Identification of the small molecule compound which induces hepatic differentiation of human mesenchymal stem cells

Itaba, Noriko; Sakabe, Tomohiko; Kanki, Keita; Azumi, Junya; Shimizu, Hiroki; Kono, Yohei; Matsumi, Yoshiaki; Abe, Ken ichiro; Tonoi, Takayuki; Oka, Hiroyuki; Sakurai, Toshihiko; Saimoto, Hiroyuki; Morimoto, Minoru; Mabuchi, Yo; Matsuzaki, Yasushi; Shiota, Goshi

doi:10.1016/j.reth.2015.10.001

Cited by 11 publications

(28 citation statements)

References 35 publications

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“…It has been reported that ICG-001 suppresses Wnt/β-catenin signals by binding CREB-binding protein (CBP). 12 Since IC-2 is a derivative of ICG-001, IC-2 and IC-2 derivatives may interact with CBP. Further examination will be required to clarify the molecular mechanisms of IC-2 and IC-2 derivatives on Wnt/β-catenin signals.…”

Section: Discussionmentioning

confidence: 99%

“…9, 10, 12 TCF4-CMVpro-GL4.20 was developed as a TCF-4 motif-responsive luciferase reporter gene. 12 In brief, three copies of the optimal TCF-4 motif CCTTTGATC and cytomegalovirus (CMV) promoter into the multiple cloning site of the pGL4.20 luciferase reporter plasmid (Promega Corp., Fitchburg, WI), subsequently designated pTCF-CMVpro-GL4.20. This plasmid is sensitive reporter plasmid to assess Wnt/ β-catenin signals.…”

Section: Reporter Assaymentioning

confidence: 99%

“…11 Furthermore, we identified IC-2, a derivative of ICG-001, as a potent inhibitor of Wnt/β-catenin signaling in human mesenchymal stem cells. 12 Transplantation of IC-2-engineered cell sheets potently improved acute liver injury and reversed liver fibrosis. 13,14 We also found that IC-2 suppressed cancer stem cells of hepatocellular carcinoma (HCC) and colon cancer, respectively.…”

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confidence: 99%

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Identification of a Novel Deactivating Small-Molecule Compound for Fibrogenic Hepatic Stellate Cells

et al. 2020

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Background Liver fibrosis progresses to decompensated liver cirrhosis, for which medical needs remain unmet. We recently developed IC-2, a small-molecule compound that suppresses Wnt/β-catenin signaling, and found that IC-2 also suppresses liver fibrosis. In this study, we performed three-step screening of newly synthesized IC-2 derivatives to identify other smallmolecule compounds that suppress liver fibrosis. Methods The screening system consisted of three steps: a cell viability assay, a transcription factor 4 (TCF4) reporter assay, and induction of α-smooth muscle actin (α-SMA) and collagen 1α1 (Col1A1) expression in response to each compound. Screening using human LX-2 hepatic stellate cells (HSCs) was performed to target HSCs, which are the driver cells of liver fibrosis. Results In the first step, since 9b and 9b-CONH 2 at 100 μM did not have any effects on cell viability, they were omitted in the next screening. Additionally, the conditions that led to > 40% inhibition of the controls were also excluded in subsequent screening. The second step was performed under 31 conditions for 19 smallmolecule compounds. Sixteen small-molecule compounds caused significant reduction of TCF4 activity relative to that of 0.1% DMSO. Of the 16 compounds, the 10 showing the greatest suppression of TCF4 activity were selected for the third step. Expressions of mRNA for α-SMA and Col1A1 were significantly reduced by seven and three small-molecule compounds, respectively. The greatest reductions in the α-SMA and Col1A1 mRNA expressions were observed in the cells treated with IC-2-F. Protein expressions of α-SMA and Col1A1 caused by IC-2-F were also comparable to those caused by IC-2. Conclusion IC-2-F was identified as a novel deactivating small-molecule compound for HSCs in vitro. These data suggest that IC-2-F is a promising medicine for liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Reporter Assaymentioning

confidence: 99%

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Identification of a Novel Deactivating Small-Molecule Compound for Fibrogenic Hepatic Stellate Cells

et al. 2020

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“…We have previously shown that IC-2 efficiently induces hepatic differentiation of human MSCs (15,16), thus IC-2 may also enhance differentiation of CSCs, which could contribute to inhibition of sphere formation. Since CSCs are relatively resistant to chemotherapy including 5-FU (21), if CSC differentiation is stimulated by IC-2, it may potentiate the sensitivity of CRC to 5-FU.…”

