Cited by 18Pancreatic function and diabetesPluripotent Stem Cells ResearchDiabetes and associated disorders

Development of insulin-producing cells from primitive biologic precursors

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Evans-Molina, Carmella, Vestermark, George L, Mirmira, Raghavendra G·2009·Current Opinion in Organ Transplantation

Abstract

PURPOSE OF REVIEW: The differentiation of pluripotent and multipotent stem cells into insulin-producing cells has the potential to create a renewable supply of replacement beta cells with tremendous utility in the treatment of diabetes. The purpose of this review is to summarize recent advancements in the field, with emphasis on the limitations of this technology as it relates to the beta cell. RECENT FINDINGS: Multiple groups have developed successful in-vitro protocols to differentiate human embryonic stem cells and selected tissue specific stem cells into progenitors capable of insulin production and glucose-stimulated insulin secretion. The resulting cells are immature beta cell-like cells that coexpress multiple islet hormones and lack the full complement of genes necessary for normal function. Protocols that include in-vivo maturation in immune-compromised mice produce cells with a more mature phenotype. SUMMARY: Although tremendous progress has been made in differentiating stem cells into insulin-producing cells, there is still more research needed to produce a fully functional adult beta cell.

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  • There has been a steady series of improvements to directed differentiation strategies for generating beta-like cells over the past 20 years.

    “there has been a steady series of improvements to directed differentiation strategies over the past 20 years135–138.”

    From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [138]

    The “Human embryonic stem cells as precursors” section (page not provided) describes increasingly sophisticated differentiation methods for generating insulin-producing cells. The paper was published in 2009 and discusses progress over the preceding several years; it does not establish a steady series of improvements over 20 years. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • A beta-like cell with behavior that fully recapitulates the physiology of a normal beta cell is yet to be realized.

    “While a beta-like cell with behavior that fully recapitulates the physiology of a normal beta cell is yet to be realized”

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Research works printed but not linked: 67

