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Am J Physiol Gastrointest Liver Physiol 290: G859-G870, 2006. First published December 1, 2005; doi:10.1152/ajpgi.00456.2005
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TRANSLATIONAL PHYSIOLOGY

Hedgehog signaling maintains resident hepatic progenitors throughout life

Jason K. Sicklick,1,2 Yin-Xiong Li,1,3,4 Alaa Melhem,5 Eva Schmelzer,5 Marzena Zdanowicz,1 Jiawen Huang,1 Montserrat Caballero,6 Jeff H. Fair,6 John W. Ludlow,7 Randall E. McClelland,5 Lola M. Reid,5,* and Anna Mae Diehl1,*

1Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; 2Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; Departments of 3Cell Biology and 4Pediatrics, Duke University Medical Center, Durham; 5Program in Molecular Biology and Biotechnology, Department of Cell and Molecular Physiology, and 6Department of Surgery, University of North Carolina, Chapel Hill; and 7Vesta Therapeutics Incorporated, Durham, North Carolina

Submitted 29 September 2005 ; accepted in final form 28 November 2005

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.

Indian hedgehog; liver; Patched; progenitor cell; Sonic hedgehog


Address for reprint requests and other correspondence: A. M. Diehl, Div. of Gastroenterology, Duke Univ. Medical Center, Snyderman-GSRB I, Suite 1073, 595 LaSalle St., Box 3256, Durham, NC 27710 (e-mail:diehl004{at}mc.duke.edu) or L. M. Reid, Univ. of North Carolina, 32-36 Glaxo Bldg., Campus Box 7038, Chapel Hill, NC 27599 (e-mail: stemcell{at}med.unc.edu)




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