Sertoli cell-induced reversal of adult rat pancreatic islet β-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 therapy of diabetes mellitus is hampered by several pitfalls, primarily including the restricted availability of donor tissue and the immune- and/or non-immune-related TX's early loss, with the latter not necessarily being prevented by the host's general immunosuppression, Finally, adult islet beta -cells 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 examined whether in vitro co-culturing adult rat islets (I) with prepubertal homologous Sertoli cells (SC) would stimulate I beta -cell expansion. SC-derived effects on the islets were studied in vitro, both morphologically (confocal 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 replication, as I beta -cell mitotic activity increased from 1% to greater than 8%, which coincided with the adult elements reversing into fetal-like status, This finding was coupled with significantly greater insulin release either 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, potentially powerful tool that could significantly enhance the functional performance of islet TX in diabetic recipients.