  1. [3]Narayan KM Boyle JP Geiss LS Impact of recent increase in incidence on future diabetes burden: U.S., 2005–2050 Diabetes Care 2006 29 2114 2116 16936162
  2. [5]Berney T Toso C Monitoring of the islet graft Diabetes Metab 2006 32 503 512 17130809
  3. [7]Shim JH Kim SE Woo DH Directed differentiation of human embryonic stem cells towards a pancreatic cell fate Diabetologia 2007 50 1228 1238 17457565 One of the recent hallmark articles outlining a successful protocol for differentiating human embryonic stem cells into insulin producing cells.
  4. [8]Jiang W Shi Y Zhao D In vitro derivation of functional insulin-producing cells from human embryonic stem cells Cell Res 2007 17 333 344 17426693 One of the recent hallmark articles outlining a successful protocol for differentiating human embryonic stem cells into insulin producing cells.
  5. [9]D'Amour KA Bang AG Eliazer S Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells Nat Biotechnol 2006 24 1392 1401 17053790 One of the first accounts outlining a successful protocol for differentiating human embryonic stem cells into insulin producing cells. The authors considered a multi-step differentiation protocol that recapitulated the signaling cascade of normal development.
  6. [10]Hori Y Rulifson IC Tsai BC Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells Proc Natl Acad Sci U S A 2002 99 16105 16110 12441403 PMC138572
  7. [11]Murtaugh LC Pancreas and beta-cell development: from the actual to the possible Development 2007 134 427 438 17185316 A comprehensive review of pancreatic and islet development.
  8. [12]Edlund H Pancreatic organogenesis--developmental mechanisms and implications for therapy Nat Rev Genet 2002 3 524 532 12094230
  9. [13]Oliver-Krasinski JM Stoffers DA On the origin of the beta cell Genes Dev 2008 22 1998 2021 18676806 PMC2735346 A very recent and extremely comprehensive review of cell development.
  10. [14]Babu DA Deering TG Mirmira RG A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis Mol Genet Metab 2007 92 43 55 17659992 PMC2042521 A comprehensive review of the role of Pdx-1 in pancreatic development and cell function.
  11. [15]Kawahira H Ma NH Tzanakakis ES Combined activities of hedgehog signaling inhibitors regulate pancreas development Development 2003 130 4871 4879 12917290
  12. [16]Stafford D Hornbruch A Mueller PR Prince VE A conserved role for retinoid signaling in vertebrate pancreas development Dev Genes Evol 2004 214 432 441 15322880
  13. [17]Ahlgren U Jonsson J Edlund H The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice Development 1996 122 1409 1416 8625829
  14. [18]Hale MA Kagami H Shi L The homeodomain protein PDX1 is required at mid-pancreatic development for the formation of the exocrine pancreas Dev Biol 2005 286 225 237 16126192
  15. [20]Wiebe PO Kormish JD Roper VT Ptf1a binds to and activates area III, a highly conserved region of the Pdx1 promoter that mediates early pancreas-wide Pdx1 expression Mol Cell Biol 2007 27 4093 4104 17403901 PMC1900007
  16. [21]Jensen J Pedersen EE Galante P Control of endodermal endocrine development by Hes-1 Nat Genet 2000 24 36 44 10615124
  17. [22]Li H Arber S Jessell TM Edlund H Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9 Nat Genet 1999 23 67 70 10471501
  18. [23]Harrison KA Thaler J Pfaff SL Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice Nat Genet 1999 23 71 75 10471502
  19. [24]Jacquemin P Durviaux SM Jensen J Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3 Mol Cell Biol 2000 20 4445 4454 10825208 PMC85812
  20. [25]Jacquemin P Lemaigre FP Rousseau GG The Onecut transcription factor HNF-6 (OC-1) is required for timely specification of the pancreas and acts upstream of Pdx-1 in the specification cascade Dev Biol 2003 258 105 116 12781686
  21. [26]Ahlgren U Jonsson J Jonsson L beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes Genes Dev 1998 12 1763 1768 9637677 PMC316911
  22. [27]Stoffers DA Zinkin NT Stanojevic V Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence Nat Genet 1997 15 106 110 8988180
  23. [28]Krapp A Knofler M Ledermann B The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas Genes Dev 1998 12 3752 3763 9851981 PMC317250
  24. [29]Seymour PA Freude KK Tran MN SOX9 is required for maintenance of the pancreatic progenitor cell pool Proc Natl Acad Sci U S A 2007 104 1865 1870 17267606 PMC1794281
  25. [30]Wilson ME Yang KY Kalousova A The HMG Box Transcription Factor Sox4 Contributes to the Development of the Endocrine Pancreas Diabetes 2005 54 3402 3409 16306355
  26. [31]Kim SK Selleri L Lee JS Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus Nat Genet 2002 30 430 435 11912494
  27. [32]Dutta S Gannon M Peers B PDX:PBX complexes are required for normal proliferation of pancreatic cells during development Proc Natl Acad Sci U S A 2001 98 1065 1070 11158595 PMC14709
  28. [33]Haumaitre C Barbacci E Jenny M Lack of TCF2/vHNF1 in mice leads to pancreas agenesis Proc Natl Acad Sci U S A 2005 102 1490 1495 15668393 PMC547822
  29. [34]Poll AV Pierreux CE Lokmane L A vHNF1/TCF2-HNF6 cascade regulates the transcription factor network that controls generation of pancreatic precursor cells Diabetes 2006 55 61 69 16380477
  30. [35]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 1607 1611 10677506 PMC26482
  31. [36]Ahlgren U Pfaff SL Jessell TM Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells Nature 1997 385 257 260 9000074
  32. [37]Naya FJ Huang HP Qiu Y Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice Genes Dev 1997 11 2323 2334 9308961 PMC316513
  33. [38]Gierl MS Karoulias N Wende H The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells Genes Dev 2006 20 2465 2478 16951258 PMC1560419
  34. [39]St-Onge L Sosa-Pineda B Chowdhury K Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas Nature 1997 387 406 409 9163426
