Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Isolated small intestinal segments support auxiliary livers with maintenance of hepatic functions

Abstract

We determine here the functional integrity of auxiliary livers in containers fashioned from the small intestine. Liver microfragments from dipeptidyl peptidase 4 (DPP4)-deficient rats were transplanted into syngeneic normal animals with isolated intestinal segments characterized by mucosal denudation but intact vascular supply. Transplanted liver fragments were restored to confluent tissue with normal hepatic architecture and development of DPP4-positive vessels, indicating angiogenesis and revascularization. Auxiliary liver units expressed multiple hepatotrophic and angiogenic genes, and transplanted tissues remained intact for up to the 6-week duration of the studies with neither ischemic injury nor significant hepatocellular proliferation. Hepatic metabolic, transport and synthetic functions were preserved in auxiliary livers, including uptake and biliary excretion of 99mTc-mebrofenin in syngeneic recipients of liver from F344 rats, as well as secretion of albumin in allografted Nagase analbuminemic rats. This ability to produce functionally competent auxiliary livers in vascularized intestinal segments offers therapeutic potential for liver disease and genetic deficiency.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Histological analysis of auxiliary liver.
Figure 2: Ki-67 immunostaining of liver.
Figure 3: Revascularization of transplanted tissue after 12 d.
Figure 4: 99mTc-mebrofenin handling in transplanted liver.
Figure 5: Function of auxiliary liver in NAR.

References

  1. Kayler, L.K. et al. Long-term survival after liver transplantation in children with metabolic disorders. Pediatr. Transplant. 6, 295–300 (2002).

    Article  Google Scholar 

  2. Azoulay, D. et al. Auxiliary partial orthotopic versus standard orthotopic whole liver transplantation for acute liver failure: a reappraisal from a single center by a case-control study. Ann. Surg. 234, 723–731 (2001).

    Article  Google Scholar 

  3. Kiuchi, T. et al. Auxiliary liver transplantation for urea-cycle enzyme deficiencies: lessons from three cases. Transplant. Proc. 31, 528–529 (1999).

    Article  Google Scholar 

  4. Rela, M. et al. Auxiliary partial orthotopic liver transplantation for Crigler–Najjar syndrome type I. Ann. Surg. 229, 565–569 (1999).

    Article  Google Scholar 

  5. Angelis, M., Pegelow, C.H., Khan, F.A., Verzaro, R. & Tzakis, A.G. En bloc heterotopic auxiliary liver and bilateral renal transplant in a patient with homozygous protein C deficiency. J. Pediatr. 138, 120–122 (2001).

    Article  Google Scholar 

  6. Haberal, M. et al. Successful heterotopic segmental liver transplantation from a live donor to a patient with Alagille syndrome. J. Pediatr. Surg. 36, 667–671 (2001).

    Article  Google Scholar 

  7. Durand, F. et al. Auxiliary liver transplantation for fulminant hepatitis B: Results from a series of six patients with special emphasis on regeneration and recurrence of hepatitis B. Liver Transpl. 8, 701–707 (2002).

    Article  Google Scholar 

  8. Kaibori, M. et al. Selective portal blood flow diversion in auxiliary partial orthotopic liver transplantation to induce regeneration of the graft. Transplantation 66, 935–937 (1998).

    Article  Google Scholar 

  9. de Jonge, J. et al. Directing portal flow is essential for graft survival in auxiliary partial heterotopic liver transplantation in the dog. J. Pediatr. Surg. 34, 1265–1268 (1999).

    Article  Google Scholar 

  10. Gupta, S. & Roy Chowdhury, J. Hepatocyte transplantation: Back to the future! Hepatology 15, 156–162 (1992).

    Article  Google Scholar 

  11. Sundback, C.A. & Vacanti, J.P. Alternatives to liver transplantation: from hepatocyte transplantation to tissue-engineered organs. Gastroenterology 118, 438–442 (2000).

    PubMed  Google Scholar 

  12. Berishvili, E. et al. Generation of heterotopic liver in an isolated and vascularized segment of the small intestine in rats. Transplantation 75, 1827–1832 (2003).

    Article  Google Scholar 

  13. Gaglio, P.J. et al. Liver regeneration investigated in a non-human primate model (Macaca mulatta). J. Hepatol. 37, 625–632 (2002).

