title: Stroma provides an intestinal stem cell niche in the absence of  epithelial Wnts.
abstract: Wnt/β-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth cells as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intestinal stem cells when Wnt signaling is enhanced with supplemental R-Spondin 1 (RSPO1). However, in vivo, the source of Wnts in the stem cell niche is less clear. Genetic ablation of Porcn, an endoplasmic reticulum resident O-acyltransferase that is essential for the secretion and activity of all vertebrate Wnts, confirmed the role of intestinal epithelial Wnts in ex vivo culture. Unexpectedly, mice lacking epithelial Wnt activity (Porcn(Del)/Villin-Cre mice) had normal intestinal proliferation and differentiation, as well as successful regeneration after radiation injury, indicating that epithelial Wnts are dispensable for these processes. Consistent with a key role for stroma in the crypt niche, intestinal stromal cells endogenously expressing Wnts and Rspo3 support the growth of Porcn(Del) organoids ex vivo without RSPO1 supplementation. Conversely, increasing pharmacologic PORCN inhibition, affecting both stroma and epithelium, reduced Lgr5 intestinal stem cells, inhibited recovery from radiation injury, and at the highest dose fully blocked intestinal proliferation. We conclude that epithelial Wnts are dispensable and that stromal production of Wnts can fully support normal murine intestinal homeostasis.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Kabiri
authors.forename: Gediminas
authors.initials: G
authors.lastname: Greicius
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.forename: Steffen
authors.initials: S
authors.lastname: Biechele
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Zhong
authors.forename: Hamed
authors.initials: H
authors.lastname: Zaribafzadeh
authors.lastname: Edison
authors.forename: Jamal
authors.initials: J
authors.lastname: Aliyev
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wu
authors.forename: Ralph
authors.initials: R
authors.lastname: Bunte
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000217:Acyltransferases; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D004848:Epithelium / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007422:Intestines / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D019879:Paneth Cells / Q000166:cytology; D015398:Signal Transduction; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology; D017154:Stromal Cells / Q000166:cytology*; D019699:Thrombospondins / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C518903:RSPO1 protein, mouse; D019699:Thrombospondins; D051153:Wnt Proteins; D000217:Acyltransferases; C491187:Porcn protein, mouse