retinoic acid promotes the generation of pancreatic endocrine progenitor cells and their further differentiation into β-cells视黄酸促进胰腺内分泌的一代祖细胞进一步分化为β-cells.pdfVIP

Retinoic Acid Promotes the Generation of Pancreatic Endocrine Progenitor Cells and Their Further Differentiation into b-Cells ¨ ¨ 1 1 1 1 1 2 2 Maria Ostrom , Kelly A. Loffler , Sara Edfalk , Lars Selander , Ulf Dahl , Camillo Ricordi , Jongmin Jeon , 2 2 1,2 Mayrin Correa-Medina , Juan Diez , Helena Edlund * ˚ ˚ ˚ 1 Umea Centre for Molecular Medicine, Umea University, Umea, Sweden, 2 Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, United States of America Abstract The identification of secreted factors that can selectively stimulate the generation of insulin producing b-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based b-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of b-cells during normal pancreatic development such putative factors may be identified. In the mouse, b-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of b-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when b-cells are generated. We also provide evidence that RA induces the generation of Ngn3+ endocrine progenitor cells and stimulates their further differentiation into b-cells by activating a program of cell differentiation that