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The evaluation of the safety and efficacy of intravenously administered allogeneic multilineage-differentiating stress-enduring cells in a swine hepatectomy model

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Abstract

Introduction

Multilineage-differentiating stress-enduring (Muse) cells are non-tumorigenic endogenous pluripotent-like cells residing in the bone marrow that exert a tissue reparative effect by replacing damaged/apoptotic cells through spontaneous differentiation into tissue-constituent cells. Post-hepatectomy liver failure (PHLF) is a potentially fatal complication. The main purpose of this study was to evaluate the safety and efficiency of allogeneic Muse cell administration via the portal vein in a swine model of PHLF.

Methods

Swine Muse cells, collected from swine bone marrow-mesenchymal stem cells (MSCs) as SSEA-3(+) cells, were examined for their characteristics. Then, 1 × 107 allogeneic-Muse cells and allogeneic-MSCs and vehicle were injected via the portal vein in a 70% hepatectomy swine model.

Results

Swine Muse cells exhibited characteristics comparable to previously reported human Muse cells. Compared to the MSC and vehicle groups, the Muse group showed specific homing of the administered cells into the liver, resulting in improvements in the control of hyperbilirubinemia (P = 0.04), prothrombin international normalized ratio (P = 0.05), and suppression of focal necrosis (P = 0.04). Integrated Muse cells differentiated spontaneously into hepatocyte marker-positive cells.

Conclusions

Allogeneic Muse cell administration may provide a reparative effect and functional recovery in a 70% hepatectomy swine model and thus may contribute to the treatment of PHLF.

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Abbreviations

AST:

Aspartate aminotransferase

ALB:

Albumin

ALT:

Alanine aminotransferase

ALP:

Alkaline phosphatase

ANOVA:

Analysis of variance

bFGF:

Basic fibroblast growth factor

BM-MSC:

Bone marrow derived mesenchymal stem cell

CDH2:

N-cadherin

CK 18:

Cytokeratin 18

CTNNB1:

Catenin beta 1

DAPI:

4′, 6-Diamidino-2-phenylindole

ELISA:

Enzyme-linked immunosorbent assay

FACS:

Fluorescence-activated cell sorter

FITC:

Fluorescein isothiocyanate

GFP:

Green fluorescent protein

HGF:

Hepatocyte growth factor

HNF:

Hepatocyte nuclear factor

HPF:

High-power field

ISL1:

Insulin gene enhancer binding protein

IVC:

Inferior vena cava

LLL:

Left lateral lobe

LML:

Left medial lobe

MMP:

Matrix metalloproteinase

MSC:

Mesenchymal stem cell

Muse:

Multilineage-differentiating stress-enduring

NES:

Nestin

NR5A2:

Nuclear receptor subfamily 5

OCT3/4:

Octamer-binding transcription factor 4

PBS:

Phosphate-buffered saline

PFA:

Paraformaldehyde

PHLF:

Post-hepatectomy liver failure

PT-INR:

Prothrombin international normalized ratio

Pou5f1:

POU domain class 5 transcription factor-1

RLL:

Right lateral lobe

RML:

Right medial lobe

RT-PCR:

Reverse transcription polymerase chain reaction

SMA:

Alpha-smooth muscle actin

SOX2:

Sex-determining region Y-box 2

SRY:

Sex-determining region Y

SSEA-3:

Stage-specific embryonic antigen-3

TAT:

Twin arginine translocation

WBC:

White blood cell count

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Acknowledgements

This study was supported by Grants-in-Aid from Program for Basic and Clinical Research on Hepatitis of the Japan Agency for Medical Research and Development (AMED), (JP17fk0210303).

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Authors and Affiliations

  1. Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan

    Masahiro Iseki, Masamichi Mizuma, Katsuyoshi Kudo, Masahiko Fukase, Masaharu Ishida, Tomoyuki Ono, Mitsuhiro Shimura, Ichiro Ise, Yukie Suzuki & Michiaki Unno

  2. Department of Stem Cell Biology and Histology, Sendai, Japan

    Shohei Wakao, Yoshihiro Kushida & Mari Dezawa

  3. Comprehensive Education Center for Community Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

    Teruko Sueta

  4. Innovative and Clinical Research Promotion Center, Gifu University Hospital, Gifu, Japan

    Ryuta Asada

  5. Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan

    Shinobu Shimizu

  6. Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan

    Yoshiyuki Ueno

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  1. Masahiro Iseki
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Correspondence to Masahiro Iseki.

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Conflict of interest

Mari Dezawa received research funding from Life Science Institute, Inc. (LSII; Tokyo, Japan). Shohei Wakao holds a patent for Muse cells and the isolation method thereof, licensed to LSII.

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Iseki, M., Mizuma, M., Wakao, S. et al. The evaluation of the safety and efficacy of intravenously administered allogeneic multilineage-differentiating stress-enduring cells in a swine hepatectomy model. Surg Today 51, 634–650 (2021). https://doi.org/10.1007/s00595-020-02117-0

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