http://api.elsevier.com/content/article/pii/S2352345X16000138doi:10.1016/j.jcmgh.2016.01.0041-s2.0-S2352345X1600013810.1016/j.jcmgh.2016.01.004S2352-345X(16)00013-8Home Sweet Home: a Foxl1+ Mesenchymal Niche for Intestinal Stem Cells CMGH Cellular and Molecular Gastroenterology and HepatologyJournalEditorial2352345X22116117116-1172application/pdf2016-03-31March 2016Copyright © 2016 The Authors. Published by Elsevier Inc.The Authors. Published by Elsevier Inc.Mah, Amanda T.Kuo, Calvin J.1trueFullfalseElsevierWaivedhttp://creativecommons.org/licenses/by-nc-nd/4.0/849757575012-s2.0-84975757501serialJL3122042912102917422918482919023190CMGH Cellular and Molecular Gastroenterology and HepatologyCMGHCELLULARMOLECULARGASTROENTEROLOGYHEPATOLOGY2016-01-252016-01-252016-02-232016-02-232016-03-29T13:01:471-s2.0-S2352345X16000138S2352-345X(16)00013-8S2352345X1600013810.1016/j.jcmgh.2016.01.004S300S300.3FULL-TEXT1-s2.0-S2352345X16X000212016-03-29T08:40:19.171158-04:0000201603012016033120162016-01-25T21:51:27.762782Zarticleinfo articletitlenorm authfirstinitialnorm authfirstsurnamenorm cid cids contenttype copyright crossmark dateloaded dateloadedtxt datesearch datesort dateupdated dco docsubtype doctype doi eid ewtransactionid hubeid indexeddate issfirst issn issnnorm issuelist itemstage itemtransactionid itemweight oauserlicense openaccess openarchive pg pgfirst pglast pii piinorm pubdateend pubdatestart pubdatetxt pubyr sectiontitle sortorder sponsoredaccesstype srctitle srctitlenorm srctype ssids alllist content oa subj subheadings tomb volfirst volissue volumelist webpdf webpdfpagecount yearnav body affil articletitle auth authfirstini authfull authlast pubtype ref2352-345X2352345XUNLIMITEDtrue2222Volume 2, Issue 29116117116117201603March 20162016-03-012016-03-312016Editorialssimple-articleediCopyright © 2016 The Authors. Published by Elsevier Inc.HOMESWEETHOMEAFOXL1MESENCHYMALNICHEFORINTESTINALSTEMCELLSMAHA10.1016/j.jcmgh.2015.12.004S2352345X15001988ReferencesCLEVERS2013274284HTAN201477107DYEN2006203212TNOAH2013263288TKORINEK1998379383VKUHNERT2004266271FPINTO200317091713DSATO2009262265TOOTANI2009701706ASTORM201697100EYAN2012466471KKABIRI201422062215ZSATO2011415418TDURAND201289658970AKIM201239323937TSANROMAN2014127134AAOKI2016175188RMAHX2016X116MAHX2016X116X117MAHX2016X116XAMAHX2016X116X117XAFull2016-01-12T04:29:06ZElsevierWaivedhttp://creativecommons.org/licenses/by-nc-nd/4.0/itemS2352-345X(16)00013-8S2352345X160001381-s2.0-S2352345X1600013810.1016/j.jcmgh.2016.01.0043122042016-03-29T08:40:19.171158-04:002016-03-012016-03-31UNLIMITED1-s2.0-S2352345X16000138-main.pdfhttps://s3-eu-west-1.amazonaws.com/prod-ucs-content-store-eu-west/content/pii:S2352345X16000138/MAIN/application/pdf/da08151f43a3595ee448b309106278fa/main.pdfhttps://s3.amazonaws.com/prod-ucs-content-store-us-east/content/pii:S2352345X16000138/MAIN/application/pdf/da08151f43a3595ee448b309106278fa/main.pdfmain.pdfpdftrue211197MAIN21-s2.0-S2352345X16000138-main_1.pnghttps://s3-eu-west-1.amazonaws.com/prod-ucs-content-store-eu-west/content/pii:S2352345X16000138/PREVIEW/image/png/62ec9833dfef2b83782731be3b69c153/main_1.pnghttps://s3.amazonaws.com/prod-ucs-content-store-us-east/content/pii:S2352345X16000138/PREVIEW/image/png/62ec9833dfef2b83782731be3b69c153/main_1.pngmain_1.pngpng79077849656IMAGE-WEB-PDF1JCMGH108S2352-345X(16)00013-810.1016/j.jcmgh.2016.01.004S2352-345X(15)00198-810.1016/j.jcmgh.2015.12.004The AuthorsConflicts of interest The authors disclose no conflicts.Funding Supported by National Institute of Diabetes and Digestive and Kidney Diseases Intestinal Stem Cell Consortium (2U01DK085527-06 to C.J.K.).EditorialHome Sweet Home: a Foxl1+ Mesenchymal Niche for Intestinal Stem CellsAmanda T.MahPhD, MPHCalvin J.KuoMD, PhD∗cjkuo@stanford.eduDepartment of Medicine, Hematology Division, Stanford