    Article  Google Scholar 

  14. Gupta, S., Rajvanshi, P. & Lee, C.-D. Integration of transplanted hepatocytes in host liver plates demonstrated with dipeptidyl peptidase IV deficient rats. Proc. Natl. Acad. Sci. USA 92, 5860–5864 (1995).

    Article  Google Scholar 

  15. Malhi, H. et al. 99mTc-mebrofenin scintiscanning for evaluating liver disease in a rat model of Wilson's disease. J. Nucl. Med. 43, 246–252 (2002).

    PubMed  Google Scholar 

  16. Rajvanshi, P., Kerr, A., Bhargava, K.K., Burk, R.D. & Gupta, S. Studies of liver repopulation using the dipeptidyl peptidase IV-deficient rat and other rodent recipients: cell size and structure relationships regulate capacity for increased transplanted hepatocyte mass in the liver lobule. Hepatology 23, 482–496 (1996).

    Article  Google Scholar 

  17. Robotin-Johnson, M.C., Swanson, P.E., Johnson, D.C., Schuessler, R.B. & Cox, J.L. An experimental model of small intestinal submucosa as a growing vascular graft. J. Thorac. Cardiovasc. Surg. 116, 805–811 (1998).

    Article  Google Scholar 

  18. Yla-Herttuala, S. & Alitalo, K. Gene transfer as a tool to induce therapeutic vascular growth. Nat. Med. 9, 694–695 (2003).

    Article  Google Scholar 

  19. Ferrara, N., Gerber, H.P. & LeCouter, J. The biology of VEGF and its receptors. Nat. Med. 9, 669–676 (2003).

    Article  Google Scholar 

  20. Cleaver, O. & Melton, D.A. Endothelial signaling during development. Nat. Med. 9, 661–668 (2003).

    Article  Google Scholar 

  21. Selden, C. et al. Histidinemia in mice: a metabolic defect treated using a novel approach to hepatocellular transplantation. Hepatology 21, 1405–1412 (1995).

    PubMed  Google Scholar 

  22. Powell, D.W. et al. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am. J. Physiol. 277, C183–C201 (1999).

    Article  Google Scholar 

  23. LeCouter, J. et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299, 890–893 (2003).

    Article  Google Scholar 

  24. Suzuki, S. et al. Skeletal muscle injury induces hepatocyte growth factor expression in spleen. Biochem. Biophys. Res. Commun. 292, 709–714 (2002).

    Article  Google Scholar 

  25. Oh, S.H. et al. Hepatocyte growth factor induces differentiation of adult rat bone marrow cells into a hepatocyte lineage in vitro. Biochem. Biophys. Res. Commun. 279, 500–504 (2000).

    Article  Google Scholar 

  26. Scotte, M. et al. Cytokine gene expression in liver following minor or major hepatectomy in rat. Cytokine 9, 859–867 (1997).

    Article  Google Scholar 

  27. Kalyani, A.J., Mujtaba, T. & Rao, M.S. Expression of EGF receptor and FGF receptor isoforms during neuroepithelial stem cell differentiation. J. Neurobiol. 38, 207–224 (1999).

    Article  Google Scholar 

  28. Zhao, H., Patra, A., Tanaka, Y., Li, L.C. & Dahiya, R. Transforming growth factor-β(s) and their receptors in aging rat prostate. Biochem. Biophys. Res. Commun. 294, 464–469 (2002).

    Article  Google Scholar 

  29. Ishii, H., Oota, I., Arakawa, T. & Takuma, T. Differential gene expression of vascular endothelial growth factor isoforms and their receptors in the development of the rat masseter muscle. Arch. Oral. Biol. 47, 505–510 (2002).

    Article  Google Scholar 

  30. Haggstrom Rudolfsson, S., Johansson, A., Franck Lissbrant, I., Wikstrom, P. & Bergh, A. Localized expression of angiopoietin 1 and 2 may explain unique characteristics of the rat testicular microvasculature. Biol. Reprod. 69, 1231–1237 (2003).

    Article  Google Scholar 

Download references

Acknowledgements

We thank C. Zhang for technical assistance. This work was supported in part by NIH grants R01 DK46952 and P30-DK-41296 and by grant G-362 from the International Scientific Technology Center, Moscow, Russia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sanjeev Gupta.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Joseph, B., Berishvili, E., Benten, D. et al. Isolated small intestinal segments support auxiliary livers with maintenance of hepatic functions. Nat Med 10, 749–753 (2004). https://doi.org/10.1038/nm1057

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1057

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing