title: Butyrate and bioactive proteolytic form of Wnt-5a regulate colonic epithelial proliferation and spatial development.
abstract: Proliferation and spatial development of colonic epithelial cells are highly regulated along the crypt vertical axis, which, when perturbed, can result in aberrant growth and carcinogenesis. In this study, two key factors were identified that have important and counterbalancing roles regulating these processes: pericrypt myofibroblast-derived Wnt-5a and the microbial metabolite butyrate. Cultured YAMC cell proliferation and heat shock protein induction were analzyed after butryate, conditioned medium with Wnt5a activity, and FrzB containing conditioned medium. In vivo studies to modulate Hsp25 employed intra-colonic wall Hsp25 encoding lentivirus. To silence Wnt-5a in vivo, intra-colonic wall Wnt-5a silencing RNA was used. Wnt-5a, secreted by stromal myofibroblasts of the lower crypt, promotes proliferation through canonical β-catenin activation. Essential to this are two key requirements: (1) proteolytic conversion of the highly insoluble ~40 kD Wnt-5a protein to a soluble 36 mer amino acid peptide that activates epithelial β-catenin and cellular proliferation, and (2) the simultaneous inhibition of butyrate-induced Hsp25 by Wnt-5a which is necessary to arrest the proliferative process in the upper colonic crypt. The interplay and spatial gradients of these factors insures that crypt epithelial cell proliferation and development proceed in an orderly fashion, but with sufficient plasticity to adapt to physiological perturbations including inflammation.
authors: Department of Medicine, University of Chicago, Chicago, IL 60637; USA.|Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan.
authors: Kazuhiko
authors: K
authors: Uchiyama
authors: Department of Medicine, University of Chicago, Chicago, IL 60637; USA.|Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 8908520; Japan.
authors: Toshio
authors: T
authors: Sakiyama
authors: Department of Medicine, University of Chicago, Chicago, IL 60637; USA.
authors: Takumu
authors: T
authors: Hasebe
authors: Department of Medicine, University of Chicago, Chicago, IL 60637; USA.
authors: Mark W
authors: MW
authors: Musch
authors: Department of Pathology, Washington University at St. Louis, St. Louis, MO, USA.
authors: Hiroyuki
authors: H
authors: Miyoshi
authors: Department of Medicine, University of Chicago, Chicago, IL 60637; USA.
authors: Yasushi
authors: Y
authors: Nakagawa
authors: Department of Surgery, University of Chicago; Chicago, IL 60637; USA.
authors: Tong-Chuan
authors: TC
authors: He
authors: Department of Medicine, University of Chicago, Chicago, IL 60637; USA.|Department of Gastroenterology, Soroka University Medical Center, Beer-Sheva 84101; Israel.
authors: Lev
authors: L
authors: Lichtenstein
authors: Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan.
authors: Yuji
authors: Y
authors: Naito
authors: Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan.
authors: Yoshito
authors: Y
authors: Itoh
authors: Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan.
authors: Toshikazu
authors: T
authors: Yoshikawa
authors: Department of Medicine, University of Chicago, Chicago, IL 60637; USA.
authors: Bana
authors: B
authors: Jabri
authors: Department of Pathology, Washington University at St. Louis, St. Louis, MO, USA.
authors: Thaddeus
authors: T
authors: Stappenbeck
authors: Department of Medicine, University of Chicago, Chicago, IL 60637; USA.
authors: Eugene B
authors: EB
authors: Chang
mesh_terms: D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D000071818:Wnt-5a Protein / Q000378:metabolism*
chemical_list: D002087:Butyrates; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse