Lgr5+ telocytes Are a Signaling Source at the Intestinal Villus Tip

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Apr 24

PMID 32321913

Citations 76

Authors

Keren Bahar Halpern

Hassan Massalha

Rachel K Zwick

Andreas E Moor

David Castillo-Azofeifa

Milena Rozenberg

Lydia Farack

Adi Egozi

Dan R Miller

Inna Averbukh

Yotam Harnik

Noa Weinberg-Corem

Frederic J de Sauvage

Ido Amit

Ophir D Klein

Michal Shoshkes-Carmel

Shalev Itzkovitz

Affiliations

Soon will be listed here.

Abstract

The intestinal epithelium is a structured organ composed of crypts harboring Lgr5+ stem cells, and villi harboring differentiated cells. Spatial transcriptomics have demonstrated profound zonation of epithelial gene expression along the villus axis, but the mechanisms shaping this spatial variability are unknown. Here, we combine laser capture micro-dissection and single cell RNA sequencing to uncover spatially zonated populations of mesenchymal cells along the crypt-villus axis. These include villus tip telocytes (VTTs) that express Lgr5, a gene previously considered a specific crypt epithelial stem cell marker. VTTs are elongated cells that line the villus tip epithelium and signal through Bmp morphogens and the non-canonical Wnt5a ligand. Their ablation is associated with perturbed zonation of enterocyte genes induced at the villus tip. Our study provides a spatially-resolved cell atlas of the small intestinal stroma and exposes Lgr5+ villus tip telocytes as regulators of the epithelial spatial expression programs along the villus axis.

Citing Articles

Telocytes in inflammatory bowel diseases: contributions to pathology and therapeutic potentials.

Panganiban R, McAninch C, Chulkina M, Pinchuk I Front Cell Dev Biol. 2025; 12:1452258.

PMID: 39872845 PMC: 11770051. DOI: 10.3389/fcell.2024.1452258.

Wall of Resilience: How the Intestinal Epithelium Prevents Inflammatory Onslaught in the Gut.

Liebing E, Krug S, Neurath M, Siegmund B, Becker C Cell Mol Gastroenterol Hepatol. 2024; 19(2):101423.

PMID: 39461590 PMC: 11720114. DOI: 10.1016/j.jcmgh.2024.101423.

Developmental characteristics of cutaneous telocytes in late embryos of the silky fowl.

Li H, Chen J, You W, Xu Y, Ye Y, Zhao H Eur J Histochem. 2024; 68(4).

PMID: 39410819 PMC: 11532996. DOI: 10.4081/ejh.2024.4089.

Dietary and metabolic effects on intestinal stem cells in health and disease.

Shay J, Yilmaz O Nat Rev Gastroenterol Hepatol. 2024; 22(1):23-38.

PMID: 39358589 DOI: 10.1038/s41575-024-00980-7.

Regulation of intestinal epithelial homeostasis by mesenchymal cells.

Kayama H, Takeda K Inflamm Regen. 2024; 44(1):42.

PMID: 39327633 PMC: 11426228. DOI: 10.1186/s41232-024-00355-0.

References

van der Flier L, Clevers H . Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol. 2008; 71:241-60. DOI: 10.1146/annurev.physiol.010908.163145. View

Barker N, van Es J, Kuipers J, Kujala P, van den Born M, Cozijnsen M . Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007; 449(7165):1003-7. DOI: 10.1038/nature06196. View

Potten C . Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos Trans R Soc Lond B Biol Sci. 1998; 353(1370):821-30. PMC: 1692280. DOI: 10.1098/rstb.1998.0246. View

Beumer J, Artegiani B, Post Y, Reimann F, Gribble F, Nguyen T . Enteroendocrine cells switch hormone expression along the crypt-to-villus BMP signalling gradient. Nat Cell Biol. 2018; 20(8):909-916. PMC: 6276989. DOI: 10.1038/s41556-018-0143-y. View

Gehart H, van Es J, Hamer K, Beumer J, Kretzschmar K, Dekkers J . Identification of Enteroendocrine Regulators by Real-Time Single-Cell Differentiation Mapping. Cell. 2019; 176(5):1158-1173.e16. DOI: 10.1016/j.cell.2018.12.029. View

