Effect of retinoic acid on transglutaminase and ornithine decarboxylase activities during liver regeneration

Ohtake, Yosuke; Maruko, Akiko; Ohishi, Nao; Kawaguchi, Masasumi; Satoh, T.; Ohkubo, Yasuhito

doi:10.1002/cbf.1451

Cited by 13 publications

(8 citation statements)

References 42 publications

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“…The study by Song et al (28) revealed differential expression of a subset of miRNAs, notably the induction of miR-21 and repression of miR-378. For both miRNAs, they identified Btg2 and ODC1 as novel targets, which are relevant for DNA synthesis in hepatocytes after liver resection (24,29). These previous studies all show that specific miRNAs are crucial to induce liver regeneration and promote cell proliferation, but they did not consider the regenerative peak after PH.…”

Section: Discussionmentioning

confidence: 92%

Temporal expression profiles indicate a primary function for microRNA during the peak of DNA replication after rat partial hepatectomy

Raschzok

Werner

Sallmon

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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The liver has the unique capacity to regenerate after surgical resection. However, the regulation of liver regeneration is not completely understood. Recent reports indicate an essential role for small noncoding microRNAs (miRNAs) in the regulation of hepatic development, carcinogenesis, and early regeneration. We hypothesized that miRNAs are critically involved in all phases of liver regeneration after partial hepatectomy. We performed miRNA microarray analyses after 70% partial hepatectomy in rats under isoflurane anesthesia at different time points (0 h to 5 days) and after sham laparotomy. Putative targets of differentially expressed miRNAs were determined using a bioinformatic approach. Two-dimensional (2D)-PAGE proteomic analyses and protein identification were performed on specimens at 0 and 24 h after resection. The temporal dynamics of liver regeneration were characterized by 5-bromo- 2-deoxyuridine, proliferating cell nuclear antigen, IL-6, and hepatocyte growth factor. We demonstrate that miRNA expression patterns changed during liver regeneration and that these changes were most evident during the peak of DNA replication at 24 h after resection. Expression of 13 miRNAs was significantly reduced 12-48 h after resection (>25% change), out of which downreguation was confirmed in isolated hepatocytes for 6 miRNAs at 24 h, whereas three miRNAs were significantly upregulated. Proteomic analysis revealed 65 upregulated proteins; among them, 23 represent putative targets of the differentially expressed miRNAs. We provide a temporal miRNA expression and proteomic dataset of the regenerating rat liver, which indicates a primary function for miRNA during the peak of DNA replication. These data will assist further functional studies on the role of miRNAs during liver regeneration.

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Section: Discussionmentioning

confidence: 92%

Temporal expression profiles indicate a primary function for microRNA during the peak of DNA replication after rat partial hepatectomy

Raschzok

Werner

Sallmon

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Notably, pluripotency genes, such as OCT4 and NANOG , were unchanged. Genes involved in liver repair [24], [25], such as CXCL9 , CXCL10 , and ODC1 were activated. Control genes, such as ACTB and B2M , were unchanged.…”

Section: Resultsmentioning

confidence: 99%

Direct Reprogramming of Human Fibroblasts to Hepatocyte-Like Cells by Synthetic Modified mRNAs

Simeonov¹,

Uppal²

2014

PLoS ONE

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Direct reprogramming by overexpression of defined transcription factors is a promising new method of deriving useful but rare cell types from readily available ones. While the method presents numerous advantages over induced pluripotent stem (iPS) cell approaches, a focus on murine conversions and a reliance on retroviral vectors limit potential human applications. Here we address these concerns by demonstrating direct conversion of human fibroblasts to hepatocyte-like cells via repeated transfection with synthetic modified mRNAs. Hepatic induction was achieved with as little as three transcription factor mRNAs encoding HNF1A plus any two of the factors, FOXA1, FOXA3, or HNF4A in the presence of an optimized hepatic growth medium. We show that the absolute necessity of exogenous HNF1A mRNA delivery is explained both by the factor's inability to be activated by any other factors screened and its simultaneous ability to strongly induce expression of other master hepatic transcription factors. Further analysis of factor interaction showed that a series of robust cross-activations exist between factors that induce a hepatocyte-like state. Transcriptome and small RNA sequencing during conversion toward hepatocyte-like cells revealed global preferential activation of liver genes and miRNAs over those associated with other endodermal tissues, as well as downregulation of fibroblast-associated genes. Induced hepatocyte-like cells also exhibited hepatic morphology and protein expression. Our data provide insight into the process by which direct hepatic reprogramming occurs in human cells. More importantly, by demonstrating that it is possible to achieve direct reprogramming without the use of retroviral gene delivery, our results supply a crucial step toward realizing the potential of direct reprogramming in regenerative medicine.

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“…Among 64 genes predicted as targets of miR‐378 in both mice and humans, four genes were previously reported to have a positive effect on cell proliferation (Supporting Information Table 3). Intriguingly, one of these genes, Odc1 , encodes a polyamine‐synthesizing enzyme that is needed for efficient and timely DNA synthesis in liver regeneration 28. Furthermore, Odc1 had the highest score and free energy of the predicted conserved miR‐378 target genes with established proliferation‐promoting function (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

MicroRNAs control hepatocyte proliferation during liver regeneration

Song¹,

Sharma²,

Roll³

et al. 2010

Hepatology

196

169

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MicroRNAs (miRNAs) constitute a new class of regulators of gene expression. Among other actions, miRNAs have been shown to control cell proliferation in development and cancer. However, whether miRNAs regulate hepatocyte proliferation during liver regeneration is unknown. We addressed this question by performing 2/3 partial hepatectomy (2/3 PH) on mice with hepatocyte-specific inactivation of DiGeorge syndrome critical region gene 8 (DGCR8), an essential component of the miRNA processing pathway. Hepatocytes of these mice were miRNA-deficient and exhibited a delay in cell cycle progression involving the G1 to S phase transition. Examination of livers of wildtype mice after 2/3 PH revealed differential expression of a subset of miRNAs, notably an induction of miR-21 and repression of miR-378. We further discovered that miR-21 directly inhibits Btg2, a cell cycle inhibitor that prevents activation of forkhead box M1 (FoxM1), which is essential for DNA synthesis in hepatocytes after 2/3 PH. In addition, we found that miR-378 directly inhibits ornithine decarboxylase (Odc1), which is known to promote DNA synthesis in hepatocytes after 2/3 PH. Conclusion Our results show that miRNAs are critical regulators of hepatocyte proliferation during liver regeneration. Because these miRNAs and target gene interactions are conserved, our findings may also be relevant to human liver regeneration.

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Effect of retinoic acid on transglutaminase and ornithine decarboxylase activities during liver regeneration

Cited by 13 publications

References 42 publications

Temporal expression profiles indicate a primary function for microRNA during the peak of DNA replication after rat partial hepatectomy

Temporal expression profiles indicate a primary function for microRNA during the peak of DNA replication after rat partial hepatectomy

Direct Reprogramming of Human Fibroblasts to Hepatocyte-Like Cells by Synthetic Modified mRNAs

MicroRNAs control hepatocyte proliferation during liver regeneration

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