Engraftment of Cells from Porcine Islets of Langerhans and Normalization of Glucose Tolerance Following Transplantation of Pig Pancreatic Primordia in Nonimmune-suppressed Diabetic Rats

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2010 Jun 29

PMID 20581052

Citations 7

Authors

Sharon A Rogers

Thalachallour Mohanakumar

Helen Liapis

Marc R Hammerman

Affiliations

Soon will be listed here.

Abstract

Transplantation therapy for human diabetes is limited by the toxicity of immunosuppressive drugs. However, even if toxicity can be minimalized, there will still be a shortage of human donor organs. Xenotransplantation of porcine islets may be a strategy to overcome these supply problems. Xenotransplantation in mesentery of pig pancreatic primordia obtained very early during organogenesis [embryonic day 28 (E28)] can obviate the need for immune suppression in rats or rhesus macaques. Here, in rats transplanted previously with E28 pig pancreatic primordia in the mesentery, we show normalization of glucose tolerance in nonimmune-suppressed streptozotocin-diabetic LEW rats and insulin and porcine proinsulin mRNA-expressing cell engraftment in the kidney following implantation of porcine islets beneath the renal capsule. Donor cell engraftment was confirmed using fluorescent in situ hybridization for the porcine X chromosome and electron microscopy. In contrast, cells from islets did not engraft in the kidney without prior transplantation of E28 pig pancreatic primordia in the mesentery. This is the first report of prolonged engraftment and sustained normalization of glucose tolerance following transplantation of porcine islets in nonimmune-suppressed, immune-competent rodents. The data are consistent with tolerance induction to a cell component of porcine islets induced by previous transplantation of E28 pig pancreatic primordia.

Citing Articles

Classic and current opinion in embryonic organ transplantation.

Hammerman M Curr Opin Organ Transplant. 2014; 19(2):133-9.

PMID: 24535425 PMC: 4094307. DOI: 10.1097/MOT.0000000000000054.

Xenotransplantation of embryonic pig pancreas for treatment of diabetes mellitus in non-human primates.

Hammerman M J Biomed Sci Eng. 2013; 6(5A).

PMID: 24312695 PMC: 3848958. DOI: 10.4236/jbise.2013.65A002.

Development of a novel xenotransplantation strategy for treatment of diabetes mellitus in rat hosts and translation to non-human primates.

Hammerman M Organogenesis. 2012; 8(2):41-8.

PMID: 22699748 PMC: 3429511. DOI: 10.4161/org.20930.

Engraftment of insulin-producing cells from porcine islets in non-immune-suppressed rats or nonhuman primates transplanted previously with embryonic pig pancreas.

Hammerman M J Transplant. 2011; 2011:261352.

PMID: 21969909 PMC: 3182564. DOI: 10.1155/2011/261352.

Engraftment of cells from porcine islets of Langerhans following transplantation of pig pancreatic primordia in non-immunosuppressed diabetic rhesus macaques.

Rogers S, Tripathi P, Mohanakumar T, Liapis H, Chen F, Talcott M Organogenesis. 2011; 7(3):154-62.

PMID: 21654197 PMC: 3243028. DOI: 10.4161/org.7.3.16522.

References

Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D . Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci U S A. 2009; 106(35):14978-83. PMC: 2736429. DOI: 10.1073/pnas.0809784106. View

Rogers S, Liapis H, Hammerman M . Intraperitoneal transplantation of pancreatic anlagen. ASAIO J. 2003; 49(5):527-32. DOI: 10.1097/01.mat.0000084174.33319.7f. View

Rogers S, Chen F, Talcott M, Liapis H, Hammerman M . Glucose tolerance normalization following transplantation of pig pancreatic primordia into non-immunosuppressed diabetic ZDF rats. Transpl Immunol. 2006; 16(3-4):176-84. DOI: 10.1016/j.trim.2006.08.007. View

Korsgren O, Wallgren A, Satake M, Karlsson-Parra A . Xenograft rejection of fetal porcine islet-like cell clusters in the rat: effects of active and passive immunization. Xenotransplantation. 2000; 6(4):271-80. DOI: 10.1034/j.1399-3089.1999.00032.x. View

