Natural Flavonol, Myricetin, Enhances the Function and Survival of Cryopreserved Hepatocytes In Vitro and In Vivo
by
Changhao Cui 1,†, Shin Enosawa 1,*
, Hitomi Matsunari 2, Hiroshi Nagashima 2 and Akihiro Umezawa 3
Changhao Cui 1,†, Shin Enosawa 1,*, Hitomi Matsunari 2, Hiroshi Nagashima 2 and Akihiro Umezawa 3
1
Division for Advanced Medical Sciences, National Center for Child Health and Development, Tokyo 157-8535, Japan
2
Laboratory of Developmental Engineering, School of Agriculture, Meiji University, Kanagawa 214-8571, Japan
3
Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo 157-8535, Japan
*
Author to whom correspondence should be addressed.
†
Present address: School of Life Science and Medicine, Dalian University of Technology, Liaoning 116024, China.
Int. J. Mol. Sci. 2019, 20(24), 6123; https://doi.org/10.3390/ijms20246123 (registering DOI)
Received: 29 October 2019 / Revised: 28 November 2019 / Accepted: 2 December 2019 / Published: 4 December 2019
(This article belongs to the Special Issue Selected Papers from the JSOPB—Organ Molecular and Cellular Biology)
To improve the therapeutic potential of hepatocyte transplantation, the effects of the mitogen-activated protein kinase kinase 4 (MKK4) inhibitor, myricetin (3,3′,4′,5,5′,7-hexahydroxylflavone) were examined using porcine and human hepatocytes in vitro and in vivo. Hepatocytes were cultured, showing the typical morphology of hepatic parenchymal cell under 1–10 µmol/L of myricetin, keeping hepatocyte specific gene expression, and ammonia removal activity. After injecting the hepatocytes into neonatal Severe combined immunodeficiency (SCID) mouse livers, cell colony formation was found at 10–15 weeks after transplantation. The human albumin levels in the sera of engrafted mice were significantly higher in the recipients of myricetin-treated cells than non-treated cells, corresponding to the size of the colonies. In terms of therapeutic efficacy, the injection of myricetin-treated hepatocytes significantly prolonged the survival of ornithine transcarbamylase-deficient SCID mice from 32 days (non-transplant control) to 54 days. Biochemically, the phosphorylation of MKK4 was inhibited in the myricetin-treated hepatocytes. These findings suggest that myricetin has a potentially therapeutic benefit that regulates hepatocyte function and survival, thereby treating liver failure.
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Keywords:
myricetin; hepatocyte; culture; cell transplantation; ornithine transcarbamylase; kusabira orange
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Cui, C.; Enosawa, S.; Matsunari, H.; Nagashima, H.; Umezawa, A. Natural Flavonol, Myricetin, Enhances the Function and Survival of Cryopreserved Hepatocytes In Vitro and In Vivo. Int. J. Mol. Sci. 2019, 20, 6123.
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