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Hedgehog signaling influences gender-specific response of liver to radiation in mice

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Abstract

Background

It is unclear why the response to radiation in the female liver is different from that of the male liver. Hedgehog (Hh) that remains latent in healthy adult livers is activated in the injured liver and promotes the proliferation of progenitors and myofibroblastic hepatic stellate cells, leading to hepatic fibrosis.

Objective

These findings have led to the hypothesis that the gender-specific expression of Hh signaling could affect the different response of the female liver to radiation.

Methods

Male and female mice irradiated with a single dose of 6 Gy were killed at 1 week post irradiation, and the livers were collected for biochemical analysis.

Results

A greater accumulation of fatty hepatocytes and apoptotic cells was observed in irradiated female mice. Sox-9 and pancytokeratin-positive cells were expanded in the livers of irradiated female, but not male, mice. The expression of the Hh ligand, Sonic Hh, Hh receptor, Smoothened, and Hh-target gene, Gli2, showed a greater increase in the liver of radiation-treated female. The levels of epithelial-to-mesenchymal transition (EMT)-stimulating factor, transforming growth factor-β, collagen α1, and N-cadherin were upregulated, while the EMT inhibitor, bmp7, was downregulated in the damaged liver of females compared to controls. In addition, increased fibrosis was seen in the injured livers of female mice. No significant changes in Hh expression and EMT were detected in the irradiated male mice.

Conclusion

These results demonstrated that the increased expression of Hh signaling contributed to the different repair process in the irradiated female mice by promoting proliferation of progenitor and EMT process.

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Abbreviations

EMT:

Epithelial-to-mesenchymal transition

Gli:

Glioblastoma

Hh:

Hedgehog

HIP:

Hedgehog-interacting protein

H&E:

Hematoxylin and eosin

HSC:

Hepatic stellate cell

Ihh:

Indian hedgehog

IHC:

Immunohistochemistry

MF-HSC:

Myofibroblastic hepatic stellate cells

Pan-CK:

Pancytokeratin

Ptc:

Patched

Shh:

Sonic hedgehog

Smo:

Smoothened

TGF-β:

Transforming growth factor-β

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Acknowledgements

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012-0007141) and the Research Fund Program of Research Institute for Basic Sciences, Pusan National University, Korea, 2009, project no. RIBS-PNU-2010-305.

Compliance with Ethical Requirements

Animal care and surgical procedures were approved by the Pusan National University Institutional Animal Care and Use Committee and carried out in accordance with the provisions of the NIH Guide for the Care and Use of Laboratory Animals.

Conflict of interest

None

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Authors and Affiliations

  1. Department of Biological Sciences, Pusan National University, Biology Building (302), 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan, 609-735, Korea

    Sihyung Wang, Keumju Lee, Jeongeun Hyun, Youngjae Lee & Youngmi Jung

  2. Department of Emergency Medical Technology, Kyungil University, Gyeongsan, Korea

    Younghwa Kim

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  1. Sihyung Wang
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  2. Keumju Lee
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  3. Jeongeun Hyun
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  4. Youngjae Lee
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Corresponding author

Correspondence to Youngmi Jung.

Additional information

Sihyung Wang and Keumju Lee contributed equally to the work.

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Wang, S., Lee, K., Hyun, J. et al. Hedgehog signaling influences gender-specific response of liver to radiation in mice. Hepatol Int 7, 1065–1074 (2013). https://doi.org/10.1007/s12072-013-9461-0

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