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WIREs Dev Biol
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Blueprint for an intestinal villus: Species‐specific assembly required

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Efficient absorption of nutrients by the intestine is essential for life. In mammals and birds, convolution of the intestinal surface into finger‐like projections called villi is an important adaptation that ensures the massive surface area for nutrient contact that is required to meet metabolic demands. Each villus projection serves as a functional absorptive unit: it is covered by a simple columnar epithelium that is derived from endoderm and contains a mesodermally derived core with supporting vasculature, lacteals, enteric nerves, smooth muscle, fibroblasts, myofibroblasts, and immune cells. In cross section, the consistency of structure in the billions of individual villi of the adult intestine is strikingly beautiful. Villi are generated in fetal life, and work over several decades has revealed that villus morphogenesis requires substantial “crosstalk” between the endodermal and mesodermal tissue components, with soluble signals, cell–cell contacts, and mechanical forces providing specific dialects for sequential conversations that orchestrate villus assembly. A key part of this process is the formation of subepithelial mesenchymal cell clusters that act as signaling hubs, directing overlying epithelial cells to cease proliferation, thereby driving villus emergence and simultaneously determining the location of future stem cell compartments. Interestingly, distinct species‐specific differences govern how and when tissue‐shaping signals and forces generate mesenchymal clusters and control villus emergence. As the details of villus development become increasingly clear, the emerging picture highlights a sophisticated local self‐assembled cascade that underlies the reproducible elaboration of a regularly patterned field of absorptive villus units.

This article is categorized under:

  • Vertebrate Organogenesis > From a Tubular Primordium: Non‐Branched
  • Comparative Development and Evolution > Organ System Comparisons Between Species
  • Early Embryonic Development > Development to the Basic Body Plan
Progressive bending of the chick epithelium into ridges and then zigzags is driven by sequential differentiation of smooth muscle layers. Prior to muscle formation (E6) the epithelium is flat. Ridges are formed following the differentiation of the inner circular muscle marked by anti‐α‐smooth muscle actin (green; E8–12). Zigzags evolve with the formation of the outer longitudinal muscle (E13–15). Villus emergence is concomitant with the formation of the muscular mucosa at E16. Scalebars are 100 μm. Arrowheads denote the new muscle layer formed at that stage (From Shyer et al. (2013). Villification: How the Gut Gets Its Villi. Science 342(6155): 212‐218. Reprinted with permission from AAAS. https://doi.org/10.1126/science.1238842)
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Mesenchymal clusters participate in epithelial/mesenchymal crosstalk. (a)–(d) In situ hybridization analysis of the Pdgf signaling pathway, as demonstrated by Karlsson et al. (). Pdgfa ligand transcripts are seen throughout the pre‐villus pseudostratified epithelium and cells in the muscle layer (a) and are later concentrated in intervillus epithelium (c, arrows). The receptor, Pdgfra is highly expressed in the subepithelial mesenchyme in the pre‐villus intestine (b) and later robustly expressed in mesenchymal clusters in the tips of emerged villi as well as in nascent forming clusters (d, arrows). Abbreviations are: pep, pseudostratified epithelium; sm, submucosal mesenchyme; ml, muscle layer; ep, epithelium. (e)–(l) Mesenchymal clusters are signaling centers that express transcripts corresponding to multiple soluble signaling proteins, including Bmp2 (e), Bmp4 (f), Twsg1 (g), Bmp1 (h), Wnt5a (i), Fgf9 (j), Hgf (k), and Nog (l) (Panels a‐d are reproduced with permission from Karlsson et al. (2000). Abnormal gastrointestinal development in PDGF‐A and PDGFR‐(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. Development 127 (16): 3457‐3466. Copyright Company of Biologists. http://dev.biologists.org/content/127/16/3457.article‐info; Panels e‐l are reprinted with permission from Walton, Whidden, et al. (2016). Villification in the mouse: Bmp signals control intestinal villus patterning. Development 143: 427‐436. Copyright Company of Biologists)
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Evolutionary relationships among species and the appearance of the intestinal mucosa in those species. The appearance of villi may have arisen independently three times during evolutionary time, but the survey needs broadening to clarify this issue
