title: Dormant Intestinal Stem Cells Are Regulated by PTEN and Nutritional Status.
abstract: The cellular and molecular mechanisms underlying adaptive changes to physiological stress within the intestinal epithelium remain poorly understood. Here, we show that PTEN, a negative regulator of the PI3K→AKT→mTORC1-signaling pathway, is an important regulator of dormant intestinal stem cells (d-ISCs). Acute nutrient deprivation leads to transient PTEN phosphorylation within d-ISCs and a corresponding increase in their number. This release of PTEN inhibition renders d-ISCs functionally poised to contribute to the regenerative response during re-feeding via cell-autonomous activation of the PI3K→AKT→mTORC1 pathway. Consistent with its role in mediating cell survival, PTEN is required for d-ISC maintenance at baseline, and intestines lacking PTEN have diminished regenerative capacity after irradiation. Our results highlight a PTEN-dependent mechanism for d-ISC maintenance and further demonstrate the role of d-ISCs in the intestinal response to stress.
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Camilla A
authors.initials: CA
authors.lastname: Richmond
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Manasvi S
authors.initials: MS
authors.lastname: Shah
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Luke T
authors.initials: LT
authors.lastname: Deary
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Danny C
authors.initials: DC
authors.lastname: Trotier
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Horatio
authors.initials: H
authors.lastname: Thomas
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Ambruzs
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Lijie
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 02138, USA.
authors.forename: Bristol B
authors.initials: BB
authors.lastname: Whiles
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Hannah D
authors.initials: HD
authors.lastname: Rickner
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Montgomery
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Alessio
authors.initials: A
authors.lastname: Tovaglieri
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 02138, USA.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Carlone
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 02138, USA. Electronic address: david.breault@childrens.harvard.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Breault
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005260:Female; D017930:Genes, Reporter; D007422:Intestines / Q000166:cytology* / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D009752:Nutritional Status; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
chemical_list: D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase; C509187:Tert protein, mouse
keywords: MTORC1; PTEN; dormant; fasting; intestinal stem cells; quiescent