University, Stanford, CaliforniaDepartment of MedicineHematology DivisionStanford UniversityStanfordCalifornia∗Correspondence Address correspondence to: Calvin J. Kuo, MD, PhD, Department of Medicine, Hematology Division, Stanford University, Lokey Stem Cell G2034A, 265 Campus Drive, Stanford, California 94305.Department of MedicineHematology DivisionStanford UniversityLokey Stem Cell G2034A265 Campus DriveStanfordCalifornia 94305The intestinal epithelium undergoes rapid and constant renewal accomplished by intestinal stem cells (ISCs) every 3–5 days. ISCs divide and give rise to highly proliferative transit-amplifying progenitor cells that differentiate into the multiple differentiated cell types present in the crypt and villus.1 ISCs reside in a microenvironment surrounded by epithelial and underlying mesenchymal cells within the lamina propria populated by multiple cell types. Over the past decade, considerable advances have shown that the ISC niche is composed of molecular mediators that act in a paracrine or autocrine manner to maintain proper ISC behavior marked by self-renewal and multipotency.2 Within this niche, it is well established that Wnt and Notch signaling are active, bone morphogenic protein (BMP) signaling is inhibited, and that this collective regulation is essential for proper intestinal epithelial renewal.3,4 Blocking Wnt signaling by genetic deletion of Wnt pathway components or ectopic expression of Wnt antagonist Dickkopf-1 disrupts intestinal epithelial homeostasis, marked by crypt loss, decreased proliferation, and altered differentiation.5–7Paneth cells (PCs) secrete Wnt and Notch ligands whereas mesenchymal cells secrete Wnts and Gremlin proteins (BMP antagonists).2 R-spondins, proteins that enhance basal Wnt signaling, may be important for ISC maintenance because R-spondins promote intestinal organoid growth in vitro, regulate Lgr5+ ISC in vivo,8–11 and are expressed in the intestinal stroma.12 However, the definitive identification of niche cell types responsible for ISC homeostasis has been elusive.It has been suggested that PCs are essential for the ISC niche based on Wnt expression and support of in vitro ISC self-renewal.13 However, subsequent studies in animal models lacking PCs showed no ISC dysfunction, suggesting that PCs are dispensable for ISC homeostasis.14,15 Conditional ablation of Porcn, required for Wnt secretion, in myosin heavy chain 11 (Myh11)-expressing myofibroblasts16 or villin-expressing epithelial cells,12 resulted in normal intestinal homeostasis, suggesting that Wnts from these cell types are not responsible for maintenance of ISCs and the intestinal epithelium. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Aoki et al17 showed that a subset of mesenchymal cells marked by the winged-helix transcription factor Foxl1 are critical in maintaining ISC by contributing to the ISC niche.By using anti-Foxl1 antibodies and Foxl1-Cre; Rosa-mT/mG mice, the investigators confirmed that Foxl1 marks a novel mesenchymal population that is closely apposed to crypts and is distinct from α-smooth muscle actin–positive and Myh11+ smooth muscle cells and myofibroblasts. Foxl1+ cells also express high levels of growth factors capable of inducing Wnt signaling such as Wnt2b, Wnt5a, Rspo3, Grem1, and Grem2, and are de-enriched for the ISC marker Lgr5. Based on their location and ability to regulate Wnt signaling, the investigators hypothesized that Foxl1+ mesenchymal cells could regulate the ISC niche. To explore this, Aoki et al used 2 independent models mediated by diphtheria toxin administration to ablate Foxl1+ cells: (1) transgenic animals expressing a bacterial artificial chromosome in which the Foxl1 coding region was replaced with the human diphtheria toxin receptor (hDTR), and (2) Foxl1-Cre–mediated activation