Hanayuki Okura1, Mayumi Soeda2, Mitsuko Morita2, Maiko Fujita2, Kyoko Naba2, Chiyoko Ito2, Akihiro Ichinose3, Akifumi Matsuyama4. 1. Platform of Therapeutics for Rare Disease, National Institute of Biomedical Innovation, 5-5-2-602 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; The Center for Medical Engineering and Informatics, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0879, Japan. 2. Platform of Therapeutics for Rare Disease, National Institute of Biomedical Innovation, 5-5-2-602 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. 3. Department of Plastic Surgery, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, Japan. 4. Platform of Therapeutics for Rare Disease, National Institute of Biomedical Innovation, 5-5-2-602 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; The Center for Medical Engineering and Informatics, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0879, Japan. Electronic address: akifumi-matsuyama@umin.ac.jp.
Abstract
INTRODUCTION: Liver fibrosis is characterized by excessive accumulation of extracellular matrix. In a mouse model of liver fibrosis, systemic injection of bone marrow mesenchymal stem cells (BM-MSCs) was considered to rescue the diseased phenotype. The aim of this study was to assess the effectiveness of human adipose tissue-derived multi-lineage progenitor cells (hADMPCs) in improving liver fibrosis. METHODS AND RESULTS: hADMPCs were isolated from subcutaneous adipose tissues of healthy volunteers and expanded. Six week-old male nude mice were treated with carbon tetra-chloride (CCl4) by intraperitoneal injection twice a week for 6 weeks, followed by a tail vein injection of hADMPCs or placebo control. After 6 more weeks of CCl4 injection (12 weeks in all), nude mice with hADMPCs transplants exhibited a significant reduction in liver fibrosis, as evidenced by Sirius Red staining, compared with nude mice treated with CCl4 for 12 weeks without hADMPCs transplants. Moreover, serum glutamic pyruvate transaminase and total bilirubin levels in hADMPCs-treated nude mice were lower levels than those in placebo controls. Production of fibrinolytic enzyme MMPs from hADMPCs were examined by ELISA and compared to that from BM-MSCs. MMP-2 levels in the culture media were not significantly different, whereas those of MMP-3 and -9 of hADMPCs were higher than those by BM-MSCs. CONCLUSION: These results showed the mode of action and proof of concept of systemic injection of hADMPCs, which is a promising therapeutic intervention for the treatment of patients with liver fibrosis.
INTRODUCTION:Liver fibrosis is characterized by excessive accumulation of extracellular matrix. In a mouse model of liver fibrosis, systemic injection of bone marrow mesenchymal stem cells (BM-MSCs) was considered to rescue the diseased phenotype. The aim of this study was to assess the effectiveness of human adipose tissue-derived multi-lineage progenitor cells (hADMPCs) in improving liver fibrosis. METHODS AND RESULTS:hADMPCs were isolated from subcutaneous adipose tissues of healthy volunteers and expanded. Six week-old male nude mice were treated with carbon tetra-chloride (CCl4) by intraperitoneal injection twice a week for 6 weeks, followed by a tail vein injection of hADMPCs or placebo control. After 6 more weeks of CCl4 injection (12 weeks in all), nude mice with hADMPCs transplants exhibited a significant reduction in liver fibrosis, as evidenced by Sirius Red staining, compared with nude mice treated with CCl4 for 12 weeks without hADMPCs transplants. Moreover, serum glutamic pyruvate transaminase and total bilirubin levels in hADMPCs-treated nude mice were lower levels than those in placebo controls. Production of fibrinolytic enzyme MMPs from hADMPCs were examined by ELISA and compared to that from BM-MSCs. MMP-2 levels in the culture media were not significantly different, whereas those of MMP-3 and -9 of hADMPCs were higher than those by BM-MSCs. CONCLUSION: These results showed the mode of action and proof of concept of systemic injection of hADMPCs, which is a promising therapeutic intervention for the treatment of patients with liver fibrosis.
Authors: Zixuan Jiang; David E Harrison; Makayla E Parsons; Susan McClatchy; Lawrence Jacobs; Robert Pazdro Journal: Mamm Genome Date: 2016-07-08 Impact factor: 2.957