TGF-? superfamily member Nodal stimulates human ?-cell proliferation while maintaining cellular viability.

ABSTRACT: In an effort to expand human islets and enhance allogeneic islet transplant for the treatment of type 1 diabetes, identifying signaling pathways that stimulate human ?-cell proliferation is paramount. TGF-? superfamily members, in particular activin-A, are likely involved in islet development and may contribute to ?-cell proliferation. Nodal, another TGF-? member, is present in both embryonic and adult rodent islets. Nodal, along with its coreceptor, Cripto, are pro-proliferative factors in certain cell types. Although Nodal stimulates apoptosis of rat insulinoma cells (INS-1), Nodal and Cripto signaling have not been studied in the context of human islets. The current study investigated the effects of Nodal and Cripto on human ?-cell proliferation, differentiation, and viability. In the human pancreas and isolated human islets, we observed Nodal mRNA and protein expression, with protein expression observed in ? and ?-cells. Cripto expression was absent from human islets. Furthermore, in cultured human islets, exogenous Nodal stimulated modest ?-cell proliferation and inhibited ?-cell proliferation with no effect on cellular viability, apoptosis, or differentiation. Nodal stimulated the phosphorylation of mothers against decapentaplegic (SMAD)-2, with no effect on AKT or MAPK signaling, suggesting phosphorylated SMAD signaling was involved in ?-cell proliferation. Cripto had no effect on human islet cell proliferation, differentiation, or viability. In conclusion, Nodal stimulates human ?-cell proliferation while maintaining cellular viability. Nodal signaling warrants further exploration to better understand and enhance human ?-cell proliferative capacity.

SUBMITTER: Boerner BP 

PROVIDER: S-EPMC3800770 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature