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Domino hepatocyte transplantation using explanted human livers with metabolic defects attenuates D-GalN/LPS-induced acute liver failure.
- Source :
-
Journal of translational medicine [J Transl Med] 2022 Oct 20; Vol. 20 (1), pp. 479. Date of Electronic Publication: 2022 Oct 20. - Publication Year :
- 2022
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Abstract
- Background: Explanted livers from patients with inherited metabolic liver diseases possess the potential to be a cell source of good-quality hepatocytes for hepatocyte transplantation (HT). This study evaluated the therapeutic effects of domino HT using hepatocytes isolated from explanted human livers for acute liver failure (ALF).<br />Methods: Isolated hepatocytes were evaluated for viability and function and then transplanted into D-galactosamine/lipopolysaccharide-induced ALF mice via splenic injection. The survival rate was analyzed by the Kaplan-Meier method and log-rank test. Liver function was evaluated by serum biochemical parameters, and inflammatory cytokine levels were measured by ELISA. The pathological changes in the liver tissues were assessed by hematoxylin-eosin staining. Hepatocyte apoptosis was investigated by TUNEL, and hepatocyte apoptosis-related proteins were detected by western blot. The localization of human hepatocytes in the injured mouse livers was detected by immunohistochemical analyses.<br />Results: Hepatocytes were successfully isolated from explanted livers of 10 pediatric patients with various liver-based metabolic disorders, with an average viability of 85.3% ± 13.0% and average yield of 9.2 × 10 <superscript>6</superscript> ± 3.4 × 10 <superscript>6</superscript> cells/g. Isolated hepatocytes had an excellent ability to secret albumin, produce urea, uptake indocyanine green, storage glycogen, and express alpha 1 antitrypsin, albumin, cytokeratin 18, and CYP3A4. Domino HT significantly reduced mortality, decreased serum levels of alanine aminotransferase and aspartate aminotransferase, and improved the pathological damage. Moreover, transplanted hepatocytes inhibited interleukin-6 and tumor necrosis factor-α levels. Domino HT also ameliorates hepatocyte apoptosis, as evidenced by decreased TUNEL positive cells. Positive staining for human albumin suggested the localization of human hepatocytes in ALF mice livers.<br />Conclusion: Explanted livers from patients with inheritable metabolic disorders can serve as a viable cell source for cell-based therapies. Domino HT using hepatocytes with certain metabolic defects has the potential to be a novel therapeutic strategy for ALF.<br /> (© 2022. The Author(s).)
- Subjects :
- Animals
Child
Humans
Mice
Alanine Transaminase metabolism
Albumins metabolism
alpha 1-Antitrypsin metabolism
Aspartate Aminotransferases metabolism
Cytochrome P-450 CYP3A metabolism
Galactosamine adverse effects
Glycogen metabolism
Interleukin-6 metabolism
Keratin-18 metabolism
Lipopolysaccharides
Serum Albumin, Human metabolism
Tumor Necrosis Factor-alpha metabolism
Urea metabolism
Liver Failure, Acute chemically induced
Liver Failure, Acute surgery
Metabolic Diseases chemically induced
Metabolic Diseases surgery
Hepatocytes transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 1479-5876
- Volume :
- 20
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 36266691
- Full Text :
- https://doi.org/10.1186/s12967-022-03674-3