title: Differentiation of Islet Progenitors Regulated by Nicotinamide into Transcriptome-Verified β Cells That Ameliorate Diabetes.
abstract: Developmental stage-specific differentiation of stem or progenitor cells into safe and functional cells is of fundamental importance in regenerative medicine, including β-cell replacement. However, the differentiation of islet progenitor cells (IPCs) into insulin-secreting β cells remains elusive. Here, we report that the multifunctional molecule nicotinamide (NIC) is a specific differentiation regulator of mouse IPCs. The differentiated cells regulated by NIC exhibited many characteristics of adult β cells, including ameliorating preclinical diabetes and a highly comparable transcriptome profile. Gene set enrichment analysis showed that during differentiation, numerous IPC transcription factor genes, including Ngn3, Pax4, Fev, and Mycl1, were all down regulated. Pharmacological, biochemical, and gene knockdown analyses collectively demonstrated that NIC regulated the differentiation via inhibiting Sirt1 (silent information regulator transcript 1). Finally, NIC also regulates human IPC differentiation. Thus, our study advances islet developmental biology and impacts on translational research and regenerative therapies to diabetes and other diseases. Stem Cells 2017;35:1341-1354.
authors.affiliation: Islet Cell Development Program, Harry Perkins Institute of Medical Research, and Centre for Medical Research.|Centre for Diabetes Research, Harry Perkins Institute of Medical Research, and Centre for Medical Research.
authors.forename: Fang-Xu
authors.initials: FX
authors.lastname: Jiang
authors.affiliation: Islet Cell Development Program, Harry Perkins Institute of Medical Research, and Centre for Medical Research.|Centre for Diabetes Research, Harry Perkins Institute of Medical Research, and Centre for Medical Research.
authors.forename: Kevin
authors.initials: K
authors.lastname: Li
authors.affiliation: School of Animal Biology.
authors.forename: Michael
authors.initials: M
authors.lastname: Archer
authors.affiliation: Centre for Diabetes Research, Harry Perkins Institute of Medical Research, and Centre for Medical Research.
authors.forename: Munish
authors.initials: M
authors.lastname: Mehta
authors.affiliation: Centre for Diabetes Research, Harry Perkins Institute of Medical Research, and Centre for Medical Research.
authors.forename: Emma
authors.initials: E
authors.lastname: Jamieson
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Nedlands, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Charles
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Nedlands, Australia.
authors.forename: Jan E
authors.initials: JE
authors.lastname: Dickinson
authors.affiliation: Department of Molecular Biology, Saitama Medical School, Saitama, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Centre for Diabetes Research, Harry Perkins Institute of Medical Research, and Centre for Medical Research.
authors.forename: Grant
authors.initials: G
authors.lastname: Morahan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000637:transplantation* / Q000648:ultrastructure; D008164:Luminescent Proteins / Q000378:metabolism; D016513:Mice, SCID; D009536:Niacinamide / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*
chemical_list: D008164:Luminescent Proteins; D014157:Transcription Factors; C413663:fluorescent protein 583; D009536:Niacinamide; D056564:Sirtuin 1
keywords: Diabetes; Differentiation; Islet progenitors; Nicotinamide; Transcriptome