  35. [40]Smith SB Ee HC Conners JR German MS Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development Mol Cell Biol 1999 19 8272 8280 10567552 PMC84911
  36. [41]Artner I Blanchi B Raum JC MafB is required for islet beta cell maturation Proc Natl Acad Sci U S A 2007 104 3853 3858 17360442 PMC1803762
  37. [42]Nishimura W Kondo T Salameh T A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells Dev Biol 2006 293 526 539 16580660 PMC2390934
  38. [43]Zhang C Moriguchi T Kajihara M MafA is a key regulator of glucose-stimulated insulin secretion Mol Cell Biol 2005 25 4969 4976 15923615 PMC1140590
  39. [44]Sussel L Kalamaras J Hartigan-O'Connor DJ Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells Development 1998 125 2213 2221 9584121
  40. [45]Doyle MJ Loomis ZL Sussel L Nkx2.2-repressor activity is sufficient to specify {alpha}-cells and a small number of {beta}-cells in the pancreatic islet Development 2007 134 515 523 17202186 PMC2805074
  41. [46]Sander M Sussel L Conners J Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas Development 2000 127 5533 5540 11076772
  42. [47]Scott CT Reijo Pera RA The road to pluripotence: the research response to the embryonic stem cell debate Hum Mol Genet 2008 17 R3 R9 18632694 This article includes practical definitions of a stem cell and outlines some of the controversies associated with stem cell research.
  43. [48]Soria B In-vitro differentiation of pancreatic beta-cells Differentiation 2001 68 205 219 11776473
  44. [49]Soria B Roche E Berna G Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice Diabetes 2000 49 157 162 10868930
  45. [50]Kurosawa H Methods for inducing embryoid body formation: in vitro differentiation system of embryonic stem cells J Biosci Bioeng 2007 103 389 398 17609152 Informative review of the concept of an embryoid body.
  46. [51]Assady S Maor G Amit M Insulin production by human embryonic stem cells Diabetes 2001 50 1691 1697 11473026
  47. [52]Fukazawa T Matsuoka J Naomoto Y Development of a novel beta-cell specific promoter system for the identification of insulin-producing cells in in vitro cell cultures Exp Cell Res 2006 312 3404 3412 16934249
  48. [53]Leon-Quinto T Jones J Skoudy A Burcin M Soria B In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells Diabetologia 2004 47 1442 1451 15309294
  49. [54]Lavon N Yanuka O Benvenisty N The effect of overexpression of Pdx1 and Foxa2 on the differentiation of human embryonic stem cells into pancreatic cells Stem Cells 2006 24 1923 1930 16675598
  50. [55]Rajagopal J Anderson WJ Kume S Insulin staining of ES cell progeny from insulin uptake Science 2003 299 363 12532008
  51. [56]Phillips BW Hentze H Rust WL Directed differentiation of human embryonic stem cells into the pancreatic endocrine lineage Stem Cells Dev 2007 16 561 578 17784830 One of the recent hallmark articles outlining a successful protocol for differentiating human embryonic stem cells into insulin producing cells.
  52. [57]D'Amour KA Agulnick AD Eliazer S Efficient differentiation of human embryonic stem cells to definitive endoderm Nat Biotechnol 2005 23 1534 1541 16258519
  53. [58]McLean AB D'Amour KA Jones KL Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed Stem Cells 2007 25 29 38 17204604 The authors show that in addition to activin signaling, PI3K inhibition is necessary to specify definitive endoderm.
  54. [59]Pearsall RS Canalis E Cornwall-Brady M A soluble activin type IIA receptor induces bone formation and improves skeletal integrity Proc Natl Acad Sci U S A 2008 105 7082 7087 18460605 PMC2383948
  55. [60]Lavon N Narwani K Golan-Lev T Buehler N Hill D Benvenisty N Derivation of euploid human embryonic stem cells from aneuploid embryos Stem Cells 2008 26 1874 1882 18450823
  56. [61]Ferdaoussi M Abdelli S Yang JY Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway Diabetes 2008 57 1205 1215 18252896
  57. [62]Gedulin BR Nikoulina SE Smith PA Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight Endocrinology 2005 146 2069 2076 15618356
  58. [63]Jin CX Li WL Xu F Conversion of immortal liver progenitor cells into pancreatic endocrine progenitor cells by persistent expression of Pdx-1 J Cell Biochem 2008 104 224 236 17979180 Account of a protocol to convert LEPCs into insulin producing cells.
  59. [64]Hori Y Gu X Xie X Kim SK Differentiation of insulin-producing cells from human neural progenitor cells PLoS Med 2005 2 e103 15839736 PMC1087208
  60. [65]Liu M Han ZC Mesenchymal stem cells: Biology and clinical potential in Type 1 Diabetes Therapy J Cell Mol Med 2008 PMC3865657 18298656 Comprehensive review of the status of research efforts to convert mesenchymal stem cells into insulin producing cells.
  61. [66]Moriscot C de Fraipont F Richard MJ Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro Stem Cells 2005 23 594 603 15790780
  62. [67]Jiang Y Jahagirdar BN Reinhardt RL Pluripotency of mesenchymal stem cells derived from adult marrow Nature 2002 418 41 49 12077603
  63. [68]Ai C Todorov I Slovak ML Human marrow-derived mesodermal progenitor cells generate insulin-secreting islet-like clusters in vivo Stem Cells Dev 2007 16 757 770 17999597 The authors outline a protocol used to differentitate human mesodermal progenitor cells into insulin producing cells.
  64. [69]Mantel C Guo Y Lee MR Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability Blood 2007 109 4518 4527 17289813 PMC1885509
  65. [70]Chidgey AP Layton D Trounson A Boyd RL Tolerance strategies for stem-cell-based therapies Nature 2008 453 330 337 18480814
  66. [71]Dominguez-Bendala J Klein D Ribeiro M TAT-mediated neurogenin 3 protein transduction stimulates pancreatic endocrine differentiation in vitro Diabetes 2005 54 720 726 15734848
  67. [72]Denker HW Human embryonic stem cells: the real challenge for research as well as for bioethics is still ahead of us Cells Tissues Organs 2008 187 250 256 18268403 Discussion of some of the ethical concerns associated with stem cell research.

