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Endocrinology. 2013 Nov;154(11):4099-112. doi: 10.1210/en.2013-1197. Epub 2013 Aug 22.

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

Author information

1
MD, and Nora E. Sarvetnick, PhD, University of Nebraska Medical Center, 985965 Nebraska Medical Center, Omaha, Nebraska 68198-5965. bboerner@unmc.edu; or noras@unmc.edu.

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 β-cell proliferation is paramount. TGF-β superfamily members, in particular activin-A, are likely involved in islet development and may contribute to β-cell proliferation. Nodal, another TGF-β 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 β-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 β and α-cells. Cripto expression was absent from human islets. Furthermore, in cultured human islets, exogenous Nodal stimulated modest β-cell proliferation and inhibited α-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 β-cell proliferation. Cripto had no effect on human islet cell proliferation, differentiation, or viability. In conclusion, Nodal stimulates human β-cell proliferation while maintaining cellular viability. Nodal signaling warrants further exploration to better understand and enhance human β-cell proliferative capacity.

PMID:
23970788
PMCID:
PMC3800770
DOI:
10.1210/en.2013-1197
[Indexed for MEDLINE]
Free PMC Article
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