Hedgehog regulates yes‐associated protein 1 in regenerating mouse liver
| Autor: | Gregory A. Michelotti, Mark L. Jewell, Marzena Swiderska-Syn, Richard T. Premont, Anna Mae Diehl, Guanhua Xie, Wing-Kin Syn |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty medicine.medical_treatment Cell Cycle Proteins Mice Transgenic Biology Article 03 medical and health sciences Internal medicine Paracrine Communication Hepatic Stellate Cells medicine Animals Hepatectomy Hedgehog Proteins Hedgehog Adaptor Proteins Signal Transducing Cell Proliferation YAP1 Hepatology Regeneration (biology) YAP-Signaling Proteins Cell Dedifferentiation Phosphoproteins medicine.disease Hedgehog signaling pathway Liver regeneration Liver Regeneration Up-Regulation Cell biology Mice Inbred C57BL 030104 developmental biology Endocrinology Hepatocytes Hepatic stellate cell Liver cancer |
| Zdroj: | Hepatology. 64:232-244 |
| ISSN: | 1527-3350 0270-9139 |
| Popis: | Introduction: Adult liver regeneration requires induction and suppression of proliferative activity in multiple types of liver cells. The mechanisms that orchestrate the global changes in gene expression that are required for proliferative activity to change within individual liver cells, and that coordinate proliferative activity among different types of liver cells, are not well understood. Morphogenic signaling pathways that are active during fetal development, including Hedgehog and Hippo/Yes-associated protein 1 (Yap1), regulate liver regeneration in adulthood. Cirrhosis and liver cancer result when these pathways become dysregulated but relatively little is known about the mechanisms that coordinate and control morphogenic signaling during effective liver regeneration. Methods: We evaluated the hypothesis that the Hedgehog pathway controls Yap1 activation during liver regeneration by studying intact mice and cultured liver cells. Results: In cultured hepatic stellate cells (HSC), disrupting Hedgehog signaling blocked activation of Yap1, and knocking down Yap1 inhibited induction of both Yap1 and Hedgehog-regulated genes that enable HSC to become myofibroblasts (MF). In mice, disrupting Hedgehog signaling in MF inhibited liver regeneration after PH. Reduced proliferative activity in the liver epithelial compartment resulted from loss of stroma-derived paracrine signals that activate Yap1 and the Hedgehog pathway in hepatocytes. This prevented hepatocytes from up-regulating Yap1- and Hedgehog-regulated transcription factors that normally promote their proliferation. Conclusion: Morphogenic signaling in HSC is necessary to reprogram hepatocytes to regenerate the liver epithelial compartment after partial hepatectomy. This discovery identifies novel molecules that might be targeted to correct defective repair during cirrhosis and liver cancer. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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