Sertoli cell-induced reversal of adult rat pancreatic islet beta-cells into fetal-like status: Potential implications for islet transplantation in type I diabetes mellitus

Background: Clinical success of pancreatic islet allograft (TX) for the the rapy of diabetes mellitus is hampered by several pitfalls, primarily includ ing the restricted availability of donor tissue and the immune- and/or non- immune-related TX's early loss, with the latter not necessarily being preve nted by the host's general immunosuppression, Finally, adult islet beta -ce lls normally exhibit minimal proliferation capacity, which would not permit restoration of an eventually declining TX mass. Methods: To address the limited beta -cell growth capacity, we have examine d whether in vitro co-culturing adult rat islets (I) with prepubertal homol ogous Sertoli cells (SC) would stimulate I beta -cell expansion. SC-derived effects on the islets were studied in vitro, both morphologically (confoca l laser microscopy) and functionally (glucose-stimulated insulin release). We have also preliminarily examined the in vivo impact of microencapsulated SC+I co-cultures on TX in diabetic mice, Results: In vitro, we observed that SCs promoted significant beta -cell rep lication, as I beta -cell mitotic activity increased from 1% to greater tha n 8%, which coincided with the adult elements reversing into fetal-like sta tus, This finding was coupled with significantly greater insulin release ei ther in basal or in response to glucose, as compared with controls. Conclusions: Addition of SC to islets promotes reversal of the adult beta - cell elements into fetal-like conditions, thereby providing a new, potentia lly powerful tool that could significantly enhance the functional performan ce of islet TX in diabetic recipients.