Identification of small-molecule inducers of pancreatic beta-cell expansion.
To identify small molecules that can induce beta-cell replication, a large chemical library was screened for proliferation of growth-arrested, reversibly immortalized mouse beta cells by using an automated high-throughput screening platform. A number of structurally diverse, active compounds were identified, including phorbol esters, which likely act through protein kinase C, and a group of thiophene-pyrimidines that stimulate beta-cell proliferation by activating the Wnt signaling pathway. A group of dihydropyridine (DHP) derivatives was also shown to reversibly induce beta-cell replication in vitro by activating L-type calcium channels (LTCCs). Our data suggest that the LTCC agonist 2a affects the expression of genes involved in cell cycle progression and cellular proliferation. Furthermore, treatment of beta cells with both LTCC agonist 2a and the Glp-1 receptor agonist Exendin-4 showed an additive effect on beta-cell replication. The identification of small molecules that induce beta-cell proliferation suggests that it may be possible to reversibly expand other quiescent cells to overcome deficits associated with degenerative and/or autoimmune diseases.
Wang
Weidong
W
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Walker
John R
JR
Wang
Xia
X
Tremblay
Matthew S
MS
Lee
Jae Wook
JW
Wu
Xu
X
Schultz
Peter G
PG
D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects*; D004095:Dihydropyridines / Q000494:pharmacology; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014688:Venoms / Q000494:pharmacology; D051153:Wnt Proteins / Q000819:agonists
D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D051153:Wnt Proteins; D000077270:Exenatide