Islet cell engraftment and control of diabetes in rats after transplantation of pig pancreatic anlagen

Abstract

The insufficient supply of tissue, loss posttransplantation, and limited potential for expansion of beta-cells restrict the use of islet allotransplantation for diabetes. A way to overcome the supply and expansion problems is to xenotransplant embryonic tissue. We have shown that whole rat pancreatic anlagen isotransplanted into the omentum of rats, or xenotransplanted into costimulatory blocked mice, undergo growth and differentiate into islets surrounded by stoma without exocrine tissue. Isotransplants normalize glucose tolerance in diabetic hosts. Here, we show that embryonic day 29 porcine pancreas transplanted into the omentum of adult diabetic rats undergoes endocrine tissue differentiation over 20 wk and normalizes body weights and glucose tolerance. Unlike rat-to-rodent transplants, individual alpha- and beta-cells engraft without a stromal component, and no immunosuppression is required for pig-to-rat transplants. Herein is described a novel means to effect the xenotransplantation of individual islet cells across a highly disparate barrier.

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

“…However, the immune suppression required to maintain the implants was either too toxic or included anti-CD40L, which cannot be used in human patients due to its thrombotic properties. Other studies suggested that E28 pancreatic tissue might be accepted in nonimmunosuppressed rats (33) and monkeys (34). In contrast, our mouse (9) and rat (35) data has revealed fierce rejection of pig embryonic tissue of any gestational time point in the absence of immune suppression, while demonstrating that the immunogenicity of E42 tissue was relatively lower compared to tissues harvested at E56 or beyond (9).…”

Embryonic pig liver, pancreas, and lung as a source for transplantation: Optimal organogenesis without teratoma depends on distinct time windows

“…Among them are such widespread diseases as diabetes, end-stage renal disease, Parkinson's disease, acute and chronic liver failure, and inherited metabolic disorders. The efficacy of committed embryonic pig or human kidney (13,28), pancreas (29)(30)(31)(32)(33)(34), lung (35), heart, or intestine (35,36) as well as hepatocytes (37)(38)(39)(40) or neuronal precursors (41)(42)(43), which grew and differentiated upon implantation into SCID or nude mice or rats, has been extensively Embryonic pig pancreas tissues obtained at various gestational ages were implanted under the kidney capsule. Tissue growth and serum levels of pig insulin were evaluated 6 weeks after implantation as described in Methods.…”

Pancreas and Kidney Transplantation Using Embryonic Donor Organs

“…[29][30][31][32][33][34][35][36][37][38] No matter whether dispersed or intact developing pancreas is transplanted, there is a selective survival of the endocrine portion (islets) of pancreatic anlagen grafts. In studies that compared directly, host beta cell mass post-transplantation of whole versus digested pancreas, it was found that mass was larger if whole pancreas were transplanted.…”

“…30 We have transplanted pancreatic anlagen from embryos into the peritoneal membranes of rodents using techniques developed for the transplantation of metanephroi. 35,36 Rat to Rat Isotransplantation. Shown in Figure 7A is a photograph of a section of duodenum (duo) from an E12.5 Lewis rat embryo.…”

“…10 To determine whether induction of normoglycemia in diabetic hosts can be accelerated if pancreatic anlagen are incubated with two of them prior to implantation, we added vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in the media in which anlagen are stored prior to placement into hosts. 36 Rats in transplant, diabetic and control groups had levels of glucose measured during the next 40 weeks.…”