/10.1007/s00383-015-3829-2

Other articles of this Issue 2/2016

Pediatric Surgery International 2/2016 Go to the issue