Skip to main content
Log in

Growing organs for transplantation from embryonic precursor tissues

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Our recent data pinpoint a window of time in human and pig kidney organogenesis that may be optimal for transplantation into mature recipients. ‘Window’ transplants are defined by their remarkable ability to grow, differentiate and undergo vascularization, achieving successful organogenesis of urine-producing miniature kidneys. The transplanted tissue shows no evidence of trans-differentiation into non-renal cell types or tumorogenicity, and displays reduced immunogenicity compared to its adult counterparts. Very recently, we demonstrated that this approach can be extended to transplantation of embryonic pig liver, pancreas, and lung tissue. Furthermore, it was demonstrated that E42 pancreatic tissue is optimally suited for induction of normoglycemia in diabetic mice. These results emphasize the importance of selecting precursors of the correct gestational age for optimal growth and function, and with reduced immunogenicity, and provide a proof of principle for the curative potential of E42 embryonic pig pancreatic tissue for transplantation in diabetic patients.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145–7.

    Article  PubMed  CAS  Google Scholar 

  2. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 2000;18:399–404.

    Article  PubMed  CAS  Google Scholar 

  3. Bjorklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IYC, McNaught KSP, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci 2002;99:2344–9.

    Article  PubMed  CAS  Google Scholar 

  4. Freed C. Will embryonic stem cells be a useful source of dopamine neurons for transplant into patients with Parkinson’s disease? Proc Natl Acad Sci 2002;99:1755–7.

    Article  PubMed  CAS  Google Scholar 

  5. Eiges R, Schuldiner M, Drukker M, Yanuka O, I.-E. J, Benvenisty N. Establishment of human embryonic stem cell-transfected clones carrying a marker for undifferentiated cells. Curr Biol 2001;11:514–8.

    Article  PubMed  CAS  Google Scholar 

  6. Ishizaka S, Shiroi A, Kanda S, Yoshikawa M, Tsuinoue H, Kuriyama S, Hasuma T, Nakatani K, Tahakashi K. Development of hepatocytes from ES cells after transfection with the HNF-3beta gene. FASEB J 2002;16:1444–6.

    PubMed  CAS  Google Scholar 

  7. Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK. Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci 2002;99:16105–10.

    Article  PubMed  CAS  Google Scholar 

  8. Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M. Insulin production by human embryonic stem cells. Diabetes 2001;50:1691–97.

    Article  PubMed  CAS  Google Scholar 

  9. Jones EA, Tosh D, Wilson DI, Lindsay S, Forrester LM. Hepatic differentiation of murine embryonic stem cells. Exp Cell Res 2002;272:15–22.

    Article  PubMed  CAS  Google Scholar 

  10. Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 2001;292:1389–94.

    Article  PubMed  CAS  Google Scholar 

  11. Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 2000;49:157–62.

    Article  PubMed  CAS  Google Scholar 

  12. Schuldiner M, Itskovitz-Eldor J, Benvenisty N. Selective ablation of human embryonic stem cells expressing a “suicide” gene. Stem Cells 2003;21:257–65.

    Article  PubMed  CAS  Google Scholar 

  13. Dekel B, Burakova T, Arditti FD, Reich-Zeliger S, Milstein O, Aviel-Ronen S, Rechavi G, Friedman N, Kaminski N, Passwell JH, Reisner Y. Human and porcine early kidney precursors as a new source for transplantation. Nat Med 2003;9:53–60.

    Article  PubMed  CAS  Google Scholar 

  14. Eventov-Friedman S, Katchman H, Shezen E, Aronovich A, Tchorsh D, Dekel B, Freud E, Reisner Y. Embrynic pig liver, pancreas, and lung as a source for transplantation: optimal organogenesis without teratoma depends on distinct time windows. PNAS 2005;102:2928–33.

    Article  PubMed  CAS  Google Scholar 

  15. Groth CG, Korsgen O, Tibell A, et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet 1994;344:1402–4.

    Article  PubMed  CAS  Google Scholar 

  16. Eventov-Friedman S, Tchorsh D, Katchman H, Shezen E, Aronovich A, Hecht G, Dekel B, Rechavi G, Blazar BR, Feine I, Tal O, Freud E, Reisner Y. Embryonic pig pancreatic tissue transplantation for the treatment of diabetes. PLOS Med 2006;3:1.

    Article  Google Scholar 

  17. Rogers SA, Chen F, Talcott M, Hammerman MR. Islet cell engraftment and control of diabetes in rats after transplantation of pig pancreatic anlagen. Am J Physiol Endocrinol Metab 2004;286:E502–9.

    Article  PubMed  CAS  Google Scholar 

  18. Rogers SA, Liapis H, Hammerman MR. Normalization of glucose post-transplantation of pig pancreatic anlagen into non-immunosuppressed diabetic rats depends on obtaining anlagen prior to embryonic day 35. Transplant Immunol 2005;14:67–75.

    Article  CAS  Google Scholar 

  19. Groth CG, Tibell W, Wennberg L, Korsgren O. Xenoislet transplantation: experimental and clinical aspects. J Mol Med 1999;77:153–4.

