Glucose tolerance normalization following transplantation of pig pancreatic primordia into non-immunosuppressed diabetic ZDF rats

Rogers, Sharon A.; Chen, Feng; Talcott, Mike; Liapis, Helen; Hammerman, Marc R.

doi:10.1016/j.trim.2006.08.007

Cited by 20 publications

(77 citation statements)

References 28 publications

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“…[5][6][7][8] No rat insulin can be detected in STZ-treated rats. Porcine insulin circulates posttransplantation of E28 pig pancreatic primordia (embryonic pancreas) and levels increase after a glucose load.…”

Section: 3mentioning

confidence: 97%

“…2,3 We have shown that glucose tolerance can be normalized in streptozotocin (STZ)-diabetic (type 1) LEW rats or ZDF (type 2) diabetic rats within 4 weeks following transplantation in mesentery of pig pancreatic primordia obtained very early during embryogenesis [on embryonic day 28 (E28)-just after the organ differentiates and before the time dorsal and ventral anlagen fuse] without host immune suppression. [5][6][7][8] No rat insulin can be detected in STZ-treated rats. Porcine insulin circulates posttransplantation of E28 pig pancreatic primordia (embryonic pancreas) and levels increase after a glucose load.…”

Section: Transplantation Therapy For Human Diabetes Is Limited By Thementioning

confidence: 97%

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

Rogers

Mohanakumar

Liapis

et al. 2010

The American Journal of Pathology

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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, immunecompetent rodents. The data are consistent with tolerance induction to a cell component of porcine islets induced by previous transplantation of E28 pig pancreatic primordia. In that pigs are plentiful and because porcine insulin works well in humans, the pig has been suggested to be a pancreas organ donor for humans with diabetes. The severity of humoral rejection due to pre-existing natural antibodies effectively precludes their use as whole pancreas donors in nonhuman primates or humans.1-4 However, isolated islets of Langerhans (islets) can be transplanted into nonhuman primates 2,3 or humans with diabetes 1 without initiating humoral rejection. Unfortunately, recent experience with pig to primate islet 2 or neonatal islet 3 transplantation shows that sustained insulin independence can be achieved, but only through the use of immune suppressive agents that are not approved for human use or would result in an unacceptable level of morbidity in humans. 2,3We have shown that glucose tolerance can be normalized in streptozotocin (STZ)-diabetic (type 1) LEW rats or ZDF (type 2) diabetic rats within 4 weeks following transplantation in mesentery of pig pancreatic primordia obtained very early during embryogenesis [on embryonic day 28 (E28)-just after the organ differentiates and before the time dorsal and ventral anlagen fuse] without host immune suppression. [5][6][7][8] No rat insulin can be detected in STZ-treated rats. Porcine insulin circulates posttransplantation of E28 pig pancreatic primordia (embryonic pancreas) and levels increase after a glucose load.6,7 Cells expressing insulin and porcine proinsulin mRNA with ␤ cell morphology engraft in host mesentery, mesenteric lymph nodes, liver, and pancreas posttransplantation.5-8 Cells originating from E28 pig pa...

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Section: 3mentioning

confidence: 97%

Section: Transplantation Therapy For Human Diabetes Is Limited By Thementioning

confidence: 97%

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

Rogers

Mohanakumar

Liapis

et al. 2010

The American Journal of Pathology

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“…The transplantation of porcine pancreatic β cells to type 1 and type 2 diabetic rats results in the recovery of glucose tolerance without host immune-suppression (10). Porcine embryonic pancreatic tissue is transplanted into human diabetic patients since transplantations of gestational stage porcine pancreas are ineffective.…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of porcine pancreas development

Choi

Cho²,

Yoon³

et al. 2009

BMB Reports

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Porcine pancreas development is not well studied at the molecular level despite being a therapeutic resource for diabetic patients. In this study, we investigated expression of lineage markers and performed proteomic analysis. Expression of the early lineage markers Pdx1 and Ptf1a was developmentally conserved between mice and pigs, whereas expression of the islet differentiation marker Pax4 was delayed in porcine compared with murine pancreas development. Proteomic analysis found that expression levels of chymotrypsinogen were downregulated during porcine pancreas development while those of digestive enzymes like lipases, elastase and serine protease were up-regulated. In addition, specific isoforms of protein folding assistants such as protein disulfide isomerase and prefoldin were expressed at specific stages during the maturation of digestive enzymes. Taken together, these results show that development of the porcine pancreas is regulated by a concerted interplay of pancreas lineage marker proteins and other specified proteins, resulting in a functional endocrine and exocrine organ. [BMB reports 2009; 42(10): 661-666]

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“…3F) porcine proinsulin mRNA engraft in host mesentery, mesenteric lymph nodes, liver and pancreas post-transplantation. [10][11][12][13] Cells originating from E28 pig pancreatic primordia engraft similarly in non immune-suppressed STZ-diabetic rhesus macaques. 3 Glucose tolerance can be nearly normalized in non-immunesuppressed diabetic rhesus macaques following transplantation of E28 pig pancreatic primordia (Fig.…”

mentioning

confidence: 99%

“…Induction of organogenetic tolerance for endocrine pancreas is critically dependent on the methodology employed to transplant pig pancreatic primordia. 3,[10][11][12][13]18,19 The phenomenon may be applicable to other organs with appropriate modifications in techniques used for implantation. For example, adaptations in methodology used to xenotransplant embryonic pig kidneys 11 so as to result in engraftment that recapitulates the pattern observed following xenotransplantation of embryonic pancreas (i.e., renal cells engrafted in mesenteric lymph nodes) could render hosts tolerant to the embryonic kidney tissue and also to cells originating from adult kidneys from the same donor species.…”

mentioning

confidence: 99%