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1 Division of Gastroenterology and Department of Medicine, Duke University Medical Center, Durham, NC, USA; Department of Surgery and Division of Surgical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Division of Gastroenterology and Department of Medicine, Duke University Medical Center, Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
3 Departments of Cell and Molecular Physiology and Program in Molecular Biology and Biotechnology, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA
4 Division of Gastroenterology and Department of Medicine, Duke University Medical Center, Durham, NC, USA
5 Department of Surgery, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA
6 Vesta Therapeutics, Inc., Durham, NC, USA
* To whom correspondence should be addressed. E-mail: diehl004{at}mc.duke.edu.
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 the 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 influenced 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.
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