In the zone for liver proliferation

doi:10.1126/science.abg4864

GSTDTAP > 气候变化

DOI	10.1126/science.abg4864
	In the zone for liver proliferation
	Emma R. Andersson
	2021-02-26
发表期刊	Science
出版年	2021
英文摘要	In humans, the liver is the most regenerative solid organ, able to regrow to normal size after removal of up to 90% of the liver volume ([ 1 ][1], [ 2 ][2]). The liver is also distinct because it scales with body size, a characteristic that has been attributed to a “hepatostat” that adjusts liver size to the needs of the body ([ 3 ][3]). Identifying the cells contributing to liver homeostasis and repair could lead to therapies that can activate specific cellular compartments responsible for regeneration. On pages 906 and 905 of this issue, Wei et al. ([ 4 ][4]) and He et al. ([ 5 ][5]), respectively, find that, in mice, a subset of cells in a particular region of the liver, called midlobular zone 2, are the major contributors to hepatocyte proliferation during homeostasis and identify other hepatocyte subsets that contribute to regeneration after damage. This raises questions regarding the mechanisms that induce hepatocyte proliferation and the zonal division of labor with respect to the hepatostat. At first glance, the liver appears to be composed of a “simple” repeating architectural element, the liver lobule. Conceptually, the liver lobule is a hexagonal unit with a central vein in the middle and a portal vein, hepatic artery, and bile duct (lined by biliary cells) at each of its six corners, separated by hepatocyte sinusoids and other cell types (see the figure). However, a strategic division of labor in the liver is achieved through specialization of cellular roles as a function of the architectural gradient ([ 6 ][6]–[ 8 ][7]) from the portal or central vein, spanning three zones from periportal to midlobular to pericentral. Most emphasis thus far has been placed on the specialization of the periportal zone (zone 1), which is enriched for gluconeogenesis and cholesterol and urea biosynthesis functions, and the pericentral zone (zone 3), which is enriched for glycolysis and glutamine and bile acid biosynthesis functions. Less is known of the role of zone 2, which has largely been considered a transition zone, in addition to its function in the regulation of iron concentration in the blood ([ 6 ][6]). Both hepatocytes ([ 9 ][8], [ 10 ][9]) and biliary cells ([ 11 ][10]–[ 13 ][11]) can contribute to regeneration of hepatocytes, depending on the context. Although a tendency toward repopulation from zone 2 had been noted, homeostatic proliferation has been suggested to be broadly and relatively equally distributed among different liver zones. The studies of Wei et al. and He et al. describe new tools to trace and identify proliferating cells in liver. By indelibly labeling cells of interest at a given time point and examining their status at a later time point, it is possible to trace the lineages of cells derived from the original cells of interest to unravel principles of development, homeostasis, or pathology ([ 14 ][12]). The workhorse of genetic lineage tracing uses induction of permanent expression of a fluorophore, through excision of an upstream stop cassette by site-specific recombinases (SSRs), usually the Cre-LoxP system. By directing SSR expression to specific cell types using cell type–or cell function–specific promotors, distinct cell types, or cells undergoing defined processes, can be followed over time. Maintaining liver size in normal conditions, during homeostasis, requires repopulation of cells lost because of normal turnover. By contrast, in response to damage, cells must regenerate damaged tissue. To determine the competence of hepatocytes in different zones to repopulate or regenerate the liver, Wei et al. generated 11 new conditional Cre mouse strains that allow inducible fluorescent labeling of hepatocytes in different zones and performed lineage tracing with these and three other extant Cre strains under homeostatic or damaging conditions. To exclusively trace proliferating cells in a cell type–specific and inducible manner, He et al. developed a strategy to inducibly and permanently fluorescently label specific proliferating cells using combinatorial SSRs, dubbed ProTracer. Collectively, using these new tools and approaches demonstrated that zone 2 midlobular hepatocytes are the main source of repopulating hepatocytes during homeostasis but that regeneration of hepatocytes is dependent on where the liver injury occurs. Random lineage tracing after liver injury has demonstrated that periportal and midlobular hepatocytes reconstitute liver after a pericentral injury, whereas pericentral and midlobular hepatocytes reconstitute liver after periportal injury ([ 9 ][8]). Although hepatocytes from all zones have the capacity to proliferate, Wei et al. show that during homeostasis, zone 1 hepatocytes diminish in number, whereas zone 3 hepatocytes remain steady in number. By contrast, zone 2 hepatocytes increase more than threefold over a year, suggesting that zone 2 hepatocytes are the main source of proliferating hepatocytes during homeostatic