Adenovirus-mediated hepatocyte growth factor expression in mouse islets improves pancreatic islet transplant performance and reduces beta cell death.
Hepatocyte growth factor (HGF) increases beta cell proliferation and function in rat insulin promoter (RIP)-targeted transgenic mice. RIP-HGF mouse islets also function superiorly to normal islets in a transplant setting. Here, we aimed to determine whether viral gene transfer of the HGF gene into mouse islets ex vivo could enhance the performance of normal islets in a streptozotocin-diabetic severe combined immunodeficient mouse marginal islet mass model in which 300 uninfected or adenovirus (Adv) LacZ-transduced islet equivalents were insufficient to correct hyperglycemia. In dramatic contrast, 300 AdvHGF-transduced islet equivalents promptly (day 1) and significantly (p < 0.01) decreased random non-fasting blood glucose levels, from 351 +/- 20 mg/dl to an average of 191 +/- 7 mg/dl over 8 weeks. At day 1 post-transplant, beta cell death was significantly (p < 0.05) decreased, and the total insulin content was significantly (p < 0.05) increased in AdvHGF-transduced islets containing grafts. This anti-beta cell death action of HGF was independently confirmed in RIP-HGF mice and in INS-1 cells, both treated with streptozotocin. Activation of the phosphatidylinositol 3-kinase/Akt intracellular-signaling pathway appeared to be involved in this beta cell protective effect of HGF in vitro. In summary, adenoviral delivery of HGF to murine islets ex vivo improves islet transplant survival and blood glucose control in a subcapsular renal graft model in immuno-incompetent diabetic mice.
Garcia-Ocana
Adolfo
A
Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Takane
Karen K
KK
Reddy
Vasumathi T
VT
Lopez-Talavera
Juan-Carlos
JC
Vasavada
Rupangi C
RC
Stewart
Andrew F
AF
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D000730:Androstadienes / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D004791:Enzyme Inhibitors / Q000378:metabolism; D018014:Gene Transfer Techniques; D005947:Glucose / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014161:Transduction, Genetic; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D005947:Glucose; D017228:Hepatocyte Growth Factor; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C494918:AKT1 protein, human