Retinoic Acid Promotes the Generation of Pancreatic Endocrine Progenitor Cells and Their Further Differentiation into Beta-cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2008 Jul 31

PMID 18665267

Citations 63

Authors

Maria Ostrom

Kelly A Loffler

Sara Edfalk

Lars Selander

Ulf Dahl

Camillo Ricordi

Jongmin Jeon

Mayrin Correa-Medina

Juan Diez

Helena Edlund

Affiliations

Soon will be listed here.

Abstract

The identification of secreted factors that can selectively stimulate the generation of insulin producing beta-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based beta-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of beta-cells during normal pancreatic development such putative factors may be identified. In the mouse, beta-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 beta-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 beta-cells are generated. We also provide evidence that RA induces the generation of Ngn3(+) endocrine progenitor cells and stimulates their further differentiation into beta-cells by activating a program of cell differentiation that recapitulates the normal temporal program of beta-cell differentiation.

Citing Articles

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References

Damm K, HEYMAN R, Umesono K, Evans R . Functional inhibition of retinoic acid response by dominant negative retinoic acid receptor mutants. Proc Natl Acad Sci U S A. 1993; 90(7):2989-93. PMC: 46222. DOI: 10.1073/pnas.90.7.2989. View

Esni F, Johansson B, Radice G, Semb H . Dorsal pancreas agenesis in N-cadherin- deficient mice. Dev Biol. 2002; 238(1):202-12. DOI: 10.1006/dbio.2001.0405. View

Miralles F, Czernichow P, Ozaki K, Itoh N, Scharfmann R . Signaling through fibroblast growth factor receptor 2b plays a key role in the development of the exocrine pancreas. Proc Natl Acad Sci U S A. 1999; 96(11):6267-72. PMC: 26870. DOI: 10.1073/pnas.96.11.6267. View

Chambers D, Wilson L, Maden M, Lumsden A . RALDH-independent generation of retinoic acid during vertebrate embryogenesis by CYP1B1. Development. 2007; 134(7):1369-83. DOI: 10.1242/dev.02815. View

Gradwohl G, Dierich A, Lemeur M, Guillemot F . neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A. 2000; 97(4):1607-11. PMC: 26482. DOI: 10.1073/pnas.97.4.1607. View

Herrera P, Huarte J, Sanvito F, Meda P, Orci L, Vassalli J . Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene. Development. 1991; 113(4):1257-65. DOI: 10.1242/dev.113.4.1257. View

Novitch B, Wichterle H, Jessell T, Sockanathan S . A requirement for retinoic acid-mediated transcriptional activation in ventral neural patterning and motor neuron specification. Neuron. 2003; 40(1):81-95. DOI: 10.1016/j.neuron.2003.08.006. View

Martin M, Gallego-Llamas J, Ribes V, Kedinger M, Niederreither K, Chambon P . Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice. Dev Biol. 2005; 284(2):399-411. DOI: 10.1016/j.ydbio.2005.05.035. View

Jensen J, PEDERSEN E, Galante P, Hald J, Heller R, Ishibashi M . Control of endodermal endocrine development by Hes-1. Nat Genet. 1999; 24(1):36-44. DOI: 10.1038/71657. View

10.

Edlund H . Pancreas: how to get there from the gut?. Curr Opin Cell Biol. 1999; 11(6):663-8. DOI: 10.1016/s0955-0674(99)00033-2. View

11.

Molotkov A, Molotkova N, Duester G . Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. Dev Dyn. 2005; 232(4):950-7. DOI: 10.1002/dvdy.20256. View

12.

Sockanathan S, Perlmann T, Jessell T . Retinoid receptor signaling in postmitotic motor neurons regulates rostrocaudal positional identity and axonal projection pattern. Neuron. 2003; 40(1):97-111. DOI: 10.1016/s0896-6273(03)00532-4. View

13.

Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P . The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature. 1997; 386(6623):399-402. DOI: 10.1038/386399a0. View

14.

Selander L, Edlund H . Nestin is expressed in mesenchymal and not epithelial cells of the developing mouse pancreas. Mech Dev. 2002; 113(2):189-92. DOI: 10.1016/s0925-4773(02)00023-0. View

15.

Li Z, Manna P, Kobayashi H, Spilde T, Bhatia A, Preuett B . Multifaceted pancreatic mesenchymal control of epithelial lineage selection. Dev Biol. 2004; 269(1):252-63. DOI: 10.1016/j.ydbio.2004.01.043. View

16.

Apelqvist A, Li H, Sommer L, Beatus P, Anderson D, Honjo T . Notch signalling controls pancreatic cell differentiation. Nature. 1999; 400(6747):877-81. DOI: 10.1038/23716. View

17.

Johansson K, Dursun U, Jordan N, Gu G, Beermann F, Gradwohl G . Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev Cell. 2007; 12(3):457-65. DOI: 10.1016/j.devcel.2007.02.010. View

18.

Ohlsson H, Karlsson K, Edlund T . IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 1993; 12(11):4251-9. PMC: 413720. DOI: 10.1002/j.1460-2075.1993.tb06109.x. View

19.

Stafford D, Prince V . Retinoic acid signaling is required for a critical early step in zebrafish pancreatic development. Curr Biol. 2002; 12(14):1215-20. DOI: 10.1016/s0960-9822(02)00929-6. View

20.

Fan X, Molotkov A, Manabe S, Donmoyer C, Deltour L, Foglio M . Targeted disruption of Aldh1a1 (Raldh1) provides evidence for a complex mechanism of retinoic acid synthesis in the developing retina. Mol Cell Biol. 2003; 23(13):4637-48. PMC: 164835. DOI: 10.1128/MCB.23.13.4637-4648.2003. View