title: Hox6 genes modulate in vitro differentiation of mESCs to insulin-producing cells.
abstract: The differentiation of glucose-responsive, insulin-producing cells from ESCs in vitro is promising as a cellular therapy for the treatment of diabetes, a devastating and common disease. Pancreatic β-cells are derived from the endoderm in vivo and therefore most current protocols attempt to generate a pure population of first endoderm, then pancreas epithelium, and finally insulin-producing cells. Despite this, differentiation protocols result in mixed populations of cells that are often poorly defined, but also contain mesoderm. Using an in vitro mESC-to-β cell differentiation protocol, we show that expression of region-specific Hox genes is induced. We also show that the loss of function of the Hox6 paralogous group, genes expressed only in the mesenchyme of the pancreas (not epithelium), affect the differentiation of insulin-producing cells in vitro. This work is consistent with the important role for these mesoderm-specific factors in vivo and highlights contribution of supporting mesenchymal cells in in vitro differentiation.
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Larsen
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Leilani
authors.initials: L
authors.lastname: Marty-Santos
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Micaleah
authors.initials: M
authors.lastname: Newman
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Derek T
authors.initials: DT
authors.lastname: Lukacs
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109-2200, USA.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Spence
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, 48109-2200, USA. dwellik@umich.edu.|Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109-2200, USA. dwellik@umich.edu.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109-2200, USA. dwellik@umich.edu.
authors.forename: Deneen M
authors.initials: DM
authors.lastname: Wellik
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D004707:Endoderm / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics
chemical_list: D055415:Bone Morphogenetic Protein 4; D018398:Homeodomain Proteins; C000605398:Hox6 protein, mouse; D007328:Insulin
keywords: Endocrine cells; Hox genes; In vitro ESC differentiation; Insulin-producing cells; Pancreas development