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Published in: Immunologic Research 1-3/2007

01-07-2007

Growing organs for transplantation from embryonic precursor tissues

Author: Yair Reisner

Published in: Immunologic Research | Issue 1-3/2007

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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.
Literature
1.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
2.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
3.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
4.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
5.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
6.
go back to reference 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 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
7.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
8.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
9.
go back to reference Jones EA, Tosh D, Wilson DI, Lindsay S, Forrester LM. Hepatic differentiation of murine embryonic stem cells. Exp Cell Res 2002;272:15–22.PubMedCrossRef Jones EA, Tosh D, Wilson DI, Lindsay S, Forrester LM. Hepatic differentiation of murine embryonic stem cells. Exp Cell Res 2002;272:15–22.PubMedCrossRef
10.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
11.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
12.
go back to reference Schuldiner M, Itskovitz-Eldor J, Benvenisty N. Selective ablation of human embryonic stem cells expressing a “suicide” gene. Stem Cells 2003;21:257–65.PubMedCrossRef Schuldiner M, Itskovitz-Eldor J, Benvenisty N. Selective ablation of human embryonic stem cells expressing a “suicide” gene. Stem Cells 2003;21:257–65.PubMedCrossRef
13.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
14.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
15.
go back to reference Groth CG, Korsgen O, Tibell A, et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet 1994;344:1402–4.PubMedCrossRef Groth CG, Korsgen O, Tibell A, et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet 1994;344:1402–4.PubMedCrossRef
16.
go back to reference 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.CrossRef 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.CrossRef
17.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
18.
go back to reference 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.CrossRef 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.CrossRef
19.
go back to reference Groth CG, Tibell W, Wennberg L, Korsgren O. Xenoislet transplantation: experimental and clinical aspects. J Mol Med 1999;77:153–4.PubMedCrossRef Groth CG, Tibell W, Wennberg L, Korsgren O. Xenoislet transplantation: experimental and clinical aspects. J Mol Med 1999;77:153–4.PubMedCrossRef
20.
go back to reference 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 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
21.
go back to reference 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 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
22.
go back to reference Jiang FX, Cram DS, De Aizpurua HJ, Harrison LC. Laminin-1 promotes differentiation of fetal mouse pancreatic beta-cells. Diabetes 1999;48:722–30.PubMedCrossRef Jiang FX, Cram DS, De Aizpurua HJ, Harrison LC. Laminin-1 promotes differentiation of fetal mouse pancreatic beta-cells. Diabetes 1999;48:722–30.PubMedCrossRef
23.
go back to reference 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 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
24.
go back to reference 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 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
25.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
26.
go back to reference Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science 2001;294:564–7.PubMedCrossRef Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science 2001;294:564–7.PubMedCrossRef
27.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
28.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
29.
go back to reference 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 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
30.
go back to reference Si Z, Tuch BE, Walsh DA. Development of human fetal pancreas after transplantation into SCID mice. Cells Tissues Organs 2001;168:147–57.PubMedCrossRef Si Z, Tuch BE, Walsh DA. Development of human fetal pancreas after transplantation into SCID mice. Cells Tissues Organs 2001;168:147–57.PubMedCrossRef
31.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
32.
go back to reference Medawar P. Some immunological and endocriinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol 1953;7:320. Medawar P. Some immunological and endocriinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol 1953;7:320.
33.
go back to reference Velasco AL, Hegre OD. Decreased immunogenicity of fetal kidneys: the role of passenger leukocytes J Pediatr Surg 1989;24:59–63.PubMedCrossRef Velasco AL, Hegre OD. Decreased immunogenicity of fetal kidneys: the role of passenger leukocytes J Pediatr Surg 1989;24:59–63.PubMedCrossRef
34.
35.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
36.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
37.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
38.
go back to reference Samstein B, Platt JL. Xenotransplantation and tolerance. Philos Trans R Soc Lond B Biol Sci 2001;356:749–58.PubMedCrossRef Samstein B, Platt JL. Xenotransplantation and tolerance. Philos Trans R Soc Lond B Biol Sci 2001;356:749–58.PubMedCrossRef
39.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
40.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
Metadata
Title
Growing organs for transplantation from embryonic precursor tissues
Author
Yair Reisner
Publication date
01-07-2007
Publisher
Humana Press Inc
Published in
Immunologic Research / Issue 1-3/2007
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-007-0041-z

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