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Effect of Stem Cell Treatment on Acute Liver Failure Model Using Scaffold

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Abstract

Background

Injecting MSCs via blood vessel is most commonly used method, which has a major drawback of safety. The aim of our study was to evaluate efficacy using scaffold-loaded MSCs in acute liver failure model.

Method

Acute liver failure was induced in mice using thioacetamide (TAA) (200 mg/kg, i.p) once a day for two consecutive days. The animals were divided in four acute liver failure groups: (1) TAA; (2) empty scaffold; (3) MSCs injected through tail vein; (4) MSC + Scaffold, scaffold loaded with MSCs, to evaluate the mortality and changes in liver function. Polylactic-co-glycolic acid scaffold alone and loaded with human MSCs was implanted on mice dorsum.

Results

TAA dose was titrated until one-third mortality rate was achieved. TAA (200 mg/kg) once daily for two consecutive days was injected to establish the acute liver failure model. The mortality of TAA and scaffold groups was 55.9% and 63.2%, respectively. Although, mortality of MSC-TV group decreased 14.7% as compared to TAA group (p = 0.200), MSC + Scaffold group had the lowest mortality (31.4%) (p = 0.013). Cells implanted in PLGA biomaterial were survived until 3 weeks, and their function was increased. Area of hepatic inflammation and necrosis was significantly reduced in MSC-TV and MSC + Scaffold groups; but there was no difference between the two groups. Gene expressions related to inflammation were significantly decreased in MSC-TV and MSC + Scaffold groups compared to TAA group. In MSC + Scaffold group, no migration of stem cells to liver tissue was observed. Although, not all cells in scaffold were stained, some of them were differentiated into hepatocyte-like cells which stained positive for PAS and CYP2E1 antibody.

Conclusion

Scaffold loaded with MSCs showed protective effects via paracrine signaling on acute liver failure model.

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Abbreviations

ALB:

Albumin

ALF:

Acute liver failure

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

FGF:

Fibroblast growth factor

GAPDH:

Glyceraldehydes-3-phosphate dehydrogenase

HGF:

Hepatocyte growth factor

INR:

International normalized ratio

MELD:

Model for end-stage liver disease

MSC:

Mesenchymal stem cell

PLGA:

Polylactic-co-glycolic acid

PT:

Prothrombin time

TAA:

Thioacetamide

TBIL:

Total bilirubin

VEGF:

Vascular endothelial growth factor

TNF:

Tumor necrosis factor

MCP:

Monocyte chemoattractant protein

NLRP:

NACHT, LRR, and PYD domains-containing protein

ASC:

Apoptosis-associated speck-like protein containing carboxy-terminal CARD

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2015R1D1A1A02061717).

Author information

Author notes

  1. Dae Won Jun, and Kiseok Jang have contributed equally to this work.

Authors and Affiliations

  1. Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul, Korea

    Hyeon Tae Kang, Dae Won Jun, Jai Sun Lee & Yeon Ji Chae

  2. Department of Internal Medicine, Hanyang University School of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Korea

    Dae Won Jun & Waqar Khalid Saeed

  3. Department of Advanced Materials, Hannam University, Daejeon, Korea

    Jin Ho Lee

  4. Department of Pathology, Hanyang University School of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Korea

    Kiseok Jang

  5. Department of Obstetrics and Gynecology, Hanyang University School of Medicine, Seoul, Korea

    Jeong-Kyu Hoh

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  1. Hyeon Tae Kang
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Contributions

DWJ and JHL contributed to study design and grant; JSL, HTK, and YJC did animal care and analyzed the data; HTK wrote the manuscript, WKS assisted with English language use; and KJ interpreted histological finding.

Corresponding authors

Correspondence to Dae Won Jun or Kiseok Jang.

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The authors declare that they have no conflict of interest.

Guarantor of the article

Dae Won Jun.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10620_2018_5363_MOESM1_ESM.tif

Supplementary Figure 1. Mesenchymal stem cells (5x105) were stained for flow cytometry and analyzed using FACS CANTO II (Becton–Dickinson & Co., San Jose, CA) using CD73, CD90, CD105 antibody as stem cell surface marker. (A) Co-stain with CD90 and CD105 antibody, 99.9% of stem cells were positively expressed. (B) Co-stain with CD73 and CD90 antibody, 99.9% of stem cells were positively expressed. (C) Co-stain with CD73 and CD105 antibody, 100% of stem cells were positively expressed. (TIFF 2865 kb)

10620_2018_5363_MOESM2_ESM.tif

Supplementary Figure 2. AST and ALT levels of each groups. At first, all groups had high level of AST and ALT and as time goes on to the third day, AST and ALT level were naturally decreased but they were more decreased in MSC + Scaffold group compared to control group. AST and ALT data were given as the mean ± SEM with one-way ANOVA test with Tukey’s multiple comparisons test by GraphPad Prism7 (p = 0.01 to 0.05: *, p = 0.001 to 0.01: **, p = 0.0001 to 0.001: ***, p < 0.0001: ****) (TIFF 1814 kb)

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Kang, H.T., Jun, D.W., Jang, K. et al. Effect of Stem Cell Treatment on Acute Liver Failure Model Using Scaffold. Dig Dis Sci 64, 781–791 (2019). https://doi.org/10.1007/s10620-018-5363-2

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  • DOI: https://doi.org/10.1007/s10620-018-5363-2

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