Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration

Ding, Bi Sen; Nolan, Daniel J.; Butler, Jason M.; James, Daylon; Babazadeh, Alexander O.; Rosenwaks, Zev; Mittal, Vivek; Kobayashi, Hideki; Shido, Koji; Lyden, David; Sato, Thomas N.; Rabbany, Sina Y.; Rafii, Shahin

doi:10.1038/nature09493

Cited by 690 publications

(758 citation statements)

References 38 publications

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“…10 Wnt2 has previously been shown to be released from the endothelial cells in the liver; macrophages have also been shown to be a source of Wnt proteins, and these collectively activate b-catenin signaling in hepatocytes during LR after PH in a paracrine manner. 10,34 This induces expression of cyclin-D1, 3,4 which is known to eventually stimulate G 1 to S phase transition in hepatocytes to initiate the process of hepatocyte proliferation. 35 In the current study, we show that Wnt5a is released from hepatocytes at 24 hours after PH, and at the same time, there is enhanced expression of Frizzled-2.…”

Section: Resultsmentioning

confidence: 99%

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Yang

Cusimano

Monga

et al. 2015

The American Journal of Pathology

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Activation of Wnt/b-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased b-catenineT-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in b-catenineT-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression.In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of b-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses b-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process. (Am J Pathol 2015, 185: 2194e2205; http:// dx

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Section: Resultsmentioning

confidence: 99%

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Yang

Cusimano

Monga

et al. 2015

The American Journal of Pathology

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“…Studies have demonstrated that the non-parenchymal cells are important for maintaining the function of hepatocytes. [21][22][23] Consequently, our subsequent work is to co-culture non-parenchymal cells with hepatocytes to improve the hepatocytes' growth and functions.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Culture in Autologous Decellularized Spleen Matrix

Gao¹,

Xiang³

et al. 2015

Organogenesis

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ABSTRACT. Background and Aims: Using decellularized scaffold to reengineer liver tissue is a promising alternative therapy for end-stage liver diseases. Though the decellularized human liver matrix is the ideal scaffold for reconstruction of the liver theoretically, the shortage of liver donors is still an obstacle for potential clinical application. Therefore, an appropriate alternative scaffold is needed. In the present study, we used a tissue engineering approach to prepare a rat decellularized spleen matrix (DSM) and evaluate the effectiveness of this DSM for primary rat hepatocytes culture. Methods: Rat decellularized spleen matrix (DSM) was prepared by perfusion of a series of detergents through spleen vasculature. DSM was characterized by residual DNA and specific extracellular matrix distribution. Thereafter, primary rat hepatocytes were cultured in the DSM in a 3-dimensional dynamic culture system, and liver cell survival and biological functions were evaluated by comparison with 3-dimensional sandwich culture and also with cultured in decellularized liver matrix (DLM). Results: Our research found that DSM did not exhibit any cellular components, but preserved the main extracellular matrix and the intact vasculature evaluated by DNA detection, histology, immunohistochemical staining, vessel corrosion cast and upright metallurgical microscope. *Correspondence to: Yi Lv; Email: luyi169@126.com Received July 7, 2014; Revised September 10, 2014; Accepted January 18, 2015.16 Organogenesis, 11:16-29, 2015 Ó 2015 Taylor & Francis Group, LLC ISSN: 1547-6278 print / 1555-8592 online DOI: 10.1080/15476278.2015 Moreover, the method of DSM preparation procedure was relatively simple with high success rate (100%). After seeding primary hepatocytes in DSM, the cultured hepatocytes survived inside DSM with albumin synthesis and urea secretion within 10 d. Additionally, hepatocytes in dynamic culture medium had better biological functions at day 10 than that in sandwich culture. Albumin synthesis was 85.67 § 6.34 mg/10 7 cell/24h in dynamic culture in DSM compared to 62.43 § 4.59 mg/10 7 cell/ 24h in sandwich culture (P < 0.01) and to 87.54 § 5.25 mg/10 7 cell/24h in DLM culture (P > 0.05); urea release was 32.14 § 8.62 mg/10 7 cell/24h in dynamic culture in DSM compared to 20.47 § 4.98 mg/10 7 cell/24h in sandwich culture (P < 0.05) and to 37.38 § 7.29 mg/10 7 cell/24h cultured in DLM (P > 0.05). Conclusion: The present study demonstrates that DSM can be prepared successfully using a tissue engineering approach. The DSM is an appropriate scaffold for primary hepatocytes culture.

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“…Moreover, VEGF-A also has nonangiogenic functions in normal physiology. In liver tissue, VEGF-A elicits hepatocyte proliferation by elevating expression of hepatocyte mitogens in liver sinusoidal endothelial cells ( 24,25 ).…”

Section: Introductionmentioning

confidence: 99%

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

et al. 2014

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Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplifi cation, displaying distinct biologic characteristics. Unlike common tumor amplifi cations, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifi cally in amplicon-positive mouse HCCs. Sorafenib-the fi rst-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild benefi cial effect. We found that VEGFA amplifi cation specifi es mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA -amplifi ed HCCs, suggesting that VEGFA amplifi cation is a potential biomarker for HCC response to VEGF-A-blocking drugs. SIGNIFICANCE:Using a mouse model of infl ammation-driven cancer, we identifi ed a subclass of HCC carrying VEGFA amplifi cation, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplifi cation in human HCC identifi es patients who favorably responded to sorafenib-the fi rst-line treatment of advanced HCC-which has an overall moderate therapeutic effi cacy. Cancer Discov; 4(6);

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Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration

Cited by 690 publications

References 38 publications

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Hepatocyte Culture in Autologous Decellularized Spleen Matrix

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

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