Hepatocyte growth factor is essential for amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts.

Abstract

It is crucial for clinical islet transplantation to find a procedure to improve the success rate of insulin independence after islet transplantation. In the present study, we determined whether hepatocyte growth factor (HGF) has a favorable effect on amelioration of hyperglycemia in streptozotocin (STZ, 200 mg/kg)-induced diabetic mice (C57BL/6) receiving a marginal mass of intrahepatic islet isografts. Isolated syngeneic islets were transplanted into the liver of recipients. HGF with dextran sulfate (DS) was administered intraperitoneally once a day at day 0, 2, 4, 6, and 8 relative to islet transplantation. DS has been known to enhance the effect of HGF. It was found that the number of 250 islets was a marginal mass as donor islets in this model, in which 2 out of 14 diabetic mice receiving 250 islets became normoglycemic by 90 days after transplantation. The treatment with HGF (100 microg) in conjunction with DS (200 microg) produced normoglycemia in all mice (n = 5). Morphological study as well as intraperitoneal glucose tolerance test revealed the beneficial effects of HGF. To our surprise, six out of nine mice receiving 250 islets and treated with DS alone became normoglycemic. Additional anti-HGF antibody treatment (100 microg, day -1, 0, 2, 4, 6, and 8) abolished the effects of DS, indicating that the effect by DS is mediated via the endogenous HGF. The effects of DS were not observed when the renal subcapsular space was the site of islet transplantation. There was a significant increase in plasma HGF levels in mice after the intrahepatic grafts but not the renal subcapsular one. These findings demonstrate that HGF is essential for amelioration of hyperglycemia in STZ-induced diabetic mice when a marginal mass of islets was grafted into the liver. As the liver is the site of clinical islet transplantation and the inability to achieve insulin independence after transplantation is a major obstacle for successful transplantation, HGF may facilitate to overcome such an important issue for clinical islet transplantation.