Influence of Mesenchymal Stem Cell Administration on The Outcome of Partial Liver Resection in a Porcine Model of Sinusoidal Obstruction Syndrome

Pálek, Richard; Rosendorf, Jáchym; Malečková, Anna; Vištějnová, Lucie; Bajcurova, Kristyna; Mírka, Hynek; Tégl, Václav; Brzoň, Ondřej; Kumar, Arvind; Bednar, Lukas; Tonar, Zbyněk; Hošek, Petr; Moulisová, Vladimíra; Eberlová, Lada; Třeška, Vladislav; Liška, Václav

doi:10.21873/anticanres.14704

Cited by 3 publications

(2 citation statements)

References 50 publications

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“…General anesthesia was induced and maintained by intravenous injection of propofol (1% mixture 5–10 mg/kg Propofol, Fresenius Kabi Norges, Halden, Norway). Animals were sacrificed with intravenous administration of T61 solution (MSD Animal Health, Kenilworth, NJ, United States) under general anesthesia ( Palek et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4

Albadry,

Küttner,

Grzegorzewski

et al. 2024

Front. Pharmacol.

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There is a lack of systematic research exploring cross-species variation in liver lobular geometry and zonation patterns of critical drug-metabolizing enzymes, a knowledge gap essential for translational studies. This study investigated the critical interplay between lobular geometry and key cytochrome P450 (CYP) zonation in four species: mouse, rat, pig, and human. We developed an automated pipeline based on whole slide images (WSI) of hematoxylin-eosin-stained liver sections and immunohistochemistry. This pipeline allows accurate quantification of both lobular geometry and zonation patterns of essential CYP proteins. Our analysis of CYP zonal expression shows that all CYP enzymes (besides CYP2D6 with panlobular expression) were observed in the pericentral region in all species, but with distinct differences. Comparison of normalized gradient intensity shows a high similarity between mice and humans, followed by rats. Specifically, CYP1A2 was expressed throughout the pericentral region in mice and humans, whereas it was restricted to a narrow pericentral rim in rats and showed a panlobular pattern in pigs. Similarly, CYP3A4 is present in the pericentral region, but its extent varies considerably in rats and appears panlobular in pigs. CYP2D6 zonal expression consistently shows a panlobular pattern in all species, although the intensity varies. CYP2E1 zonal expression covered the entire pericentral region with extension into the midzone in all four species, suggesting its potential for further cross-species analysis. Analysis of lobular geometry revealed an increase in lobular size with increasing species size, whereas lobular compactness was similar. Based on our results, zonated CYP expression in mice is most similar to humans. Therefore, mice appear to be the most appropriate species for drug metabolism studies unless larger species are required for other purposes, e.g., surgical reasons. CYP selection should be based on species, with CYP2E1 and CYP2D6 being the most preferable to compare four species. CYP1A2 could be considered as an additional CYP for rodent versus human comparisons, and CYP3A4 for mouse/human comparisons. In conclusion, our image analysis pipeline together with suggestions for species and CYP selection can serve to improve future cross-species and translational drug metabolism studies.

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Section: Methodsmentioning

confidence: 99%

Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4

Albadry,

Küttner,

Grzegorzewski

et al. 2024

Front. Pharmacol.

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“…From the measurements of these cross-sectional areas, the volume of hepatocytes was estimated. The volume fractions V V (connective tissue, liver), V V (hepatocytes, liver), V V (MH, liver) and V V (PH, liver) were determined using the point grid method [ 51 , 52 ]. All quantitative analyses were done using Ellipse stereological software (ViDiTo, Kosice, Slovakia).…”

Section: Methodsmentioning

confidence: 99%

Mesenchymal Stromal Cell Therapy in Novel Porcine Model of Diffuse Liver Damage Induced by Repeated Biliary Obstruction

Vištějnová

Liška

Kumar

et al. 2021

IJMS

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In liver surgery, biliary obstruction can lead to secondary biliary cirrhosis, a life-threatening disease with liver transplantation as the only curative treatment option. Mesenchymal stromal cells (MSC) have been shown to improve liver function in both acute and chronic liver disease models. This study evaluated the effect of allogenic MSC transplantation in a large animal model of repeated biliary obstruction followed by partial hepatectomy. MSC transplantation supported the growth of regenerated liver tissue after 14 days (MSC group, n = 10: from 1087 ± 108 (0 h) to 1243 ± 92 mL (14 days); control group, n = 11: from 1080 ± 95 (0 h) to 1100 ± 105 mL (14 days), p = 0.016), with a lower volume fraction of hepatocytes in regenerated liver tissue compared to resected liver tissue (59.5 ± 10.2% vs. 70.2 ± 5.6%, p < 0.05). Volume fraction of connective tissue, blood vessels and bile vessels in regenerated liver tissue, serum levels of liver enzymes (AST, ALT, ALP and GGT) and liver metabolites (albumin, bilirubin, urea and creatinine), as well as plasma levels of IL-6, IL-8, TNF-α and TGF-β, were not affected by MSC transplantation. In our novel, large animal (pig) model of repeated biliary obstruction followed by partial hepatectomy, MSC transplantation promoted growth of liver tissue without any effect on liver function. This study underscores the importance of translating results between small and large animal models as well as the careful translation of results from animal model into human medicine.

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Periphery of porcine hepatic lobes has the smallest length density of hepatic sinusoids and bile canaliculi: A stereological histological study with implications for liver biopsies

Malečková,

Mik,

Liška

et al. 2023

Annals of Anatomy - Anatomischer Anzeiger

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Influence of Mesenchymal Stem Cell Administration on The Outcome of Partial Liver Resection in a Porcine Model of Sinusoidal Obstruction Syndrome

Cited by 3 publications

References 50 publications

Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4

Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4

Mesenchymal Stromal Cell Therapy in Novel Porcine Model of Diffuse Liver Damage Induced by Repeated Biliary Obstruction

Periphery of porcine hepatic lobes has the smallest length density of hepatic sinusoids and bile canaliculi: A stereological histological study with implications for liver biopsies

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