Hepatic cell sheets engineered from human mesenchymal stem cells with a single small molecule compound IC-2 ameliorate acute liver injury in mice
| Autor: | Kaori Okinaka, Goshi Shiota, Hiroyuki Oka, Tsuyoshi Yokobata, Shizuma Okazaki, Ikuya Noda, Minoru Morimoto, Noriko Itaba, Yohei Kono |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
RBP4 retinol binding protein 4 AST aspartate aminotransferase GPX glutathione peroxidase DMSO dimethyl sulfoxide ChREBP Carbohydrate-responsive element-binding protein ERK extracellular signal-regulated kinase TRXR thioredoxin reductase CCl4 carbon tetrachloride GSH glutathione HB-EGF heparin binding-epidermal growth factor-like growth factor GRX glutaredoxin GR Glutathione reductase IL-6 interleukin-6 NF-κB nuclear factor-kappa B Liver injury lcsh:R5-920 Chemistry lcsh:Cytology STAT-3 Signal Tranducer and Activator of Transcription 3 Wnt signaling pathway IL-1ra interleukin-1 receptor antagonist Liver regeneration AREG amphiregulin HGFR hepatocyte growth factor receptor TRX thioredoxin medicine.anatomical_structure A1AT α1-antitrypsin Hepatocyte Original Article C5aR complement C5a receptor lcsh:Medicine (General) mActb mouse actin beta Hepatic cell sheets PCNA proliferating cell nuclear antigen hGAPDH human glyceraldehyde 3-phosphate dehydrogenase Biomedical Engineering TNFα tumor necrosis factor alpha Biomaterials 03 medical and health sciences 8-OHdG 8-hydroxydeoxyguanosine Downregulation and upregulation ALT alanine aminotransferase SOD superoxide dismutase medicine TGFα transforming growth factor alpha BM-MSCs bone marrow-derived mesenchymal stem cells lcsh:QH573-671 CBP CREB-binding protein Wnt/β-catenin signal inhibitor MDA malondialdehyde ChoREs carbohydrate response elements Mesenchymal stem cell C4A complement C4A medicine.disease C3 complement C3 EGFR epidermal growth factor receptor TF transferrin PRX peroxiredoxin Transplantation 030104 developmental biology CP ceruloplasmin Hepatic stellate cell Cancer research Mesenchymal stem cells APOE apolipoprotein E LXR liver X receptor Acute liver failure Developmental Biology |
| Zdroj: | Regenerative Therapy, Vol 9, Iss, Pp 45-57 (2018) Regenerative Therapy |
| ISSN: | 2352-3204 |
| Popis: | Introduction We previously reported that transplantation of hepatic cell sheets from human bone marrow-derived mesenchymal stem cells (BM-MSCs) with hexachlorophene, a Wnt/β-catenin signaling inhibitor, ameliorated acute liver injury. In a further previous report, we identified IC-2, a newly synthesized derivative of the Wnt/β-catenin signaling inhibitor ICG-001, as a potent inducer of hepatic differentiation of BM-MSCs. Methods We manufactured hepatic cell sheets by engineering from human BM-MSCs using the single small molecule IC-2. The therapeutic potential of IC-2-induced hepatic cell sheets was assessed by transplantation of IC-2- and hexachlorophene-treated hepatic cell sheets using a mouse model of acute liver injury. Results Significant improvement of liver injury was elicited by the IC-2-treated hepatic cell sheets. The expression of complement C3 was enhanced by IC-2, followed by prominent hepatocyte proliferation stimulated through the activation of NF-κB and its downstream molecule STAT-3. Indeed, IC-2 also enhanced the expression of amphiregulin, resulting in the activation of the EGFR pathway and further stimulation of hepatocyte proliferation. As another important therapeutic mechanism, we revealed prominent reduction of oxidative stress mediated through upregulation of the thioredoxin (TRX) system by IC-2-treated hepatic cell sheets. The effects mediated by IC-2-treated sheets were superior compared with those mediated by hexachlorophene-treated sheets. Conclusion The single compound IC-2 induced hepatic cell sheets that possess potent regeneration capacity and ameliorate acute liver injury. Highlights • Wnt/β-catenin signal inhibitor, IC-2, is suitable for creating hepatic cell sheets. • IC-2-treated hepatic cell sheets improved acute liver injury. • IC-2-treated hepatic cell sheets-derived C3 and AREG promote regeneration. • Hepatic cell sheets possess antioxidative property through thioredoxin system. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|