CoChat
Sign Up
Cited by 144Pancreatic function and diabetesDevelopmental Biology and Gene RegulationPancreatic and Hepatic Oncology Research

Pancreatic Mesenchyme Regulates Epithelial Organogenesis throughout Development

Open access
Landsman, Limor, Nijagal, Amar, Whitchurch, Theresa J., VanderLaan, Renee L., Zimmer, Warren E., MacKenzie, Tippi C., Hebrok, Matthias·2011·PLoS Biology
DOI 10.1371/journal.pbio.1001143PMC PMC3167782
Open this paper in CoChat — free accountOpen PDF

Abstract

The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential signals from the overlying mesenchyme. Previous studies, focusing on ex vivo tissue explants or complete knockout mice, have identified an important role for the mesenchyme in regulating the expansion of progenitor cells in the early pancreas epithelium. However, due to the lack of genetic tools directing expression specifically to the mesenchyme, the potential roles of this supporting tissue in vivo, especially in guiding later stages of pancreas organogenesis, have not been elucidated. We employed transgenic tools and fetal surgical techniques to ablate mesenchyme via Cre-mediated mesenchymal expression of Diphtheria Toxin (DT) at the onset of pancreas formation, and at later developmental stages via in utero injection of DT into transgenic mice expressing the Diphtheria Toxin receptor (DTR) in this tissue. Our results demonstrate that mesenchymal cells regulate pancreatic growth and branching at both early and late developmental stages by supporting proliferation of precursors and differentiated cells, respectively. Interestingly, while cell differentiation was not affected, the expansion of both the endocrine and exocrine compartments was equally impaired. To further elucidate signals required for mesenchymal cell function, we eliminated β-catenin signaling and determined that it is a critical pathway in regulating mesenchyme survival and growth. Our study presents the first in vivo evidence that the embryonic mesenchyme provides critical signals to the epithelium throughout pancreas organogenesis. The findings are novel and relevant as they indicate a critical role for the mesenchyme during late expansion of endocrine and exocrine compartments. In addition, our results provide a molecular mechanism for mesenchymal expansion and survival by identifying β-catenin signaling as an essential mediator of this process. These results have implications for developing strategies to expand pancreas progenitors and β-cells for clinical transplantation.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pbio.1001143

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The pancreatic mesenchyme is essential for proper lineage formation.

    “Given the essential role of the pancreatic mesenchyme for proper lineage formation [49, 57], Tbx3 was also deleted in this compartment.”

    From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [49]

    The Results section, “Pancreatic Mesenchyme Is Required for Precursor Cell Proliferation” (page unavailable), reports that mesenchymal depletion reduced endocrine and exocrine cell masses, supporting a role in their expansion. But it also says every pancreatic epithelial lineage formed, and the Discussion reports no alteration in the main cell types’ differentiation capacity. The source therefore does not support an essential role in lineage formation if that means establishing or differentiating those lineages. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 56