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Schematic representation of the steps involved in villus emergence in the mouse. Cluster patterning is via a Turing‐like field, driven by BMP signals. Clusters change overlying epithelial cell shape, resulting in regions of high intraepithelial pressure; cell division in these regions aid in apical invagination, demarcating villus boundaries. Blue = epithelium; Pink = mesenchymal clusters. In the lower panel, blue cells are proliferative; white cells are withdrawing from the cell cycle
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Schematic representation of the steps involved in villus emergence in the chick. Muscular development plays a major role in patterning villi in that species by deforming epithelium so as to cause pockets of high HH ligand concentration and cluster gene induction. Blue = epithelium; Pink = underlying mesenchyme; Dark red = muscle groups
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Epithelial/mesenchymal crosstalk via the Hedgehog (HH) pathway in chick and mouse. (a)–(c) In situ hybridization of transcripts for Shh (a), Ihh (b), and Ptch1 (c) in the mouse pre‐villus epithelium. HH transcripts are confined to the epithelium while the receptor is seen in surrounding mesenchyme and concentrated in the subepithelial region. (d)–(i) Eosin and X‐Gal staining of intestinal sections from Ptch1 LacZ/+ (d)–(f) or Gli1 LacZ/+ (g)–(i) animals at E14 (d), (g), E14.5 (e), (h), and E15.5 (f), (i). Red arrows indicate clustered mesenchymal cells that are receiving HH signals. (j)–(r) In situ hybridization for Shh, Ptch1, Bmp4, and Pdgfra in the developing chick intestine. The three columns represent early fold stage (j), (m), (p), (s), zigzag stage (k), (n), (q), (t), and early villus (l), (o), (r), (u) (Panels a‐c are reprinted with permission from Kolterud et al. (2009). Paracrine Hedgehog Signaling in Stomach and Intestine: New Roles for Hedgehog in Gastrointestinal Patterning. Gastroenterology 137(2): 618‐628. Copyright Elsevier. https://doi.org/10.1053/j.gastro.2009.05.002; (Panels d‐i are reprinted with permission from Walton et al. (2012). Hedgehog‐responsive mesenchymal clusters direct patterning and emergence of intestinal villi. PNAS 109(39): 15817‐15822. Copyright National Academy of Sciences. https://doi.org/10.1073/pnas.1205669109; Panels j‐u are reprinted from Shyer et al. (2015). Bending Gradients: How the Intestinal Stem Cell Gets Its Home. Cell 161(3): 569‐580, with permission from Elsevier, https://doi.org/10.1016/j.cell.2015.03.041)
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Changes in epithelial proliferation accompany villus morphogenesis in chick and mouse. (a) and (b) Depict ridge (E12) and late zigzag/early villus (E15) stages in chick. EdU staining (pink) marks proliferative cells, which are seen throughout the epithelium at the ridge stage (a) and confined to the base of emerging villi at later stages (b), (c) and (d) Illustrate robust proliferation, as marked by BrdU staining (green), throughout the pre‐villus mouse pseudostratified epithelium (c, E13.5) and restriction of proliferative activity from the tips of emerging villi at E16 (d). Anti‐Ecadherin (ECAD) staining (red) outlines epithelial cells in (c) and (d). DAPI staining marks the nuclei (blue) (Panels a and b are from Shyer et al. (2013). Villification: How the Gut Gets Its Villi. Science 342(6155): 212‐218. Reprinted with permission from AAAS. https://doi.org/10.1126/science.1238842)
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“Invasion” of the pseudostratified epithelium by mesenchyme (arrows) is an early feature of villus morphogenesis in mammals. Arrowheads indicate invading mesenchymal clusters in developing intestines from (a) mouse at E15 (Walton, unpublished), (b) rat at E18, (c) human at stage 21, (d) pig at 35 dpf, (e) sheep at 39 dpf, and (f) cow at 30 dpf (Panel b is reprinted with permission from Dunn (1967). The fine structure of the absorptive epithelial cells of the developing small intestine of the rat. Journal of Anatomy 101(1): 57‐58. Copyright John Wiley and Sons. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1270858/; Panel c is reproduced with permission from Matsumoto (2002). Occlusion and subsequent re‐canalization in early duodenual development of human embryos: integrated organogenesis and histogenesis through a possible epithelial‐mesenchymal interaction. Anatomy and Embryology 205: 53‐65. Copyright Springer. https://doi.org/10.1007/s00429‐001‐0226‐5); Panel d is reproduced with permission from Dekaney (1997). Mucosal morphogenesis and cytodifferentiation in fetal porcine small intestine. The Anatomical Record 249: 517‐523. Copyright John Wiley and Sons. http://dx.doi.org/10.1002/(SICI)1097‐0185(199712)249:4<517::AID‐AR12>3.0.CO;2‐R; Panel e is reproduced with permission from Toofanian (1976). Histological development of the small intestinal mucosa in the ovine fetus. Research in Veterinary Science 21: 349‐353. Copyright Elsevier. PMID: 1030821; Panel f is reprinted with permission from Toofanian (1976). Histological observations on the developing intestine of the bovine fetus. Research in Veterinary Science 21: 36‐40. Copyright Elsevier. PMID: 951526)
