Bending Gradients: How the Intestinal Stem Cell Gets Its Home

We address the mechanism by which adult intestinal stem cells (ISCs) become localized to the base of each villus during embryonic development. We find that, early in gut development, proliferating progenitors expressing ISC markers are evenly distributed throughout the epithelium, in both the chick and mouse. However, as the villi form, the putative stem cells become restricted to the base of the villi. This shift in the localization is driven by mechanically influenced reciprocal signaling between the epithelium and underlying mesenchyme. Buckling forces physically distort the shape of the morphogenic field, causing local maxima of epithelial signals, in particular Shh, at the tip of each villus. This induces a suite of high-threshold response genes in the underlying mesenchyme to form a signaling center called the "villus cluster." Villus cluster signals, notably Bmp4, feed back on the overlying epithelium to ultimately restrict the stem cells to the base of each villus.

[1]  P. Carlsson,et al.  Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production , 2006, Development.

[2]  J. Coulombre,et al.  Intestinal Development: I. Morphogenesis of the Villi and Musculature , 1958 .

[3]  C. Betsholtz,et al.  Abnormal gastrointestinal development in PDGF-A and PDGFR-(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. , 2000, Development.

[4]  K. E. Dixon,et al.  Cell specialization in the small intestinal epithelium of adult Xenopus laevis: functional aspects. , 1978, Journal of anatomy.

[5]  I. Thesleff,et al.  Epithelial-mesenchymal signalling regulating tooth morphogenesis , 2003, Journal of Cell Science.

[6]  L. Junqueira,et al.  Gross, microscopic and ultrastructural study of the intestinal tube of Xenodon merremii Wagler, 1824 (Ophidia). , 1976, Journal of anatomy.

[7]  Peer Bork,et al.  Luminal signalling links cell communication to tissue architecture during organogenesis , 2014, Nature.

[8]  Xi C. He,et al.  Bridging the BMP and Wnt Pathways by PI3 Kinase/Akt and 14-3-3? , 2005, Cell cycle.

[9]  C. Tabin,et al.  A Somitic Compartment of Tendon Progenitors , 2003, Cell.

[10]  S. Schnell,et al.  Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi , 2012, Proceedings of the National Academy of Sciences.

[11]  R. Sbarbati.  Morphogenesis of the intestinal villi of the mouse embryo: chance and spatial necessity. , 1982, Journal of anatomy.

[12]  J. Keller,et al.  Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon. , 2003, Gastroenterology.

[13]  Qing Nie,et al.  Do morphogen gradients arise by diffusion? , 2002, Developmental cell.

[14]  M. Kedinger,et al.  Early organogenesis of human small intestine: scanning electron microscopy and brush border enzymology. , 1984, Gut.

[15]  Utkarsh Ayachit,et al.  The ParaView Guide: A Parallel Visualization Application , 2015 .

[16]  D. K. Lorance,et al.  Distinct SOX9 levels differentially mark stem/progenitor populations and enteroendocrine cells of the small intestine epithelium. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[17]  A. Mccarthy.  Development , 1996, Current Opinion in Neurobiology.

[18]  K. Schughart,et al.  Hoxd-12 differentially affects preaxial and postaxial chondrogenic branches in the limb and regulates Sonic hedgehog in a positive feedback loop. , 1997, Development.

[19]  K. E. Dixon,et al.  Cell specialization in the small intestinal epithelium of adult Xenopus laevis: structural aspects. , 1978, Journal of anatomy.

[20]  D Brent Polk,et al.  Bmp signaling is required for intestinal growth and morphogenesis , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[21]  Scott A. Rifkin,et al.  Imaging individual mRNA molecules using multiple singly labeled probes , 2008, Nature Methods.

[22]  S. Yasugi,et al.  cFKBP/SMAP; a novel molecule involved in the regulation of smooth muscle differentiation. , 1998, Development.

[23]  J. Deng,et al.  Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine , 2011, Nature Genetics.

[24]  H. Clevers,et al.  Identification of stem cells in small intestine and colon by marker gene Lgr5 , 2007, Nature.

[25]  S. Shen,et al.  Ectopic expression of Hoxb-8 causes duplication of the ZPA in the forelimb and homeotic transformation of axial structures , 1994, Cell.

[26]  C. Tabin,et al.  Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud , 1994, Cell.

[27]  R. Shivdasani,et al.  Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells , 2012, Proceedings of the National Academy of Sciences.

[28]  W. A. Hilton.  The morphology and development of intestinal folds and Villi in vertibrates , 1902 .

[29]  C. Jackson,et al.  Effects of growth hormone on leucine absorption, intestinal morphology, and ultrastructure of the goldish intestine. , 2004, Canadian journal of physiology and pharmacology.

[30]  W. Krause.  Intestinal mucosa of the platypus, Ornithorhynchus anatinus , 1975, The Anatomical record.

[31]  S. Kotzé,et al.  Scanning electron microscopic study of intestinal mucosa of the Nile crocodile (Crocodylus niloticus) , 1995, Journal of morphology.

[32]  A. Oudenaarden,et al.  Validating transcripts with probes and imaging technology , 2011, Nature Methods.

[33]  T. Hattori,et al.  The expression and crucial roles of BMP signaling in development of smooth muscle progenitor cells in the mouse embryonic gut. , 2009, Differentiation; research in biological diversity.

[34]  F. Netter,et al.  Supplemental References , 2002, We Came Naked and Barefoot.

[35]  C. Tabin,et al.  Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut. , 1995, Development.

[36]  Hans Clevers,et al.  SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes , 2004, The Journal of cell biology.

[37]  W. Bangerth,et al.  deal.II—A general-purpose object-oriented finite element library , 2007, TOMS.

[38]  Ossama Tawfik,et al.  BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt–β-catenin signaling , 2004, Nature Genetics.

[39]  J. Spence,et al.  Vertebrate intestinal endoderm development , 2011, Developmental dynamics : an official publication of the American Association of Anatomists.

[40]  K. Wille,et al.  Über die frühfetale Entwicklung der Dünndarm‐Mukosa des Rindes (Bos primigenius taurus). , 1998 .

[41]  Krishanu Saha,et al.  Signal dynamics in Sonic hedgehog tissue patterning , 2006, Development.

[42]  Hans Clevers,et al.  De Novo Crypt Formation and Juvenile Polyposis on BMP Inhibition in Mouse Intestine , 2004, Science.

[43]  Julian Lewis,et al.  Organizing cell renewal in the intestine: stem cells, signals and combinatorial control , 2006, Nature Reviews Genetics.

[44]  A. Oudenaarden,et al.  Optimality in the Development of Intestinal Crypts , 2012, Cell.

[45]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[46]  D. Gumucio,et al.  Epithelial hedgehog signals pattern the intestinal crypt-villus axis , 2005, Development.

[47]  David L. Kaplan,et al.  Villification: How the Gut Gets Its Villi , 2013, Science.

[48]  I. Salazar-Ciudad.  Tooth patterning and evolution. , 2012, Current opinion in genetics & development.

[49]  C. Tickle,et al.  A positive feedback loop coordinates growth and patterning in the vertebrate limb , 1994, Nature.