title: ER stress causes rapid loss of intestinal epithelial stemness through activation of the unfolded protein response.
abstract: Stem cells generate rapidly dividing transit-amplifying cells that have lost the capacity for self-renewal but cycle for a number of times until they exit the cell cycle and undergo terminal differentiation. We know very little of the type of signals that trigger the earliest steps of stem cell differentiation and mediate a stem cell to transit-amplifying cell transition. We show that in normal intestinal epithelium, endoplasmic reticulum (ER) stress and activity of the unfolded protein response (UPR) are induced at the transition from stem cell to transit-amplifying cell. Induction of ER stress causes loss of stemness in a Perk-eIF2α-dependent manner. Inhibition of Perk-eIF2α signaling results in stem cell accumulation in organoid culture of primary intestinal epithelium. Our findings show that the UPR plays an important role in the regulation of intestinal epithelial stem cell differentiation.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Jarom
authors.initials: J
authors.lastname: Heijmans
authors.forename: Jooske F
authors.initials: JF
authors.lastname: van Lidth de Jeude
authors.forename: Bon-Kyoung
authors.initials: BK
authors.lastname: Koo
authors.forename: Sanne L
authors.initials: SL
authors.lastname: Rosekrans
authors.forename: Mattheus C B
authors.initials: MC
authors.lastname: Wielenga
authors.forename: Marc
authors.initials: M
authors.lastname: van de Wetering
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrante
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.forename: Jos J M
authors.initials: JJ
authors.lastname: Onderwater
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.forename: A Mieke
authors.initials: AM
authors.lastname: Mommaas
authors.forename: Liudmila L
authors.initials: LL
authors.lastname: Kodach
authors.forename: James C
authors.initials: JC
authors.lastname: Hardwick
authors.forename: Daniël W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Vanesa
authors.initials: V
authors.lastname: Muncan
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D019892:eIF-2 Kinase