Stimulated endocrine cell proliferation and differentiation in transplanted human pancreatic islets - Effects of the ob gene and compensatory growth of the implantation organ

Neogenesis is crucial for the maintenance of beta -cell mass in the human p ancreas and possibly for the outcome of clinical islet transplantation. To date, no studies have reported a stimulation of human beta -cell neogenesis in vivo. Therefore, we investigated whether human alpha-, beta-, and duct cell growth can be stimulated when human islets are xenotransplanted to obe se hyperglycemic-hyperinsulinemic ob/ob mice immunosuppressed with anti-lym phocyte serum. Moreover, we wanted to study whether beta -cell growth and d uct-to-beta -cell differentiation were induced in the hepatocyte growth fac tor (HGF)-dependent compensatory kidney growth model. For that purpose, we evaluated human islets grafted to nude (nu/nu) mice before uninephrectomy o f the contralateral kidney for DNA-synthesis and duct cell expression of th e beta -cell-specific transcription factor Nkx 6.1 as an estimate of differ entiation. Human islet grafts were well preserved after 2 weeks when transp lanted to ob/ob mice during anti-lymphocyte immunosuppression. Both human b eta -cells (P < 0.01) and duct cells (P < 0.001) were growth stimulated whe n islets were transplanted to ob/ob mice. We also observed a correlation be tween increased duct cell proliferation and increased organ donor age (P = 0.02). Moreover, duct (P < 0.05) and <beta>-cell (P < 0.05) proliferation, as well as duct cell Nkx 6.1 expression (P < 0.05), were enhanced by the co mpensatory kidney growth after uninephrectomy. We conclude that it is possi ble to stimulate human beta -cell neogenesis in vivo, provided that the rec ipient carries certain growth-stimulatory traits. Furthermore, it seems tha t duct cell proliferation increases with increasing organ donor age. Altoge ther, these data and previous results from our laboratory suggest that huma n beta -cell neogenesis becomes more dependent on differentiation and less dependent On proliferation with increasing age.