of simian DTR. Loss of Foxl1 resulted in shorter intestines associated with decreased villus height, crypt depth, intestinal proliferation, and loss of Olfm4+ ISCs, although Lgr5 expression was not assessed directly. Despite loss of ISCs, Foxl1-hDTR animals continued to harbor Paneth and goblet cells. However, Foxl1-hDTR animals showed decreased nuclear β-catenin and Sox9+ crypt cells and ablation of Wnt2b, Wnt4, and Wnt5a messenger RNA. Interestingly, the loss of ISCs despite the presence of Lyz+ PCs indicated that Foxl1+ cells and PCs are not functionally redundant and that Foxl1+ mesenchymal cells are critical for ISC maintenance, potentially via production of Wnt2b, Wnt4, and Wnt5a or other factors.Findings from this seminal study on Foxl1+ mesenchymal cells provide a long-sought definitive identification of a niche cell type required for ISC maintenance. This work also provides a mechanistic basis for prior observations of normal ISC homeostasis upon Porcn deletion in Myh11+ smooth muscle cells or in villin-expressing intestinal epithelial cells or PC ablation.12,14–16 Future characterization of the identity of Foxl1+ mesenchymal cells and their Wnt- and non-Wnt–secreted factors should greatly illuminate our knowledge of specific mediators responsible for maintaining ISCs. The current identification of the crucial Foxl1+ population also should enable the systematic Foxl1+-specific deletion of ISC regulatory factors and subsequent phenotypic analysis. In addition, as the investigators speculated, the Foxl1+ mesenchymal population now represents an attractive cellular target for ISC-based therapeutic strategies aimed at restoration of the intestinal epithelium through modulation of the ISC niche.References1H.CleversThe intestinal crypt, a prototype stem cell compartmentCell15420132742842D.W.TanN.BarkerIntestinal stem cells and their defining nicheCurr Top Dev Biol1072014771073T.H.YenN.A.WrightThe gastrointestinal tract stem cell nicheStem Cell Rev220062032124T.K.NoahN.F.ShroyerNotch in the intestine: regulation of homeostasis and pathogenesisAnnu Rev Physiol7520132632885V.KorinekN.BarkerP.MoererDepletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4Nat Genet1919983793836F.KuhnertC.R.DavisH.T.WangEssential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1Proc Natl Acad Sci U S A10120042662717D.PintoA.GregorieffH.BegthelCanonical Wnt signals are essential for homeostasis of the intestinal epitheliumGenes Dev172003170917138T.SatoR.G.VriesH.J.SnippertSingle Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal nicheNature45920092622659A.OotaniX.LiE.SangiorgiSustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell nicheNat Med15200970170610E.E.StormS.DurinckF.de Sousa e MeloTargeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell functionNature52920169710011K.S.YanL.A.ChiaX.LiThe intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populationsProc Natl Acad Sci U S A109201246647112Z.KabiriG.GreiciusB.MadanStroma provides an intestinal stem cell niche in the absence of epithelial WntsDevelopment14120142206221513T.SatoJ.H.van EsH.J.SnippertPaneth cells constitute the niche for Lgr5 stem cells in intestinal cryptsNature469201141541814A.DurandB.DonahueG.PeignonFunctional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1)Proc Natl Acad Sci U S A10920128965897015T.H.KimS.EscuderoR.A.ShivdasaniIntact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cellsProc Natl Acad Sci U S A10920123932393716A.K.San RomanC.D.JayewickremeL.C.MurtaughWnt secretion from epithelial cells and subepithelial myofibroblasts is not required in the mouse intestinal stem cell niche in vivoStem Cell Rep2201412713417R.AokiM.Shoshkes-CarmelN.GaoFoxl1-expressing mesenchymal cells constitute the intestinal stem cell nicheCell Mol Gastroenterol Hepatol22016175188