Expression of VEGFR-2 during Liver Regeneration after Partial Hepatectomy in a Bioluminescence Mouse Model

Alizai, Patrick H.; Bertram, L.; Kroy, Daniela C.; Kummer, J; Andert, Anne; Neumann, Ulf; Ulmer, Tom Florian; Fragoulis, Athanassios

doi:10.1159/000479628

Cited by 7 publications

(7 citation statements)

References 33 publications

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“…Therefore, we analyzed the angiogenic endothelial cell activity and microvessel density in the liver after PHx by immunohistochemistry. A markedly increased mean angiogenic activity was detected at day 4 after PHx that decreased steadily until day 21 which is in accordance with previously published data (Alizai et al, 2017). Quantitative analysis of the microvessel density showed no significant differences between mice after PHx and control mice.…”

Section: Discussionsupporting

confidence: 93%

Non-invasive Imaging and Modeling of Liver Regeneration After Partial Hepatectomy

et al. 2019

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The liver has a unique regenerative capability upon injury or partial resection. The regeneration process comprises a complex interplay between parenchymal and non-parenchymal cells and is tightly regulated at different scales. Thus, we investigated liver regeneration using multi-scale methods by combining non-invasive imaging with immunohistochemical analyses. In this context, non-invasive imaging can provide quantitative data of processes involved in liver regeneration at organ and body scale. We quantitatively measured liver volume recovery after 70% partial hepatectomy (PHx) by micro computed tomography (μCT) and investigated changes in the density of CD68 + macrophages by fluorescence-mediated tomography (FMT) combined with μCT using a newly developed near-infrared fluorescent probe. In addition, angiogenesis and tissue-resident macrophages were analyzed by immunohistochemistry. Based on the results, a model describing liver regeneration and the interactions between different cell types was established. In vivo analysis of liver volume regeneration over 21 days after PHx by μCT imaging demonstrated that the liver volume rapidly increased after PHx reaching a maximum at day 14 and normalizing until day 21. An increase in CD68 + macrophage density in the liver was detected from day 4 to day 8 by combined FMT-μCT imaging, followed by a decline towards control levels between day 14 and day 21. Immunohistochemistry revealed the highest angiogenic activity at day 4 after PHx that continuously declined thereafter, whereas the density of tissue-resident CD169 + macrophages was not altered. The simulated time courses for volume recovery, angiogenesis and macrophage density reflect the experimental data describing liver regeneration after PHx at organ and tissue scale. In this context, our study highlights the importance of non-invasive imaging for acquiring quantitative organ scale data that enable modeling of liver regeneration.

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Section: Discussionsupporting

confidence: 93%

Non-invasive Imaging and Modeling of Liver Regeneration After Partial Hepatectomy

et al. 2019

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“…The monitoring of ARE activity in liver regeneration post partial hepatectomy (PHx) was made possible in vivo by using an ARE-driven luciferase reporter gene from the firefly ( Photinus pyralis ) [210] . Nrf2 activity was measured through in vivo bioluminescence imaging and in vitro luminescence assays.…”

Section: Applications Based On Aresmentioning

confidence: 99%

Antioxidant response elements: Discovery, classes, regulation and potential applications

et al. 2018

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Exposure to antioxidants and xenobiotics triggers the expression of a myriad of genes encoding antioxidant proteins, detoxifying enzymes, and xenobiotic transporters to offer protection against oxidative stress. This articulated universal mechanism is regulated through the cis-acting elements in an array of Nrf2 target genes called antioxidant response elements (AREs), which play a critical role in redox homeostasis. Though the Keap1/Nrf2/ARE system involves many players, AREs hold the key in transcriptional regulation of cytoprotective genes. ARE-mediated reporter constructs have been widely used, including xenobiotics profiling and Nrf2 activator screening. The complexity of AREs is brought by the presence of other regulatory elements within the AREs. The diversity in the ARE sequences not only bring regulatory selectivity of diverse transcription factors, but also confer functional complexity in the Keap1/Nrf2/ARE pathway. The different transcription factors either homodimerize or heterodimerize to bind the AREs. Depending on the nature of partners, they may activate or suppress the transcription. Attention is required for deeper mechanistic understanding of ARE-mediated gene regulation. The computational methods of identification and analysis of AREs are still in their infancy. Investigations are required to know whether epigenetics mechanism plays a role in the regulation of genes mediated through AREs. The polymorphisms in the AREs leading to oxidative stress related diseases are warranted. A thorough understanding of AREs will pave the way for the development of therapeutic agents against cancer, neurodegenerative, cardiovascular, metabolic and other diseases with oxidative stress.

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“…VEGFR-1 signaling facilitated liver recovery by reconstitution of sinusoids through recruitment of VEGFR-1expressing macrophages and by affecting gene expression including hepatotrophic and pro-angiogenic growth factors in mice [88]. Furthermore, VEGFR-2 activity showed a significant increase after partial hepatectomy in transgenic VEGFR-2-luc mice with maximum signals recorded on POD 3 [89]. However, data on humans are sparse.…”

Section: Vascular Endothelial Growth Factor (Vegf)mentioning

confidence: 99%

Markers of liver regeneration—the role of growth factors and cytokines: a systematic review

et al. 2020

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Background: Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. Methods: MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included.Results: Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints.Conclusion: High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual's regenerative potential in the future.

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Expression of VEGFR-2 during Liver Regeneration after Partial Hepatectomy in a Bioluminescence Mouse Model

Cited by 7 publications

References 33 publications

Non-invasive Imaging and Modeling of Liver Regeneration After Partial Hepatectomy

Non-invasive Imaging and Modeling of Liver Regeneration After Partial Hepatectomy

Antioxidant response elements: Discovery, classes, regulation and potential applications

Markers of liver regeneration—the role of growth factors and cytokines: a systematic review

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