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Review
. 2014 Nov-Dec;21(6):485-95.
doi: 10.1111/xen.12115. Epub 2014 Jul 5.

A review of piscine islet xenotransplantation using wild-type tilapia donors and the production of transgenic tilapia expressing a "humanized" tilapia insulin

James R Wright Jr  1 , Hua Yang, Olga Hyrtsenko, Bao-You Xu, Weiming Yu, Bill Pohajdak
Affiliations
Free PMC article
Review

A review of piscine islet xenotransplantation using wild-type tilapia donors and the production of transgenic tilapia expressing a "humanized" tilapia insulin

James R Wright Jr et al. Xenotransplantation. 2014 Nov-Dec.
Free PMC article

Abstract

Most islet xenotransplantation laboratories have focused on porcine islets, which are both costly and difficult to isolate. Teleost (bony) fish, such as tilapia, possess macroscopically visible distinct islet organs called Brockmann bodies which can be inexpensively harvested. When transplanted into diabetic nude mice, tilapia islets maintain long-term normoglycemia and provide human-like glucose tolerance profiles. Like porcine islets, when transplanted into euthymic mice, they are rejected in a CD4 T-cell-dependent manner. However, unlike pigs, tilapia are so phylogenetically primitive that their cells do not express α(1,3)Gal and, because tilapia are highly evolved to live in warm stagnant waters nearly devoid of dissolved oxygen, their islet cells are exceedingly resistant to hypoxia, making them ideal for transplantation within encapsulation devices. Encapsulation, especially when combined with co-stimulatory blockade, markedly prolongs tilapia islet xenograft survival in small animal recipients, and a collaborator has shown function in diabetic cynomolgus monkeys. In anticipation of preclinical xenotransplantation studies, we have extensively characterized tilapia islets (morphology, embryologic development, cell biology, peptides, etc.) and their regulation of glucose homeostasis. Because tilapia insulin differs structurally from human insulin by 17 amino acids, we have produced transgenic tilapia whose islets stably express physiological levels of humanized insulin and have now bred these to homozygosity. These transgenic fish can serve as a platform for further development into a cell therapy product for diabetes.

Keywords: Brockmann body; bio-artificial pancreas; cell transplantation; diabetes; encapsulation; insulin; pancreatic islet; teleost fish; transgenic fish; xenotransplantation.

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Figures

Figure 1
Figure 1
Left. Histologic section of pig pancreas showing scattered islets (arrows indicate the largest islet). Histologic sections showing a large (center) and small (right upper corner) tilapia Brockmann body at the same magnification as the section of pig pancreas. Note the minimal exocrine contamination (arrow) admixed with the adipose tissue surrounding the BBs which digests away during the harvesting procedure (hematoxylin and eosin). Reprinted with permission from Wright JR Jr, Yang H. Tilapia Brockmann bodies: an inexpensive simple model for discordant islet xenotransplantation. Ann Transplant 1997; 2(3): 72–76.
Figure 2
Figure 2
Whole mount produced by processing an entire “BB region” for histology. Sections were cut at three different levels through the block to provide a three-dimensional view. Sections were stained with hematoxylin and eosin. The regions are composed of adipose tissue (A), bile and pancreatic ducts (D), blood vessels (V), nerve (N), and Brockmann bodies (BB). Twelve BBs can be identified in the center frame. Reprinted with permission from Yang H, Wright JR Jr. A method for mass-harvesting islets (Brockmann bodies) from teleost fish. Cell Transplant 1995; 4: 621–628.
Figure 3
Figure 3
Dissection of female tilapia with the right ovary and omentum (O) reflected downward reveals the roughly triangular “Brockmann body (BB) region” (outlined by arrows and lines) surrounded by the liver (L), stomach (ST), and spleen (S) and gall bladder (G). LO = left ovary. Reprinted with permission from Yang H, Wright JR Jr. A method for mass-harvesting islets (BBs) from teleost fish. Cell Transplant 1995; 4: 621–628.
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References

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