Roulis M, Flavell R . Fibroblasts and myofibroblasts of the intestinal lamina propria in physiology and disease. Differentiation. 2016; 92(3):116-131. DOI: 10.1016/j.diff.2016.05.002. View

Degirmenci B, Valenta T, Dimitrieva S, Hausmann G, Basler K . GLI1-expressing mesenchymal cells form the essential Wnt-secreting niche for colon stem cells. Nature. 2018; 558(7710):449-453. DOI: 10.1038/s41586-018-0190-3. View

Shoshkes-Carmel M, Wang Y, Wangensteen K, Toth B, Kondo A, Massasa E . Subepithelial telocytes are an important source of Wnts that supports intestinal crypts. Nature. 2018; 557(7704):242-246. PMC: 5966331. DOI: 10.1038/s41586-018-0084-4. View

Kinchen J, Chen H, Parikh K, Antanaviciute A, Jagielowicz M, Fawkner-Corbett D . Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease. Cell. 2018; 175(2):372-386.e17. PMC: 6176871. DOI: 10.1016/j.cell.2018.08.067. View

10.

Aoki R, Shoshkes-Carmel M, Gao N, Shin S, May C, Golson M . Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell Mol Gastroenterol Hepatol. 2016; 2(2):175-188. PMC: 4772878. DOI: 10.1016/j.jcmgh.2015.12.004. View

11.

Ramilowski J, Goldberg T, Harshbarger J, Kloppmann E, Kloppman E, Lizio M . A draft network of ligand-receptor-mediated multicellular signalling in human. Nat Commun. 2015; 6:7866. PMC: 4525178. DOI: 10.1038/ncomms8866. View

12.

Vento-Tormo R, Efremova M, Botting R, Turco M, Vento-Tormo M, Meyer K . Single-cell reconstruction of the early maternal-fetal interface in humans. Nature. 2018; 563(7731):347-353. PMC: 7612850. DOI: 10.1038/s41586-018-0698-6. View

13.

Itzkovitz S, Lyubimova A, Blat I, Maynard M, van Es J, Lees J . Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat Cell Biol. 2011; 14(1):106-14. PMC: 3292866. DOI: 10.1038/ncb2384. View

14.

He X, Zhang J, Tong W, Tawfik O, Ross J, Scoville D . BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet. 2004; 36(10):1117-21. DOI: 10.1038/ng1430. View

15.

Naba A, Clauser K, Ding H, Whittaker C, Carr S, Hynes R . The extracellular matrix: Tools and insights for the "omics" era. Matrix Biol. 2015; 49:10-24. PMC: 5013529. DOI: 10.1016/j.matbio.2015.06.003. View

16.

Simon-Assmann P, Spenle C, Lefebvre O, Kedinger M . The role of the basement membrane as a modulator of intestinal epithelial-mesenchymal interactions. Prog Mol Biol Transl Sci. 2010; 96:175-206. DOI: 10.1016/B978-0-12-381280-3.00008-7. View

17.

Karlsson L, Lindahl P, Heath J, Betsholtz C . Abnormal gastrointestinal development in PDGF-A and PDGFR-(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. Development. 2000; 127(16):3457-66. DOI: 10.1242/dev.127.16.3457. View

18.

Cretoiu D, Cretoiu S, Simionescu A, Popescu L . Telocytes, a distinct type of cell among the stromal cells present in the lamina propria of jejunum. Histol Histopathol. 2012; 27(8):1067-78. DOI: 10.14670/HH-27.1067. View

19.

Greicius G, Kabiri Z, Sigmundsson K, Liang C, Bunte R, Singh M . pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo. Proc Natl Acad Sci U S A. 2018; 115(14):E3173-E3181. PMC: 5889626. DOI: 10.1073/pnas.1713510115. View

20.

Stzepourginski I, Nigro G, Jacob J, Dulauroy S, Sansonetti P, Eberl G . CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury. Proc Natl Acad Sci U S A. 2017; 114(4):E506-E513. PMC: 5278455. DOI: 10.1073/pnas.1620059114. View