  1. [1]Gittes G. K 2009 Developmental biology of the pancreas: a comprehensive review. Dev Biol 326 4 35 19013144
  2. [2]Puri S Hebrok M 2010 Cellular plasticity within the pancreas–lessons learned from development. Dev Cell 18 342 356 20230744 PMC4085547
  3. [3]Golosow N Grobstein C 1962 Epitheliomesenchymal interaction in pancreatic morphogenesis. Dev Biol 4 242 255 13899987
  4. [4]Puri S Hebrok M 2007 Dynamics of embryonic pancreas development using real-time imaging. Dev Biol 306 82 93 17448459 PMC1988845
  5. [5]Li Z Manna P Kobayashi H Spilde T Bhatia A 2004 Multifaceted pancreatic mesenchymal control of epithelial lineage selection. Dev Biol 269 252 263 15081371
  6. [6]Gittes G. K Galante P. E Hanahan D Rutter W. J Debase H. T 1996 Lineage-specific morphogenesis in the developing pancreas: role of mesenchymal factors. Development 122 439 447 8625795
  7. [7]Miralles F Czernichow P Scharfmann R 1998 Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. Development 125 1017 1024 9463348
  8. [8]Miralles F Serup P Cluzeaud F Vandewalle A Czernichow P 1999 Characterization of beta cells developed in vitro from rat embryonic pancreatic epithelium. Dev Dyn 214 116 126 10030591
  9. [9]Duvillie B Attali M Bounacer A Ravassard P Basmaciogullari A 2006 The mesenchyme controls the timing of pancreatic beta-cell differentiation. Diabetes 55 582 589 16505219
  10. [10]Tulachan S. S Doi R Hirai Y Kawaguchi Y Koizumi M 2006 Mesenchymal epimorphin is important for pancreatic duct morphogenesis. Dev Growth Differ 48 65 72 16512851
  11. [11]Attali M Stetsyuk V Basmaciogullari A Aiello V Zanta-Boussif M. A 2007 Control of beta-cell differentiation by the pancreatic mesenchyme. Diabetes 56 1248 1258 17322477
  12. [12]Ronzio R. A Rutter W. J 1973 Effects of a partially purified factor from chick embryos on macromolecular synthesis of embryonic pancreatic epithelia. Dev Biol 30 307 320 4350018
  13. [13]Levine S Pictet R Rutter W. J 1973 Control of cell proliferation and cytodifferentiation by a factor reacting with the cell surface. Nat New Biol 246 49 52 4519027
  14. [14]Bhushan A Itoh N Kato S Thiery J. P Czernichow P 2001 Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. Development 128 5109 5117 11748146
  15. [15]Jonckheere N Mayes E Shih H. P Li B Lioubinski O 2008 Analysis of mPygo2 mutant mice suggests a requirement for mesenchymal Wnt signaling in pancreatic growth and differentiation. Dev Biol 318 224 235 18452912 PMC2478757
  16. [16]Ahnfelt-Ronne J Ravassard P Pardanaud-Glavieux C Scharfmann R Serup P 2010 Mesenchymal bone morphogenetic protein signaling is required for normal pancreas development. Diabetes 59 1948 1956 20522595 PMC2911072
  17. [17]Stafford D White R. J Kinkel M. D Linville A Schilling T. F 2006 Retinoids signal directly to zebrafish endoderm to specify insulin-expressing beta-cells. Development 133 949 956 16452093
  18. [18]Tribioli C Frasch M Lufkin T 1997 Bapx1: an evolutionary conserved homologue of the Drosophila bagpipe homeobox gene is expressed in splanchnic mesoderm and the embryonic skeleton. Mech Dev 65 145 162 9256352
  19. [19]Schneider A Mijalski T Schlange T Dai W Overbeek P 1999 The homeobox gene NKX3.2 is a target of left-right signalling and is expressed on opposite sides in chick and mouse embryos. Curr Biol 9 911 914 10469600
  20. [20]Hecksher-Sorensen J Watson R. P Lettice L. A Serup P Eley L 2004 The splanchnic mesodermal plate directs spleen and pancreatic laterality, and is regulated by Bapx1/Nkx3.2. Development 131 4665 4675 15329346
  21. [21]Lettice L. A Purdie L. A Carlson G. J Kilanowski F Dorin J 1999 The mouse bagpipe gene controls development of axial skeleton, skull, and spleen. Proc Natl Acad Sci U S A 96 9695 9700 10449756 PMC22272
  22. [22]Tribioli C Lufkin T 1999 The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen. Development 126 5699 5711 10572046
  23. [23]Asayesh A Sharpe J Watson R. P Hecksher-Sorensen J Hastie N. D 2006 Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1-/- mice. Genes Dev 20 2208 2213 16912273 PMC1553204
  24. [24]Verzi M. P Stanfel M. N Moses K. A Kim B. M Zhang Y 2009 Role of the homeodomain transcription factor Bapx1 in mouse distal stomach development. Gastroenterology 136 1701 1710 19208343 PMC2955323
  25. [25]Takamoto N You L. R Moses K Chiang C Zimmer W. E 2005 COUP-TFII is essential for radial and anteroposterior patterning of the stomach. Development 132 2179 2189 15829524
  26. [26]Offield M. F Jetton T. L Labosky P. A Ray M Stein R. W 1996 PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122 983 995 8631275
  27. [27]Hart A Papadopoulou S Edlund H 2003 Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells. Dev Dyn 228 185 193 14517990
  28. [28]Norgaard G. A Jensen J. N Jensen J 2003 FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development. Dev Biol 264 323 338 14651921
  29. [29]Ivanova A Signore M Caro N Greene N. D Copp A. J 2005 In vivo genetic ablation by Cre-mediated expression of diphtheria toxin fragment A. Genesis 43 129 135 16267821 PMC2233880
  30. [30]Wilson M. E Scheel D German M. S 2003 Gene expression cascades in pancreatic development. Mech Dev 120 65 80 12490297
  31. [31]Pappenheimer A. M Jr Harper A. A Moynihan M Brockes J. P 1982 Diphtheria toxin and related proteins: effect of route of injection on toxicity and the determination of cytotoxicity for various cultured cells. J Infect Dis 145 94 102 6798133
  32. [32]Naglich J. G Metherall J. E Russell D. W Eidels L 1992 Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell 69 1051 1061 1606612
  33. [33]Jung S Unutmaz D Wong P Sano G De los Santos K 2002 In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity 17 211 220 12196292 PMC3689299
  34. [34]Buch T Heppner F. L Tertilt C Heinen T. J Kremer M 2005 A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat Methods 2 419 426 15908920
  35. [35]Nijagal A Le T Wegorzewska M Mackenzie T. C 2011 A mouse model of in utero transplantation. J Vis Exp PMC3182662 21307829
  36. [36]Nijagal A Wegorzewska M Jarvis E Le T Tang Q 2011 Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice. J Clin Invest 121 582 592 21245575 PMC3026737
  37. [37]Villasenor A Chong D. C Henkemeyer M Cleaver O 2010 Epithelial dynamics of pancreatic branching morphogenesis. Development 137 4295 4305 21098570 PMC2990215
  38. [38]Lammert E Cleaver O Melton D 2001 Induction of pancreatic differentiation by signals from blood vessels. Science 294 564 567 11577200
  39. [39]Brissova M Shostak A Shiota M Wiebe P. O Poffenberger G 2006 Pancreatic islet production of vascular endothelial growth factor–a is essential for islet vascularization, revascularization, and function. Diabetes 55 2974 2985 17065333
  40. [40]Nekrep N Wang J Miyatsuka T German M. S 2008 Signals from the neural crest regulate beta-cell mass in the pancreas. Development 135 2151 2160 18506029
  41. [41]Plank J. L Mundell N. A Frist A. Y LeGrone A. W Kim T 2011 Influence and timing of arrival of murine neural crest on pancreatic beta cell development and maturation. Dev Biol 349 321 330 21081123 PMC3019241
  42. [42]Matsuoka T. A Zhao L Artner I Jarrett H. W Friedman D 2003 Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol Cell Biol 23 6049 6062 12917329 PMC180917
  43. [43]Gu G Dubauskaite J Melton D. A 2002 Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129 2447 2457 11973276
  44. [44]Zhou Q Law A. C Rajagopal J Anderson W. J Gray P. A 2007 A multipotent progenitor domain guides pancreatic organogenesis. Dev Cell 13 103 114 17609113
  45. [45]Stanger B. Z Tanaka A. J Melton D. A 2007 Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 445 886 891 17259975
  46. [46]Lynn F. C Smith S. B Wilson M. E Yang K. Y Nekrep N 2007 Sox9 coordinates a transcriptional network in pancreatic progenitor cells. Proc Natl Acad Sci U S A 104 10500 10505 17563382 PMC1965542
  47. [47]Seymour P. A Freude K. K Tran M. N Mayes E. E Jensen J 2007 SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci U S A 104 1865 1870 17267606 PMC1794281
  48. [48]Kopp J. L Dubois C. L Schaffer A. E Hao E Shih H. P 2011 Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138 653 665 21266405 PMC3026412
  49. [50]Heller R. S Dichmann D. S Jensen J Miller C Wong G 2002 Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic mice suggesting a role for Wnts in pancreas and foregut pattern formation. Dev Dyn 225 260 270 12412008
  50. [51]Murtaugh L. C Law A. C Dor Y Melton D. A 2005 Beta-catenin is essential for pancreatic acinar but not islet development. Development 132 4663 4674 16192304
  51. [52]Rulifson I. C Karnik S. K Heiser P. W ten Berge D Chen H 2007 Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci U S A 104 6247 6252 17404238 PMC1847455
  52. [53]Heiser P. W Lau J Taketo M. M Herrera P. L Hebrok M 2006 Stabilization of beta-catenin impacts pancreas growth. Development 133 2023 2032 16611688
  53. [54]Apelqvist A Ahlgren U Edlund H 1997 Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr Biol 7 801 804 9368764
  54. [55]Kawahira H Scheel D. W Smith S. B German M. S Hebrok M 2005 Hedgehog signaling regulates expansion of pancreatic epithelial cells. Dev Biol 280 111 121 15766752
  55. [56]Guo T Hebrok M 2009 Stem cells to pancreatic beta-cells: new sources for diabetes cell therapy. Endocr Rev 30 214 227 19389995 PMC2726841
  56. [57]Ahnfelt-Rønne J Jørgensen M. C Hald J Madsen O. D Serup P 2007 An improved method for three-dimensional reconstruction of protein expression patterns in intact mouse and chicken embryos and organs. J Histochem Cytochem 55 925 930 17478445

