FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration
- Hinako M. Takase1,5,6,
- Tohru Itoh1,5,7,
- Seitaro Ino1,
- Ting Wang2,
- Takehiko Koji3,
- Shizuo Akira4,
- Yasuhiro Takikawa2 and
- Atsushi Miyajima1
- 1Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan;
- 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate 020-8505, Japan;
- 3Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan;
- 4Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Abstract
The liver is a unique organ with a remarkably high potential to regenerate upon injuries. In severely damaged livers where hepatocyte proliferation is impaired, facultative liver progenitor cells (LPCs) proliferate and are assumed to contribute to regeneration. An expansion of LPCs is often observed in patients with various types of liver diseases. However, the underlying mechanism of LPC activation still remains largely unknown. Here we show that a member of the fibroblast growth factor (FGF) family, FGF7, is a critical regulator of LPCs. Its expression was induced concomitantly with LPC response in the liver of mouse models as well as in the serum of patients with acute liver failure. Fgf7-deficient mice exhibited markedly depressed LPC expansion and higher mortality upon toxin-induced hepatic injury. Transgenic expression of FGF7 in vivo led to the induction of cells with characteristics of LPCs and ameliorated hepatic dysfunction. We revealed that Thy1+ mesenchymal cells produced FGF7 and appeared in close proximity to LPCs, implicating a role for those cells as the functional LPC niche in the regenerating liver. These findings provide new insights into the cellular and molecular basis for LPC regulation and identify FGF7 as a potential therapeutic target for liver diseases.
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Footnotes
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↵5 These two authors contributed equally to this work.
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↵7 Corresponding author
E-mail itohru{at}iam.u-tokyo.ac.jp
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.204776.112.
- Received August 31, 2012.
- Accepted December 13, 2012.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press