Nuclear receptor gene alteration in human induced pluripotent stem cells with hepatic differentiation propensity

Itaba, Noriko; Wairagu, Peninah M.; Aramaki, Natsumi; Yasui, Toshihiro; Matsumi, Yoshiaki; Kono, Yohei; Phan, Ai N.H.; Otsu, Makoto; Kunisada, Takahiro; Nakamura, Yukio; Jeong, Yangsik; Shiota, Goshi

doi:10.1111/hepr.12329

Cited by 9 publications

(5 citation statements)

References 48 publications

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“…In the promoter region of the human C3 , there is a liver X receptor (LXR)-responsive element, and LXR-dependent regulation of C3 expression has been reported [29] . LXR expression is upregulated in accordance with hepatic differentiation of iPSCs [30] , [31] . Moreover, LXR regulates differentiation of hepatic cells [32] .…”

Section: Discussionmentioning

confidence: 97%

Hepatic cell sheets engineered from human mesenchymal stem cells with a single small molecule compound IC-2 ameliorate acute liver injury in mice

Itaba

Noda

Oka

et al. 2018

Regenerative Therapy

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IntroductionWe 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.MethodsWe 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.ResultsSignificant 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.ConclusionThe single compound IC-2 induced hepatic cell sheets that possess potent regeneration capacity and ameliorate acute liver injury.

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Section: Discussionmentioning

confidence: 97%

Hepatic cell sheets engineered from human mesenchymal stem cells with a single small molecule compound IC-2 ameliorate acute liver injury in mice

Itaba

Noda

Oka

et al. 2018

Regenerative Therapy

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“…Nuclear receptors are one of the largest classes of transcription factors and regulate many cellular functions through manipulation of gene expression 23 . They play important roles in many physiological and pathological processes 24 . Liver X receptor alpha (LXRα) is a nuclear receptor encoded by NR1H3 gene, and forms a subfamily of the NR superfamily along with liver X receptor β.…”

Section: Discussionmentioning

confidence: 99%

NR1H3 Expression is a Prognostic Factor of Overall Survival for Patients with Muscle-Invasive Bladder Cancer

Wan

Sheng

et al. 2017

J. Cancer

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Background: Nuclear receptors (NRs) are a class of transcription factors that regulate many cellular functions through manipulation of gene expression and also play important roles in tumorigenesis, proliferation, progression and prognosis in various kinds of cancers according to recent studies. This work aimed to determine the predictive ability of NRs in muscle-invasive bladder cancer (MIBC).Patients and methods: A total of 308 MIBC patients with complete clinicopathological and RNASeq data from The Cancer Genome Atlas (TCGA) cohort were collected for filtration. Genes showed clear correlations with overall survival (OS) and recurrence free survival (RFS) were further validated in 123 MIBC patients recruited consecutively from 2008 to 2012 in Fudan University Shanghai Cancer Center (FUSCC) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors.Results: In TCGA cohort, we found that high NR1H3 (HR=0.779, 95% CI: 0.634 - 0.957), NR2C1 (HR=0.673, 95% CI: 0.458 - 0.989) and NR2F6 (HR=0.750, 95% CI: 0.574 - 0.980) expressions were independent factors of favorable OS, while only low NR1H3 (log-rank test, P=0.0076) and NR2F6 (log-rank test, P=0.0395) expressions had the ability to predict poor prognosis for RFS. Further, in FUSCC validating cohort, we confirmed that low NR1H3 expression level was independent factor of poor OS (HR=1.295, 95% CI: 1.064 - 1.576) and it had the ability to predict poor RFS (log-rank test, P=0.0059).Conclusions: Low NR1H3 expression level is an independent prognostic factor of poor OS, and can also predict worse RFS in MIBC patients. Our “TCGA filtrating and local database validating” model can help reveal more prognostic biomarkers and cast a new light in understanding certain gene function in MIBC.

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“…A human iPS cell line, TkDA3-4, was established as described previously [21]. Some of the experiments were performed using a human iPS cell line, RIKEN-2F, derived from Riken BioResource Center (Tsukuba, Japan) [22]. The study was conducted in accordance with the Declaration of Helsinki.…”

Section: Human Ips Cell Culturementioning

confidence: 99%

A Paracrine Mechanism Accelerating Expansion of Human Induced Pluripotent Stem Cell-Derived Hepatic Progenitor-Like Cells

Tsuruya

Chikada

Ida

et al. 2015

Stem Cells and Development

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Hepatic stem/progenitor cells in liver development have a high proliferative potential and the ability to differentiate into both hepatocytes and cholangiocytes. In this study, we focused on the cell surface molecules of human induced pluripotent stem (iPS) cell-derived hepatic progenitor-like cells (HPCs) and analyzed how these molecules modulate expansion of these cells. Human iPS cells were differentiated into immature hepatic lineage cells by cytokines. In addition to hepatic progenitor markers (CD13 and CD133), the cells were coimmunostained for various cell surface markers (116 types). The cells were analyzed by flow cytometry and in vitro colony formation culture with feeder cells. Twenty types of cell surface molecules were highly expressed in CD13(+)CD133(+) cells derived from human iPS cells. Of these molecules, CD221 (insulin-like growth factor receptor), which was expressed in CD13(+)CD133(+) cells, was quickly downregulated after in vitro expansion. The proliferative ability was suppressed by a neutralizing antibody and specific inhibitor of CD221. Overexpression of CD221 increased colony-forming ability. We also found that inhibition of CD340 (erbB2) and CD266 (fibroblast growth factor-inducible 14) signals suppressed proliferation. In addition, both insulin-like growth factor (a ligand of CD221) and tumor necrosis factor-like weak inducer of apoptosis (a ligand of CD266) were provided by feeder cells in our culture system. This study revealed the expression profiles of cell surface molecules in human iPS cell-derived HPCs and that the paracrine interactions between HPCs and other cells through specific receptors are important for proliferation.

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Nuclear receptor gene alteration in human induced pluripotent stem cells with hepatic differentiation propensity

Abstract: These findings will be useful for not only elucidating mechanisms of hepatic differentiation of hiPS cells but also cell-based therapy for liver diseases.

Cited by 9 publications

References 48 publications

Hepatic cell sheets engineered from human mesenchymal stem cells with a single small molecule compound IC-2 ameliorate acute liver injury in mice

Hepatic cell sheets engineered from human mesenchymal stem cells with a single small molecule compound IC-2 ameliorate acute liver injury in mice

NR1H3 Expression is a Prognostic Factor of Overall Survival for Patients with Muscle-Invasive Bladder Cancer

A Paracrine Mechanism Accelerating Expansion of Human Induced Pluripotent Stem Cell-Derived Hepatic Progenitor-Like Cells

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