Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Pediatric Surgery International Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. 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–G438

    Article  CAS  PubMed  Google Scholar 

  2. O’Brien DP, Nelson LA, Huang FS, Warner BW (2001) Intestinal adaptation: structure, function, and regulation. Sem Pediatr Surg 10:55–64

    Google Scholar 

  3. 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

    Google Scholar 

  4. Hogan BL (1996) Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 10:1580–1594

    Article  CAS  PubMed  Google Scholar 

  5. Bandyopadhyay A, Yadav PS, Prashar P (2013) BMP signaling in development and diseases: a pharmacological perspective. Biochem Pharmacol 85:857–864

    Article  CAS  PubMed  Google Scholar 

  6. Shroyer NF, Wong MH (2007) BMP signaling in the intestine: cross-talk is key. Gastroenterology 133:1035–1038

    Article  CAS  PubMed  Google Scholar 

  7. 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 126:111–121

    Article  CAS  PubMed  Google Scholar 

  8. Barker N (2008) The canonical Wnt/beta-catenin signalling pathway. Methods Mol Biol 468:5–15

    Article  CAS  PubMed  Google Scholar 

  9. Katoh M, Katoh M (2007) WNT signaling pathway and stem cell signaling network. Clin Cancer Res 13:4042–4045

    Article  CAS  PubMed  Google Scholar 

  10. Turashvili G, Bouchal J, Burkadze G, Kolar Z (2006) Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology 73:213–223

    Article  CAS  PubMed  Google Scholar 

  11. 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 30:173–180

    Article  PubMed  Google Scholar 

  12. 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 36:1117–1121

    Article  CAS  PubMed  Google Scholar 

  13. 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 267:20352–20362

    CAS  PubMed  Google Scholar 

  14. Hogan BL (1996) Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 10:1580–1594

    Article  CAS  PubMed  Google Scholar 

  15. 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–G1288

    Article  CAS  PubMed  Google Scholar 

  16. 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 27:538–551

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. 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 104:15418–15423

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Intestinal Adaptation and Recovery, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    I. Sukhotnik, T. Dorfman, Salim Halabi & Y. Pollak

  2. Department of Pediatric Surgery, Bnai Zion Medical Center, 47 Golomb St., P.O.B. 4940, 31048, Haifa, Israel

    I. Sukhotnik

  3. Department of Gastroenterology, Bnai Zion Medical Center, Haifa, Israel

    D. Berkowitz

  4. Department of Surgery and Emergency Room, Carmel Medical Center, Haifa, Israel

    Salim Halabi & A. Bitterman

  5. Department of Pathology, Bnai Zion Medical Center, Haifa, Israel

    J. Bejar

  6. Section of Pediatric Surgery, C.S. Mott Children’s Hospital, University of Michigan Medical School, Ann Arbor, MI, USA

    A. G. Coran

Authors
  1. I. Sukhotnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Berkowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Dorfman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Salim Halabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y. Pollak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Bejar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Bitterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. G. Coran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. Sukhotnik.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sukhotnik, I., Berkowitz, D., Dorfman, T. et al. The role of the BMP signaling cascade in regulation of stem cell activity following massive small bowel resection in a rat. Pediatr Surg Int 32, 169–174 (2016). https://doi.org/10.1007/s00383-015-3829-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00383-015-3829-2

Keywords

Search

Navigation