Secreted matrix metalloproteinase-14 is a predictor for antifibrotic effect of IC-2-engineered mesenchymal stem cell sheets on liver fibrosis in mice.

ALT, alanine aminotransferase AST, aspartate aminotransferase BM-MSCs, bone marrow-derived mesenchymal stem cells C3, complement C3 CCl4, carbon tetrachloride DMSO, dimethyl sulfoxide EDTA, ethylenediamine tetra-acetic acid FACS, Fluorescence-activated cell sorter FALD, fontan-associated liver disease GAPDH, Glyceraldehyde 3-phosphate dehydrogenase HCC, hepatic cellular carcinoma HLA, human leukocyte antigen HSCs, hepatic stellate cells Hepatic cell sheets IgG, immunoglobulin G LC, liver cirrhosis MMP-14, matrix metalloproteinase MSCs, mesenchymal stem cells Matrix metalloproteinase-14 Mesenchymal stem cells Wnt/β-catenin signal inhibitor chronic liver injury hBM-MNCs, human bone marrow mononuclear cells iPS cells, induced pluripotent stem cells αSMA, α-smooth muscle actin

Journal

Regenerative therapy
ISSN: 2352-3204
Titre abrégé: Regen Ther
Pays: Netherlands
ID NLM: 101709085

Informations de publication

Date de publication:
Dec 2021
Historique:
received: 07 06 2021
revised: 03 08 2021
accepted: 11 08 2021
entrez: 10 9 2021
pubmed: 11 9 2021
medline: 11 9 2021
Statut: epublish

Résumé

Transplantation of IC-2-engineered bone marrow-derived mesenchymal stem cell (BM-MSC) sheets (IC-2 sheets) was previously reported to potentially reduce liver fibrosis. This study prepared IC-2-engineered cell sheets from multiple lots of BM-MSCs and examined the therapeutic effects of these cell sheets on liver fibrosis induced by carbon tetrachloride in mice. The predictive factors for antifibrotic effect on liver fibrosis were tried to identify in advance. Secreted matrix metalloproteinase (MMP)-14 was found to be a useful predictive factor to reduce liver fibrosis. Moreover, the cutoff index of MMP-14 for 30% reduction of liver fibrosis was 0.918 fg/cell, judging from univariate analysis and receiver operating curve analysis. In addition, MMP-13 activity and thioredoxin contents in IC-2 sheets were also inversely correlated with hepatic hydroxyproline contents. Finally, IC-2 was also found to promote MMP-14 secretion from BM-MSCs of elderly patients. Surprisingly, the values of secreted MMP-14 from BM-MSCs of elderly patients were much higher than those of young persons. The results of this study suggest that the IC-2 sheets would be applicable to clinical use in autologous transplantation for patients with cirrhosis regardless of the patient's age.

Identifiants

DOI: 10.1016/j.reth.2021.08.004 PMID: 34504910 PMC: PMC8399086
pubmed: 34504910
doi: 10.1016/j.reth.2021.08.004
pii: S2352-3204(21)00063-8
pmc: PMC8399086
doi:

Types de publication

Journal Article

Langues

eng

Pagination

292-301

Informations de copyright

© 2021 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.

Déclaration de conflit d'intérêts

G.S. holds more than 5% of the total shares of KanonCure Inc. and receives compensation as a member of KanonCure Inc. The other authors have no competing interests to declare. Tottori university and KanonCure Inc. have the patents for IC-2 sheets (patent registration numbers, US 9,555,061, DE602012040872.3, ES2698365, FR2698365, GB269835, and IT502018000006592), and patent applications (patent application numbers TW107129167, US16/641,874, CN201880054224.7, EP18851336.0, PCT/JP2019/021603, US16/972,285, and EP198156721).

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Auteurs

Kenji Fukushima (K)

Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan.

Noriko Itaba (N)

Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.

Yohei Kono (Y)

Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.

Shizuma Okazaki (S)

Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.

Shinpei Enokida (S)

Division of Orthopedic Surgery, Department of Sensory and Motor Organs, School of Medicine, Faculty of Medicine, Tottori University, Yonago, 683-8504, Japan.

Naomi Kuranobu (N)

Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan.

Jun Murakami (J)

Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan.

Makoto Enokida (M)

Division of Orthopedic Surgery, Department of Sensory and Motor Organs, School of Medicine, Faculty of Medicine, Tottori University, Yonago, 683-8504, Japan.

Hideki Nagashima (H)

Division of Orthopedic Surgery, Department of Sensory and Motor Organs, School of Medicine, Faculty of Medicine, Tottori University, Yonago, 683-8504, Japan.

Susumu Kanzaki (S)

Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan.
Asahigawaso Rehabilitation & Medical Center, Okayama, 703-8555, Japan.

Noriyuki Namba (N)

Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan.

Goshi Shiota (G)

Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.

Classifications MeSH