Xenotransplantation of pancreatic and kidney primordia-where do we stand?

Abstract

Lack of donor availability limits the number of human donor organs. The need for host immunosuppression complicates transplantation procedures. It is possible to 'grow' new pancreatic tissue or kidneys in situ via xenotransplantation of organ primordia from animal embryos (organogenesis of the endocrine pancreas or kidney). The developing organ attracts its blood supply from the host, enabling the transplantation of pancreas or kidney in 'cellular' form obviating humoral rejection. In the case of pancreas, selective development of endocrine tissue takes place in post-transplantation. In the case of kidney, an anatomically-correct functional organ differentiates in situ. Glucose intolerance can be corrected in formerly diabetic rats and ameliorated in rhesus macaques on the basis of porcine insulin secreted in a glucose-dependent manner by beta cells originating from transplants. Primordia engraft and function after being stored in vitro prior to implantation. If obtained within a 'window' early during embryonic pancreas development, pig pancreatic primordia engraft in non immune suppressed diabetic rats or rhesus macaques. Engraftment of pig renal primordia transplanted directly into rats requires host immune suppression. However, embryonic rat kidneys into which human mesenchymal cells are incorporated into nephronic elements can be transplanted into non-immune suppressed rat hosts. Here we review recent findings germane to xenotransplantation of pancreatic or renal primordia as a novel organ replacement strategy.

Figure 1

Photomicrographs of stained sections of: A,B) rat kidney; or C,D) pig kidney and E,F) a pig renal primordium from an E28 embryo 8 weeks post-transplantation into rat mesentery, stained with rat-specific RECA-1 (A,B,E) or pig-specific CD31 (C,D,F). Glomerular capillaries in transplants stain positive for RECA-1 specific for rat endothelium (E) and negative for CD31 specific for pig endothelium (F). Magnifications are shown for A-D (in A) and E & F in E. Reproduced with permission [13].

Figure 2

In situ hybridization was performed using pig proinsulin antisense or sense probes on tissue originating from diabetic ZDF rats into which pig pancreatic primordia had been transplanted 40 weeks previously: A., C). Mesenteric lymph node stained using antisense probe; B, D) Mesenteric lymph node stained using sense probe. Arrow delineates germinal centers in A & B; Arrowhead delineates medullary sinus in A & B. Arrowheads delineate cells that stain positive for porcine proinuslin mRNA in C. Magnifications are shown for A & B (B) and for C & D (D). Reproduced with permission [10].

Figure 3

A-F) Sections of mesenteric lymph nodes from a formerly diabetic STZ-rat into which preserved E28 pig pancreatic primordia had been transplanted 1 year previously: In situ hybridization was performed using pig proinsulin antisense (A.C,E) or sense (B,D,F) probes. Arrow delineates medullary sinus in A and B. Arrowhead designates cells that stain positive for porcine proinsulin mRNA (C, E) and a negative-staining cell with similar morphology (F). Magnifications are shown in B for A & B; in D for C & D; and in F for E-F. Reproduced with permission [11].

Figure 4

In situ hybridization was performed using pig proinsulin antisense (A, C) or sense probes (B, D) on sections of mesenteric lymph node originating from a STZ-diabetic rhesus macaque 407 days post-transplantation of E28 pig pancreatic primordia. Magnifications are shown for A & B (B) and C& D (D). Reproduced with permission [12].