title: Mice lacking functional CD95-ligand display reduced proliferation of the intestinal epithelium without gross homeostatic alterations.
abstract: Homeostasis of the continuously self-renewing intestinal tract involves cell proliferation, migration, differentiation along the crypt-villus-axis and shedding of cells into the gut lumen. CD95-ligand (FAS-ligand, CD95L) is a cytokine that is known for its capacity to induce apoptosis by binding its cognate receptor, CD95 (Fas). More recently, it was discovered that CD95L can also induce other cellular responses, such as proliferation, differentiation and cell migration. CD95L is highly expressed in Paneth cells of the small intestine which are in close contact with intestinal stem cells. This suggests a potential role for CD95L in controlling stem cell function and, possibly, intestinal homeostasis. We analyzed the intestines of mice deficient for functional CD95L (gld) for potential alterations in the diversity of stem-cell-lineages and parameters of intestinal homeostasis. Stem cell diversity was assessed by analyzing methylation patterns of the non-transcribed mMYOD gene. Proliferation was analyzed by BrdU labeling and differentiation was assessed by immunohistochemistry. Of all parameters analyzed, only epithelial cell proliferation was significantly reduced in the small intestines of gld-mice, but not in their colons which lack CD95L expression. We conclude that CD95L has a proliferation-stimulating role during normal turnover of the small intestine, but has a marginal effect on overall intestinal homeostasis.
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Kari
authors.identifier: http://orcid.org/0000-0002-0059-1213
authors.initials: K
authors.lastname: Trumpi
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Ernst J A
authors.initials: EJ
authors.lastname: Steller
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: de Leng
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Daniëlle A
authors.initials: DA
authors.lastname: Raats
authors.affiliation: Hubrecht Institute, The Royal Dutch Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Isaäc J
authors.initials: IJ
authors.lastname: Nijman
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.
authors.forename: Folkert H M
authors.initials: FH
authors.lastname: Morsink
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Inne H M
authors.initials: IH
authors.lastname: Borel Rinkes
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. o.kranenburg@umcutrecht.nl.
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000378:metabolism*; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D019014:fas Receptor
keywords: APO-1; CD95 ligand; FAS; Homeostasis; Intestinal tract; Stem cell maintenance