Masahiro Iseki1, Masamichi Mizuma2, Shohei Wakao3, Yoshihiro Kushida3, Katsuyoshi Kudo2, Masahiko Fukase2, Masaharu Ishida2, Tomoyuki Ono2, Mitsuhiro Shimura2, Ichiro Ise2, Yukie Suzuki2, Teruko Sueta4, Ryuta Asada5, Shinobu Shimizu6, Yoshiyuki Ueno7, Mari Dezawa3, Michiaki Unno2. 1. Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan. isekimasahiro@surg.med.tohoku.ac.jp. 2. Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan. 3. Department of Stem Cell Biology and Histology, Sendai, Japan. 4. Comprehensive Education Center for Community Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. 5. Innovative and Clinical Research Promotion Center, Gifu University Hospital, Gifu, Japan. 6. Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan. 7. Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan.
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.
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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