title: TGF-β superfamily member Nodal stimulates human β-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 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.
authors: 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.
authors: Brian P
authors: BP
authors: Boerner
authors: Nicholas M
authors: NM
authors: George
authors: Natalie M
authors: NM
authors: Targy
authors: Nora E
authors: NE
authors: Sarvetnick
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology; D055457:Nodal Protein / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D055457:Nodal Protein; D051785:Smad Proteins; C070636:TDGF1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases
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