期刊
EXPERIMENTAL BIOLOGY AND MEDICINE
卷 242, 期 16, 页码 1605-1616出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1535370217707731
关键词
Liver zonation; liver diseases; induced pluripotent stem cells; microfluidics; hepatocytes; microphysiology systems
资金
- Environmental Protection Agency [83576301]
- National Center for Advancing Translational Sciences [5UH3 TR000503-05, 3UH3 TR000503-05S1]
- University of Pittsburgh Cancer Institute [2P30 CA047904-27]
- NIH [R01DK62277, R01DK100287, R01DK095498, R01CA204586]
- Endowed Chair for Experimental Pathology
- Competitive Medical Research Fund Program from UPMC Health System
- University of Pittsburgh Physicians (UPP)/UPMC Academic Foundation
- US National Institutes of Health [DK099257, UH3TR000503]
- Alternatives Research & Development Foundation Liver Disease Program
The establishment of metabolic zonation within a hepatic lobule ascribes specific functions to hepatocytes based on unique, location-dependent gene expression patterns. Recently, there have been significant developments in the field of metabolic liver zonation. A little over a decade ago, the role of -catenin signaling was identified as a key regulator of gene expression and function in pericentral hepatocytes. Since then, additional molecules have been identified that regulate the pattern of Wnt/-catenin signaling within a lobule and determine gene expression and function in other hepatic zones. Currently, the molecular basis of metabolic zonation in the liver appears to be a push and pull' between signaling pathways. Such compartmentalization not only provides an efficient assembly line for hepatocyte functions but also can account for restricting the initial hepatic damage and pathology from some hepatotoxic drugs to specific zones, possibly enabling effective regeneration and restitution responses from unaffected cells. Careful analysis and experimentation have also revealed that many pathological conditions in the liver lobule are spatially heterogeneous. We will review current research efforts that have focused on examination of the role and regulation of such mechanisms of hepatocyte adaptation and repair. We will discuss how the pathological organ-specific microenvironment affects cell signaling and metabolic liver zonation, especially in steatosis, viral hepatitis, and hepatocellular carcinoma. We will discuss how the use of new human microphysiological platforms will lead to a better understanding of liver disease progression, diagnosis, and therapies. In conclusion, we aim to provide insights into the role and regulation of metabolic zonation and function using traditional and innovative approaches.
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