The evaluation of the safety and efficacy of intravenously administered allogeneic multilineage-differentiating stress-e
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ORIGINAL ARTICLE
The evaluation of the safety and efficacy of intravenously administered allogeneic multilineage‑differentiating stress‑enduring cells in a swine hepatectomy model Masahiro Iseki1 · Masamichi Mizuma1 · Shohei Wakao2 · Yoshihiro Kushida2 · Katsuyoshi Kudo1 · Masahiko Fukase1 · Masaharu Ishida1 · Tomoyuki Ono1 · Mitsuhiro Shimura1 · Ichiro Ise1 · Yukie Suzuki1 · Teruko Sueta3 · Ryuta Asada4 · Shinobu Shimizu5 · Yoshiyuki Ueno6 · Mari Dezawa2 · Michiaki Unno1 Received: 6 March 2020 / Accepted: 10 August 2020 © Springer Nature Singapore Pte Ltd. 2020
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. Keywords Muse cells · Mesenchymal stem cells · Swine hepatectomy model · Allogeneic cell administration 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 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00595-020-02117-0) contains supplementary material, which is available to authorized users. * Masahiro Iseki [email protected] Extended author information available on the last page of the article
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 ge
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