    Article  PubMed  CAS  Google Scholar 

  20. Korsgren O, Andersson A, Sandler S. Pretreatment of fetal porcine pancreas in culture with nicotinamide accelerates reversal of diabetes after transplantation to nude mice. Surgery 1993;113:205–14.

    PubMed  CAS  Google Scholar 

  21. Tu J, Khoury P, Williams L, Tuch BE. Comparison of fetal porcine aggregates of purified beta-cells versus islet-like cell clusters as a treatment of diabetes. Cell Transplant 2004;13:525–34.

    PubMed  Google Scholar 

  22. Jiang FX, Cram DS, De Aizpurua HJ, Harrison LC. Laminin-1 promotes differentiation of fetal mouse pancreatic beta-cells. Diabetes 1999;48:722–30.

    Article  PubMed  CAS  Google Scholar 

  23. Miettinen PJ, Huotari M, Koivisto T, Ustinov J, Palgi J, Rasilainen S, Lehtonen E, Keski-Oja J, Otonkoski T. Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors. Development 2000 127:2617–27.

    PubMed  CAS  Google Scholar 

  24. Bhushan A, Itoh N, Kato S, Thiery JP, Czernichow P, Scharfmann B. Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. Development 2001;128:5109–17.

    PubMed  CAS  Google Scholar 

  25. Cras-Meneur C, Elghazi L, Czernichow P, Scharfmann R. Epidermal growth factor increases undifferentiated pancreatic embryonic cells in vitro: a balance between proliferation and differentiation. Diabetes 2001;50:1571–9.

    Article  PubMed  CAS  Google Scholar 

  26. Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science 2001;294:564–7.

    Article  PubMed  CAS  Google Scholar 

  27. Elghazi L, Cras-Meneur C, Czernichow P, Scharfmann R. Role for FGFR2IIIb-mediated signals in controlling pancreatic endocrine progenitor cell proliferation. Proc Natl Acad Sci 2002;99:3884–9.

    Article  PubMed  CAS  Google Scholar 

  28. Movassat J, Beattie GM, Lopez AD, Portha B, Hayek A. Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells. Diabetologia 2003;46:822–9.

    Article  PubMed  CAS  Google Scholar 

  29. Miralles F, Czernichow P, Scharfmann R. Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. Development 1998;125:1017–24.

    PubMed  CAS  Google Scholar 

  30. Si Z, Tuch BE, Walsh DA. Development of human fetal pancreas after transplantation into SCID mice. Cells Tissues Organs 2001;168:147–57.

    Article  PubMed  CAS  Google Scholar 

  31. Castaing M, Duvillie B, Quemeneur E, Basmaciogullari A, Scharfmann R. Ex vivo analysis of acinar and endocrine cell development in the human embryonic pancreas. Dev Dyn 2005;234:339–45.

    Article  PubMed  CAS  Google Scholar 

  32. Medawar P. Some immunological and endocriinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol 1953;7:320.

    Google Scholar 

  33. Velasco AL, Hegre OD. Decreased immunogenicity of fetal kidneys: the role of passenger leukocytes J Pediatr Surg 1989;24:59–63.

    Article  PubMed  CAS  Google Scholar 

  34. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392.:245–52.

    Article  PubMed  Google Scholar 

  35. Koulmanda M, Laufer TM, J. Auchincloss H, Smith RN. Prolonged survival of fetal pig islet xenografts in mice lacking the capacity for an indirect response. Xenotransplantation 2004;11:525–30.

    Article  PubMed  Google Scholar 

  36. Mirenda V, Golshayan D, Read J, Berton I, Warrens AN, Dorling A, Lechler RI. Achieving permanent survival of islet xenografts by independent manipulation of direct and indirect T-cell responses. Diabetes 2005;54:1048–55.

    Article  PubMed  CAS  Google Scholar 

  37. Lehnert AM, Yi S, Burgess JS, O’Connell PJ. Pancreatic islet xenograft tolerance after short-term costimulation blockade is associated with increased CD4+ T cell apoptosis but not immune deviation. Transplantation 2000;69:1176–85.

    Article  PubMed  CAS  Google Scholar 

  38. Samstein B, Platt JL. Xenotransplantation and tolerance. Philos Trans R Soc Lond B Biol Sci 2001;356:749–58.

    Article  PubMed  CAS  Google Scholar 

  39. Hering BJ, Wijkstrom M, Graham ML, et al. Prolonged diabetes reversaal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 2006;12:301–3.

    Article  PubMed  CAS  Google Scholar 

  40. Cardona K, Korbutt GS, Milas Z, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med 2006;12:304–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was funded by Tissera, Inc.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yair Reisner.

Additional information

Deans Lecture Series, June 8, 2006 at South Florida Tampa Campus

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reisner, Y. Growing organs for transplantation from embryonic precursor tissues. Immunol Res 38, 261–273 (2007). https://doi.org/10.1007/s12026-007-0041-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-007-0041-z

Keywords

Navigation