Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair

doi:10.1126/science.abc4346

GSTDTAP > 气候变化

DOI	10.1126/science.abc4346
	Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair
	Lingjuan He; Wenjuan Pu; Xiuxiu Liu; Zhenqian Zhang; Maoying Han; Yi Li; Xiuzhen Huang; Ximeng Han; Yan Li; Kuo Liu; Mengyang Shi; Liang Lai; Ruilin Sun; Qing-Dong Wang; Yong Ji; Jan S. Tchorz; Bin Zhou
	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 Cell proliferation is a fundamental process in all multicellular organisms that is required to enable development, tissue homeostasis, tissue repair, and tissue regeneration. Disrupted proliferation is the pathogenic basis of many diseases. The ability to monitor cell proliferation has been essential for a myriad of studies in developmental biology, oncology, immunology, neuroscience, and regenerative medicine. The limitations of current approaches for measuring cell proliferation in vivo have left many fundamental questions in numerous life science fields insufficiently addressed. For example, decades of research have resulted in a controversial debate around zonal hepatocyte proliferation in liver homeostasis, repair, and regeneration. ### RATIONALE To provide a high–spatiotemporal resolution examination of in vivo cell proliferation, we take advantage of two orthogonal, site-specific recombinases (Cre and Dre) to develop a genetic proliferation lineage tracing method—proliferation tracer (ProTracer). ProTracer enables the temporally continuous recording of cell proliferation events with high spatial resolution in specific cell lineages. Highlighting its capabilities, we provide insights into the regional proliferation of adult mouse hepatocytes, which are heterogeneous in gene expression and function. Previous conflicting studies identifying hepatocytes with superior proliferative capacity have mostly relied on the lineage tracing of a subset of cell populations, thereby introducing a potential selective bias. Whether a specific population of hepatocytes with increased proliferative capacity exists remains unclear. Rather than tracing only a subset of the whole hepatocyte population, an unbiased assessment of proliferative events in the entire hepatocyte pool over time is needed to address this fundamental question. ### RESULTS After an initial pulse treatment of tamoxifen, ProTracer permits the temporally continuous genetic recording of in vivo cell proliferation in diverse cell lineages over time in multiple organs and tissues. Using a hepatocyte-specific promoter, ProTracer could be primed to specifically record proliferation in hepatocytes—and not any other cell lineages—in the mouse liver. Furthermore, ProTracer enables noninvasive, long-term monitoring of hepatocyte proliferation over time in live animals. Cell proliferation tracing revealed that, at the whole hepatocyte–population level, more proliferation was detected in a subset of midzonal hepatocytes during liver homeostasis, with less proliferation in periportal hepatocytes and minimal proliferation in pericentral hepatocytes. Clonal analysis showed that most of the hepatocytes labeled by ProTracer have undergone cell division. Additionally, a highly regional and dynamic hepatocyte generation pattern was observed during repair and regeneration in response to several liver injuries, such as partial hepatectomy, bile duct ligation, and carbon tetrachloride–induced liver injury. Furthermore, genetic tracing of the proliferation of other cell lineages by ProTracer revealed distinct cell proliferation dynamics of macrophages, biliary epithelial cells, endothelial cells, and hepatic stellate cells after partial hepatectomy. ### CONCLUSION Our work provides a genetic system for the cumulative recording of cell type–specific proliferation in vivo. By genetically tracing the proliferation events of entire cell populations, ProTracer enables the unbiased detection of the specific cell population that mainly accounts for tissue homeostasis, repair, and regeneration. ProTracer reveals highly regional proliferation in midzonal hepatocytes, showing its greater contribution to maintaining the hepatocyte pool during liver homeostasis. Additionally, ProTracer revealed highly regional hepatocyte generation during liver repair and regeneration after injuries. Future applications and further iterations of ProTracer could substantially advance our understanding of cell generation and their dynamics in development, growth, regeneration, and diseases in multiple organs. ![Figure][4] Highly regional hepatocyte generation in adult liver during tissue homeostasis. Immunostaining for E-cadherin (E-CAD) (green), glutamine synthetase (GS) (blue), and tdTomato (red; ProTracer signal) on liver sections of hepatocyte-specific ProTracer mice. Hepatocyte proliferation events (tdTomato+) genetically recorded by ProTracer are highly enriched in the E-CAD−GS− midlobular zone during liver homeostasis. Organ homeostasis is orchestrated by time- and spatially restricted cell proliferation. Studies identifying cells with superior proliferative capacities often rely on the lineage tracing of a subset of cell populations, which introduces a potential selective bias. In this work, we developed a genetic system [proliferation tracer (ProTracer)] by incorporating dual recombinases to seamlessly record the proliferation events of entire cell populations over time in multiple organs. In the mouse liver, ProTracer revealed more hepatocyte proliferation in distinct zones during liver homeostasis, injury repair, and regrowth. Clonal analysis showed that most of the hepatocytes labeled by ProTracer had undergone cell division. By genetically recording proliferation events of entire cell populations, ProTracer enables the unbiased detection of specific cellular compartments with enhanced regenerative capacities. [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/315934
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Lingjuan He,Wenjuan Pu,Xiuxiu Liu,et al. Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair[J]. Science,2021.
APA	Lingjuan He.,Wenjuan Pu.,Xiuxiu Liu.,Zhenqian Zhang.,Maoying Han.,...&Bin Zhou.(2021).Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair.Science.
MLA	Lingjuan He,et al."Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair".Science (2021).