Site for Unpurified Islet Transplantation is an Important Parameter for Determination of the Outcome of Graft Survival and Function

Abstract

Transplantation of unpurified islets into the liver, unlike that of purified islets, causes portal hypertension and coagulopathy. The aim of this project was to determine the most suitable alternative site for transplantation of unpurified pancreatic islets in autotransplanted dogs. Twenty-five female mongrel dogs were divided into 5 groups depending on the site of islet transplantation: liver (3), spleen (7), skeletal muscle (5), omental pouch (6), and renal subcapsule (4). Pancreatic digestion of the total pancreatectomized specimen was carried out by distension of the pancreas with 1.5 mg/mL collagenase suspended in 250 mL Hanks' balanced salt solution using a semiautomatic method. The total number of islets equivalent isolated from 25 dogs was 90948 +/- 6053. Only islets > 60 microns in diameter were counted, and the mean islet equivalent transplanted per kg body wt was 6762 +/- 429. Islet function was achieved with transplantation into spleen in 71%, omental pouch in 50%, and muscle in 20%, but none in the renal subcapsule or liver groups. Glucose tolerance test at 30 d showed a mean K Value (decline in glucose, %/min) of 1.94 +/- 0.73, 0.79 +/- 0.15 and 1.02 in the splenic, omental pouch and muscle groups, respectively. All animals in the liver group, 2 from the splenic group, and 2 from the renal subcapsule group died of diffuse bleeding. Four out of 5 dogs in the muscle group developed necrosis at the site of transplantation and the islets never functioned. This study demonstrates that in dogs, spleen and omental pouch appear to be suitable sites for transplantation of unpurified islets.

Islet Transplantation: Alternative Sites

“…Syngeneic islets transplanted into the omental pouch of streptozotocin-induced diabetic rats restored normoglycemia and normal glucose tolerance tests that were different from those transplanted into the kidney subcapsule [30]. Histologic examination of the grafts showed numerous well-granulated insulin-containing cells in both sites and there was no difference in insulin content of the harvested grafts [31]. In diabetic mice, the omental pouch as a site for syngeneic islet transplantation was the best when compared with kidney, liver, and muscle sites in achieving glycemic control and glucose kinetics that were the most similar to controls [12].…”

“…The omental pouch of diabetic dogs has been successfully used as a site for autologous islet implant [31][32][33]. In a study by Ao et al [32], purified islets autotransplanted into the greater omental pouch successfully reversed surgically induced diabetes in totally pancreatectomized recipients.…”

“…The omental pouch also has the advantages of accepting unpurified islets that would carry the risks of portal hypertension and coagulopathy if transplanted into the portal vein [31]. In an experimental study in dogs, the spleen and omental pouch, but not the liver, skeletal muscle, or kidney subcapsule, have been shown to be suitable sites for transplantation of unpurified islets as evident from achieving islet function with less morbidity [31].…”

Clinical Islet Cell Transplantation – Recent Advances

“…The omentum has numerous blood vessel pedicles, various lymphatic vessels, exclusive portal drainage, high vascular density and neoangiogenesis capability 27 . In rodents, enough evidence is available for better function of islets transplanted in the omentum [28][29][30] . Recently, the omental pouch has been used as islet transplantation site in diabetic cynomolgus monkey, a nonhuman primate model.…”

Cellular Therapies for Type 1 Diabetes

“…Lastly, islet grafts have been shown to induce steatosis of surrounding hepatocytes [31], and there is evidence that intrahepatic transplanted islets display increased levels of glucagon unresponsiveness to hypoglycemia when compared to both islets transplanted intraperitoneally and to control animals [32]. In an attempt to control IBMIR and circumvent the early complications associated with intrahepatic transplantation, low-molecular weight dextran sulfate, and surfacing coating with heparin have been suggested [28], and additional sites of implantation are being explored [33,34].…”