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Cell shape during villus morphogenesis in the mouse. (a) and (b) Epithelium (Ecadherin [ECAD], green) thickens from 15 μm at E12.5 to 50 μm at E14.5. (c) Epithelial cells on the growing villi shorten and widen to become columnar. (d) The pre‐villus epithelium is pseudostratified, with cells touching both the apical and basal surfaces. Cells were sparsely labeled with myristylated EGFP to outline cell shapes. (e) Scanning electron micrograph of an E13.5 intestine shows epithelial cells touching the apical and basal surfaces. (f) and (g) Schematic representations of stratified and pseudostratified layers. Sparse cells labeled green illustrates expected cell shapes in each type of epithelium. Continuous green indicates apical surface. Note that mitotic cells are basal in the stratified epithelium and apical in the pseudostratified epithelium. (h) Nuclei of cells undergoing inter kinetic nuclear migration move between the apical (green) and basal (grey) surface in accord with the cell cycle. (i) Active apical invagination acts to demarcate villi. Apical (inner) and basal [outer adjacent to mesenchyme] surfaces are marked by anti‐aPKC and anticollagen IV (COL IV), respectively (red) and dividing cells are marked with anti‐pHH3 (green). (j)–(k) Constriction of the T invagination around an apically rounded cell (green in (k), marked by anti‐pHH3) is shown with phalloidin staining (white and red). Symbol asterisk (*) in (j) and (k) indicates the F‐actin rich tether extending from the cell body to the basal surface. Scalebars in (a)–(d), (j), and (K) are 20 μm (Panels a‐e are reproduced with permission from Grosse et al. (2011). Cell dynamics in fetal intestinal epithelium: implications for intestinal growth and morphogenesis. Development 138: 4423‐4432. Copyright the Company of Biologists. doi:10.1242/dev.065789; Panels f‐h are reprinted with permission from Walton et al. (2016). Generation of intestinal surface: an absorbing tale. Development 143: 2261‐2272. Copyright Company of Biologists. doi:10.1242/dev.135400; Panels i‐k are reproduced from Freddo et al. (2016). Coordination of signaling and tissue mechanics during morphogenesis of murine intestinal villi: a role for mitotic cell rounding. Integrative Biology 8(9): 918‐928 with permission of Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC. DOI: 10.1039/c6ib00046k)
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Surface views of the intestinal mucosa during development. (a)–(c) Chick at E11, E16, and E18, showing progressive formation of ridges, zigzags, and villi. DR and IR in (a) denote two different rounds of ridge formation. The arrows in (b) mark areas along the zigzags that are beginning to bulge where villi will emerge. I and II in (c) denote villi emerging atop alternating zigzags. (d)–(f) Mouse intestinal surface at E14, E14.5, and E15.5, demonstrating the flat epithelial surface prior to villus formation. Symbol ^ in (d) indicates mitotically rounded cells along the flat apical surface. Apical invaginations begin to demarcate villi (arrows in (e)), which emerge as domes from the flat epithelium. Domes of newly emerged villi in the rat (g) and human (h) (Panels a‐c are reprinted with permission from Grey (1972). Morphogenesis of intestinal villi. I. Scanning electron microscopy of the duodenal epithelium of the developing chick embryo. Journal of Morphology 137:193‐214. Copyright John Wiley and Sons. DOI: 10.1002/jmor.1051370206; Panels d‐e are reproduced from Freddo et al. (2016). Coordination of signaling and tissue mechanics during morphogenesis of murine intestinal villi: a role for mitotic cell rounding. Integrative Biology 8(9): 918‐928 with permission of Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC. DOI: 10.1039/c6ib00046k; Panel g is reproduced with permission from Nakamura and Komuro (1983). A Three‐Dimensional Study of the Embryonic Development and Postnatal Maturation of Rat Duodenal Villi. Microscopy 32(4): 338‐347. Copyright Oxford University Press. https://doi.org/10.1093/oxfordjournals.jmicro.a050423; Panel h is reproduced with permission from LaCroix et al. (1984). Early organogenesis of human small intestine: scanning electron microscopy and brush border enzymology. Gut 25(9): 925‐930. Copyright BMJ. http://dx.doi.org/10.1136/gut.25.9.925)
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Comparative Development and Evolution > Organ System Comparisons Between Species
Vertebrate Organogenesis > From a Tubular Primordium: Non-Branched
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