Section: Discussionmentioning

confidence: 99%

WNT/β-Catenin Signaling Inhibitor IC-2 Suppresses Sphere Formation and Sensitizes Colorectal Cancer Cells to 5-Fluorouracil

2017

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Abstract. Background Colorectal cancer (CRC) is one of the most common cancer types in the world and carries the second highest mortality rate (1). Although initial events in CRC are relatively well studied and treatment for early-stage disease has significantly improved over the past decades, the mechanisms of metastasis and relapse, which are the main causes of death, remain poorly characterized (2). Currently, no effective therapy is available for advanced or metastatic disease and the survival rate at 5 years of follow-up is approximately 50% (3). Thus, a novel therapeutic strategy is urgently required for improving the clinical outcome of CRC.Recent studies suggest that a small subpopulation of cells, so-called cancer stem cells (CSCs), possess high tumorigenicity (4-6). CSCs have the unique features of selfrenewal and asymmetrical division, and are resistant to radio-and chemotherapy (7,8). The CSCs remaining after conventional therapies may promote the high metastasis and relapse of CRC. Therefore, suppression of CSCs is considered a promising approach to improve therapeutic effects on many types of cancers including CRC.Most CRCs carry somatic mutations in one of two genes, adenomatous polyposis coli (APC) and β-catenin (CTNNB1) (9-11). Defect of these genes activates the canonical winglesstype MMTV integration site family (WNT)/β-catenin signaling pathway. It has been shown that the WNT/β-catenin signaling regulates expression levels of CSC marker genes and is essential for maintenance of the undifferentiated status and self-renewal capability of CSCs (12-14). Since we recently developed a derivative of a WNT/β-catenin signaling inhibitor, IC-2, which efficiently suppresses WNT/β-catenin transcriptional activity and induces hepatic differentiation of human mesenchymal stem cells (MSCs) (15, 16), we explored its effect on colorectal cancer cells. Materials and MethodsSmall molecular compounds. We recently developed WNT/β-catenin signaling inhibitors. IC-2, a derivative of ICG-001, efficiently represses WNT/β-catenin signaling and most effectively induces hepatic differentiation of human MSCs (16). The DNA/RNA synthesis inhibitor, 5-fluorouracil (5-FU) was purchased from Nacalai tesque inc. (Kyoto, Japan). The compounds were 4085

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“…) . Recently, we synthesized a novel small molecule compound that strongly induces hepatic differentiation of human MSCs . These small molecule compounds are potent tools for stem cell‐based therapy for liver disease.…”

Section: Bone Marrow‐derived Mesenchymal Stem Cell‐engineered Hepaticmentioning

confidence: 99%

Progress in stem cell‐based therapy for liver disease

Shiota

Itaba

2016

Hepatology Research

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Liver transplantation has been accepted as a useful therapeutic approach for patients with end-stage liver disease. However, the mismatch between the great demand for liver transplants and the number of available donor organs underscores the urgent need for alternative therapeutic strategies for patients with acute and chronic liver failure. The rapidly growing knowledge on stem cell biology has opened new avenues toward stem cell-based therapy for liver disease. As stem cells have capacity for high proliferation and multipotent differentiation, the characteristics of stem cells fit the cell therapy. Several types of cells have been investigated as possible sources of liver regeneration: mesenchymal stem cells, hematopoietic stem cells, liver progenitor cells, induced pluripotent stem cells, and bone marrow mononuclear cells. In vitro and in vivo experiments revealed that these cells have great potential as candidates of stem cell therapy. We reviewed the reports on clinical trials of cell therapy for liver disease that have been recently undertaken using mesenchymal stem cells, hematopoietic stem cells, bone marrow mononuclear cells, and liver progenitor cells. These reports have heterogeneity of description of trial design, types of infused cells, patient population, and efficacy of therapies. We addressed these reports from these viewpoints and clarified their significance. We hope that this review article will provide a perspective on the available approaches based on stem cell-based therapy for liver disease.

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Identification of the small molecule compound which induces hepatic differentiation of human mesenchymal stem cells

Cited by 11 publications

References 35 publications

Identification of a Novel Deactivating Small-Molecule Compound for Fibrogenic Hepatic Stellate Cells

Identification of a Novel Deactivating Small-Molecule Compound for Fibrogenic Hepatic Stellate Cells

WNT/β-Catenin Signaling Inhibitor IC-2 Suppresses Sphere Formation and Sensitizes Colorectal Cancer Cells to 5-Fluorouracil

Progress in stem cell‐based therapy for liver disease

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