title: Hedgehog signaling maintains resident hepatic progenitors throughout life.
abstract: Hedgehog signaling through its receptor, Patched, activates transcription of genes, including Patched, that regulate the fate of various progenitors. Although Hedgehog signaling is required for endodermal commitment and hepatogenesis, the possibility that it regulates liver turnover in adults had not been considered because mature liver epithelial cells lack Hedgehog signaling. Herein, we show that this pathway is essential throughout life for maintaining hepatic progenitors. Patched-expressing cells have been identified among endodermally lineage-restricted, murine embryonic stem cells as well as in livers of fetal and adult Ptc-lacZ mice. An adult-derived, murine hepatic progenitor cell line expresses Patched, and Hedgehog-responsive cells exist in stem cell compartments of fetal and adult human livers. In both species, manipulation of Hedgehog activity influences hepatic progenitor cell survival. Therefore, Hedgehog signaling is conserved in hepatic progenitors from fetal development through adulthood and may be a new therapeutic target in patients with liver damage.
authors.affiliation: Division of Gastroenterology, Duke University Medical Center, Snyderman-GSRB I, Suite 1073, 595 LaSalle St., Box 3256, Durham, NC 27710, USA.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Sicklick
authors.forename: Yin-Xiong
authors.initials: YX
authors.lastname: Li
authors.forename: Alaa
authors.initials: A
authors.lastname: Melhem
authors.forename: Eva
authors.initials: E
authors.lastname: Schmelzer
authors.forename: Marzena
authors.initials: M
authors.lastname: Zdanowicz
authors.forename: Jiawen
authors.initials: J
authors.lastname: Huang
authors.forename: Montserrat
authors.initials: M
authors.lastname: Caballero
authors.forename: Jeff H
authors.initials: JH
authors.lastname: Fair
authors.forename: John W
authors.initials: JW
authors.lastname: Ludlow
authors.forename: Randall E
authors.initials: RE
authors.lastname: McClelland
authors.forename: Lola M
authors.initials: LM
authors.lastname: Reid
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000818:Animals; D004627:Embryonic Induction; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C509239:SHH protein, human; C465570:Shh protein, mouse; D015534:Trans-Activators