Cited by

Sorted by citations

Authors
Evans-Molina, C., Vestermark, G. L., & Mirmira, R. G.
Affiliations
Indiana University Indianapolis (US)
Corresponding author
Mirmira, Raghavendra G
Venue
Current Opinion in Organ Transplantation
Published
2009-02
Volume
14
Issue
1
Pages
56-63
ISSN
1087-2418 (ISSN-L)
OpenAlex
W2024357672
Cited by
18
References
4
Citations by year
2021: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 2 · 2012: 2
FWCI
0.53
Type
journal article
Language
en
Open access
Locations
  • Current Opinion in Organ Transplantation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK60581, K08DK080225, R01DK060581)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
insulin-producing cells, beta cell differentiation, human embryonic stem cells, glucose-stimulated insulin secretion, in vivo maturation, islet hormones, diabetes mellitus, beta cell replacement therapy, multipotent stem cells
MeSH terms
Adult, Animals, Cell Differentiation, Diabetes Mellitus, Type 1, Glucose, Humans, Insulin, Stem Cells, Islets of Langerhans Transplantation, Cell Culture Techniques, Stem Cell Transplantation, Multipotent Stem Cells, Pluripotent Stem Cells, Regenerative Medicine, Cell Proliferation, Insulin-Secreting Cells, Mice, Embryonic Stem Cells

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