Hamamoto Y, Tsuura Y, Fujimoto S, Nagata M, Takeda T, Mukai E . Recovery of function and mass of endogenous beta-cells in streptozotocin-induced diabetic rats treated with islet transplantation. Biochem Biophys Res Commun. 2001; 287(1):104-9. DOI: 10.1006/bbrc.2001.5563. View

Wennberg L, Song Z, Bennet W, Zhang J, Nava S, Sundberg B . Diabetic rats transplanted with adult porcine islets and immunosuppressed with cyclosporine A, mycophenolate mofetil, and leflunomide remain normoglycemic for up to 100 days. Transplantation. 2001; 71(8):1024-33. DOI: 10.1097/00007890-200104270-00002. View

Hammerman M . Growing new endocrine pancreas in situ. Clin Exp Nephrol. 2006; 10(1):1-7. DOI: 10.1007/s10157-005-0393-4. View

Schroeder R, Marroquin C, Kuo P . Tolerance and the "Holy Grail" of transplantation. J Surg Res. 2003; 111(1):109-19. DOI: 10.1016/s0022-4804(03)00081-7. View

Cardona K, Korbutt G, Milas Z, Lyon J, Cano J, Jiang W . Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med. 2006; 12(3):304-6. DOI: 10.1038/nm1375. View

10.

Eventov-Friedman S, Katchman H, Shezen E, Aronovich A, Tchorsh D, Dekel B . Embryonic pig liver, pancreas, and lung as a source for transplantation: optimal organogenesis without teratoma depends on distinct time windows. Proc Natl Acad Sci U S A. 2005; 102(8):2928-33. PMC: 548800. DOI: 10.1073/pnas.0500177102. View

11.

Mandel T . Fetal islet xenotransplantation in rodents and primates. J Mol Med (Berl). 1999; 77(1):155-60. DOI: 10.1007/s001090050326. View

12.

Swanson C, Olack B, Goodnight D, Zhang L, Mohanakumar T . Improved methods for the isolation and purification of porcine islets. Hum Immunol. 2001; 62(7):739-49. DOI: 10.1016/s0198-8859(01)00255-5. View

13.

Groth C, Korsgren O, Tibell A, Tollemar J, Moller E, Bolinder J . Transplantation of porcine fetal pancreas to diabetic patients. Lancet. 1994; 344(8934):1402-4. DOI: 10.1016/s0140-6736(94)90570-3. View

14.

Cotter M, Ekberg K, Wahren J, Cameron N . Effects of proinsulin C-peptide in experimental diabetic neuropathy: vascular actions and modulation by nitric oxide synthase inhibition. Diabetes. 2003; 52(7):1812-7. DOI: 10.2337/diabetes.52.7.1812. View

15.

Rogers S, Liapis H, Hammerman M . Normalization of glucose post-transplantation of pig pancreatic anlagen into non-immunosuppressed diabetic rats depends on obtaining anlagen prior to embryonic day 35. Transpl Immunol. 2005; 14(2):67-75. DOI: 10.1016/j.trim.2005.02.004. View

16.

Dufrane D, Goebbels R, Saliez A, Guiot Y, Gianello P . Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept. Transplantation. 2006; 81(9):1345-53. DOI: 10.1097/01.tp.0000208610.75997.20. View

17.

Ryan E, Lakey J, Rajotte R, Korbutt G, Kin T, Imes S . Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes. 2001; 50(4):710-9. DOI: 10.2337/diabetes.50.4.710. View

18.

Hammerman M . Interaction of insulin with the renal proximal tubular cell. Am J Physiol. 1985; 249(1 Pt 2):F1-11. DOI: 10.1152/ajprenal.1985.249.1.F1. View

19.

Tchorsh-Yutsis D, Hecht G, Aronovich A, Shezen E, Klionsky Y, Rosen C . Pig embryonic pancreatic tissue as a source for transplantation in diabetes: transient treatment with anti-LFA1, anti-CD48, and FTY720 enables long-term graft maintenance in mice with only mild ongoing immunosuppression. Diabetes. 2009; 58(7):1585-94. PMC: 2699862. DOI: 10.2337/db09-0112. View

20.

Begum S, Chen W, Herold K, Papaioannou V . Remission of type 1 diabetes after anti-CD3 antibody treatment and transplantation of embryonic pancreatic precursors. Endocrinology. 2009; 150(10):4512-20. PMC: 2754682. DOI: 10.1210/en.2009-0287. View