conditions, confirming previous work using random rainbow lineage tracing ([ 9 ][8]). Similar to previous findings, the response to periportal injury resulted in expansion of zone 3– and zone 2–traced hepatocytes, whereas pericentral injury resulted in expansion of zone 1– and zone 2–traced hepatocytes. It is thus now clear that the capacity of hepatocytes to proliferate is broadly spread among lobule zones but that predominantly zone 2 hepatocytes maintain homeostasis, whereas predominantly zone 1 and zone 3 hepatocytes respond to injury and repopulate the liver after injury to zones 3 and 1, respectively. Liver function and repair are thus maintained by hepatocytes in general and not by a rare stem cell population. Thanks to these newly developed mouse Cre strains, it will be possible to unravel exactly which hepatocytes and signaling mechanisms contribute to liver homeostasis, growth, repair, or cancer. It will also be interesting to investigate the sexual dimorphism of increased liver regeneration in females. ProTracer is an interesting approach to tracing cells that have proliferated. This method allows inducible lineage tracing of cells that proliferate from a specific time point. During homeostasis, continuous proliferation tracing using ProTracer showed that zone 2 hepatocytes proliferate twice as much as zone 1 hepatocytes and eight times more than zone 3 hepatocytes, further strengthening the concept that zone 2 hepatocytes are the main contributors to liver homeostasis. By contrast, regeneration after partial hepatectomy in which whole liver lobes are removed, and which induces enlargement of the remaining liver lobes, was first dominated by proliferation of zone 1 hepatocytes (at 40 hours), and by 7 days, zones 1 and 2 were 80% populated by hepatocytes that had undergone proliferation, whereas only half of zone 3 hepatocytes had undergone proliferation. ![Figure][13] Hepatocyte repopulation and regeneration Liver architecture is defined by repeating units, called liver lobules, which have a hexagonal structure with a central vein and a portal triad (portal vein, hepatic artery, and bile duct) at each corner, separated by hepatocytes. Hepatocytes exhibit specialized functions from the portal vein to the central vein, creating three zones. Zone 2 hepatocytes are the main contributors to homeostatic proliferation, whereas hepatocytes in zones 1 and 3 are capable of regenerating liver after damage to zones 3 and 1, respectively. GRAPHIC: N.DESAI/ SCIENCE The ProTracer mouse model opens up the possibility of tracing cell proliferation from adult stages over longer time scales (several months) in a continuous manner, enabling the identification of slowly cycling cells and rare stem cells in various organs. This may unveil previously unknown stem cell populations. In the liver, regeneration after injury is usually maintained by cells with phenotypic fidelity: Typically, hepatocytes regenerate hepatocytes, and biliary cells regenerate biliary cells. By distributing proliferative potential widely across zones, and soliciting recovery from the least-damaged regions, the liver achieves a capacity to rapidly respond to damage with proliferation of the healthiest hepatocytes without the use of stem cells. Whether specific hepatocyte zones are more or less important for regeneration and whether certain hepatotoxins are more damaging because they target important subsets of hepatocytes are questions that can be addressed with these new tools. The studies of Wei et al. and He et al. raise several questions. Zone 1 hepatocytes proliferate far more than zone 3 hepatocytes, yet zone 1 hepatocyte numbers decline with time, whereas zone 3 numbers remain steady. Do hepatocytes have different life spans depending on their location? It is also unclear which molecular mechanisms induce zone-specific hepatocyte proliferation in response to distinct modes of injury; perhaps these can be leveraged therapeutically to induce or accelerate regeneration of hepatocytes. Although hepatocytes can transdifferentiate to regenerate the biliary tree ([ 15 ][14]), it is not yet known whether transdifferentiation is a function of only a subset of hepatocytes and whether this also could be leveraged therapeutically to induce regeneration in biliary diseases. These questions and others can now begin to be addressed, building a foundation to approach liver disease therapeutically. 1. [↵][15]1. A. P. Monaco, 2. J. Hallgrimsson, 3. W. V. McDermott Jr. , Ann. Surg. 159, 513 (1964). [OpenUrl][16][PubMed][17][Web of Science][18] 2. [↵][19]1. B. Cady, 2. M. Bonneval, 3. H. R. Fender Jr. , Am. J. Surg. 137, 514 (1979). [OpenUrl][20][CrossRef][21][PubMed][22][Web of Science][23] 3. [↵][24]1. G. K. Michalopoulos, 2. B. Bhushan , Nat. Rev. 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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/315926
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Emma R. Andersson. In the zone for liver proliferation[J]. Science,2021.
APA	Emma R. Andersson.(2021).In the zone for liver proliferation.Science.
MLA	Emma R. Andersson."In the zone for liver proliferation".Science (2021).