Cited by

Sorted by citations

Authors
Landsman, L., Nijagal, A., Whitchurch, T. J., VanderLaan, R. L., Zimmer, W. E., MacKenzie, T. C., & Hebrok, M.
Affiliations
  • University of California, San Francisco (US)
  • Texas A&M Health Science Center (US)
Corresponding author
Hebrok, Matthias
ORCID
Venue
PLoS Biology
Publisher
Public Library of Science (PLoS)
Published
2011-09-06
Volume
9
Issue
9
Pages
e1001143
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.1001143
PMC
PMC3167782
OpenAlex
W2133154776
Cited by
144
References
1
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 8 · 2021: 12 · 2020: 7 · 2019: 8 · 2018: 13 · 2017: 8 · 2016: 15 · 2015: 10 · 2014: 11 · 2013: 11 · 2012: 11
FWCI
11.14
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
  • OakTrust (Texas A&M University Libraries) (submittedVersion)
Funders
  • American Diabetes Association
  • National Institutes of Health
  • University of California, San Francisco
  • National Institute of Allergy and Infectious Diseases (K08AI085042)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK-63720, DK60533, P30DK063720, R01DK060533)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Keywords
pancreatic development, epithelial-mesenchymal interactions, diphtheria toxin ablation, β-catenin signaling, endocrine differentiation, beta-cell expansion, pancreas transplantation
MeSH terms
Animals, Diphtheria Toxin, Embryo, Mammalian, Epithelium, Mesoderm, Pancreas, Mice, Knockout, Gene Expression Regulation, Developmental, Organogenesis, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review