Liver homeostasis is maintained by midlobular zone 2 hepatocytes

doi:10.1126/science.abb1625

GSTDTAP > 气候变化

DOI	10.1126/science.abb1625
	Liver homeostasis is maintained by midlobular zone 2 hepatocytes
	Yonglong Wei; Yunguan G. Wang; Yuemeng Jia; Lin Li; Jung Yoon; Shuyuan Zhang; Zixi Wang; Yu Zhang; Min Zhu; Tripti Sharma; Yu-Hsuan Lin; Meng-Hsiung Hsieh; Jeffrey H. Albrecht; Phuong T. Le; Clifford J. Rosen; Tao Wang; Hao Zhu
	2021-02-26
发表期刊	Science
出版年	2021
英文摘要	For organ homeostasis or regrowth after injury or disease, one or more stem cell populations is needed to rebuild lost tissue. There is considerable debate about the source of new cells in the liver. Two groups now identify the source of new hepatocytes (see the Perspective by Andersson). Although the liver may seem to lack major variation across its structure, its lobule is organized into concentric zones where hepatocytes express different metabolic enzymes. Wei et al. sought to systematically define the source of new liver cells by comparing 14 fate-mapping mice that label different liver cell types. They found that different regions of the liver lobule exhibit differences in hepatocyte turnover, with zone 2 representing a primary source of new hepatocytes during homeostasis and regeneration. Similarly, He et al. designed a genetic approach to record cell proliferation in vivo with high spatial and temporal resolution to enable continuous recording of proliferative events of any specific cell type at the whole-cell population level. Using this method, they identified zone 2 as having the highest proliferative activity and contributing the most to liver regrowth. These findings have implications for the cellular basis of chronic disease pathogenesis, cancer development, and regenerative medicine strategies. Science , this issue p. [eabb1625][1], p. [eabc4346][2]; see also p. [887][3] ### INTRODUCTION The liver’s remarkable capacity to maintain proper tissue mass after injury has been known since ancient times. However, there has been considerable debate about the source of new liver cells that contribute to tissue growth, maintenance, and regeneration. Multiple studies have reported that disparate cell populations in the liver serve as rare stem cells, whereas others have proposed that most hepatocytes are similar in their regenerative activity regardless of position or function. Although hepatocytes appear histologically homogeneous, the liver lobule is actually organized into concentric zones, or rings, in which hepatocytes express different metabolic enzymes across the portal vein–to–central vein axis through which blood flows. Recently, single-cell profiling has enriched our understanding of the extraordinary diversity of hepatocytes, but this “zonal” heterogeneity has not been functionally interrogated in the context of tissue homeostasis, because the critical genetic labeling tools have not been available. ### RATIONALE Previous efforts to identify the most-regenerative hepatocytes have not definitively resolved fundamental questions about whether regenerative activity is spatially restricted within particular zones or whether rare or common subsets of hepatocytes are responsible. This uncertainty was in part because fate mapping had only been performed on a few hepatocyte subsets and without side-by-side comparisons. We sought to systematically address fundamental questions about the source of new liver cells by generating a panel of 11 new CreER knock-in mouse models that label zonal subpopulations across the liver lobule. By using these tools in tandem with three existing CreER lines, tissue maintenance and regeneration as a function of zonal position were assessed. ### RESULTS In contrast to the idea that all hepatocytes across the lobule contribute equally to regeneration, we identified major differences between hepatocytes from different locations. During steady-state homeostasis, zone 1 cells near the portal vein decreased in number over time, as did zone 3 cells near the central vein on the opposite end of the lobule. However, midlobular zone 2 hepatocytes marked by the hepcidin antimicrobial peptide 2 ( Hamp2 ) gene were in large part responsible for homeostatic repopulation. Zone 2 cells were also sheltered from toxic injuries affecting either end of the lobule and thus were well positioned to contribute to regeneration after these insults. To define the mechanistic basis of these lineage-tracing results, single-cell and bulk RNA sequencing transcriptomics were used to define genes that were specifically up- or down-regulated in zone 2. We then used in vivo CRISPR knockout and activation screening to identify functionally important pathways that regulate zone 2 proliferation. These methods revealed that zone 2 repopulation is driven by the insulin-like growth factor binding protein 2–mechanistic target of rapamycin–cyclin D1 (IGFBP2-mTOR-CCND1) axis. ### CONCLUSION Different regions of the liver lobule exhibit differences in their contributions to hepatocyte turnover, and zone 2 is an important source of new hepatocytes during homeostasis and regeneration. These results challenge the idea that stem cells near the portal or central veins have the highest rates of liver repopulation, but they also support the principle that there are important zonal differences in hepatocyte biology. This study reconciles findings from multiple groups and offers a more unified view of hepatocyte repopulation. The identification of zone 2 hepatocytes as a regenerative population has far-reaching implications for the cellular basis of chronic disease pathogenesis, cancer development, and regenerative medicine strategies. ![Figure][4] Fate-mapping strains label different zones across the liver lobule. Cross-sectional images of a liver lobe from a glutaminase 2 (Gls2)–CreER reporter mouse in which hepatocytes from different metabolic zones are labeled. Panels from left to right: (i) 4′,6-diamidino-2-phenylindole (DAPI) staining (blue) of cell nuclei, (ii) glutamine synthetase staining (green) of hepatocytes adjacent to central veins, (iii) Tomato fluorescence (red) that labels Gls2 -expressing hepatocytes in zone 1, and (iv) a merged composite image of all three channels. This reporter strain is one of 14 used to track metabolically heterogeneous hepatocytes in the liver. Collectively, these strains were used to understand the regenerative capacity of different liver cell subtypes under homeostatic and injury conditions. The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain undefined, because fate mapping has only been performed on a few hepatocyte subsets. Here, 14 murine fate-mapping strains were used to systematically compare distinct subsets of hepatocytes. During homeostasis, cells from both periportal zone 1 and pericentral zone 3 contracted in number, whereas cells from midlobular zone 2 expanded in number. Cells within zone 2, which are sheltered from common injuries, also contributed to regeneration after pericentral and periportal injuries. Repopulation from zone 2 was driven by the insulin-like growth factor binding protein 2–mechanistic target of rapamycin–cyclin D1 (IGFBP2-mTOR-CCND1) axis. Therefore, different regions of the lobule exhibit differences in their contribution to hepatocyte turnover, and zone 2 is an important source of new hepatocytes during homeostasis and regeneration. [1]: /lookup/doi/10.1126/science.abb1625 [2]: /lookup/doi/10.1126/science.abc4346 [3]: /lookup/doi/10.1126/science.abg4864 [4]: pending:yes
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/315931
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Yonglong Wei,Yunguan G. Wang,Yuemeng Jia,et al. Liver homeostasis is maintained by midlobular zone 2 hepatocytes[J]. Science,2021.
APA	Yonglong Wei.,Yunguan G. Wang.,Yuemeng Jia.,Lin Li.,Jung Yoon.,...&Hao Zhu.(2021).Liver homeostasis is maintained by midlobular zone 2 hepatocytes.Science.
MLA	Yonglong Wei,et al."Liver homeostasis is maintained by midlobular zone 2 hepatocytes".Science (2021).