Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair

Abstract

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.

Polyploidy control in hepatic health and disease

“…After this initial wave hepatocyte polyploidy increases only modestly over the lifetime of the organism. Consistent with this, a recent study shows that homeostatic proliferation is very low (an estimated cell fraction of only 0.042% in zone 2) but coincides with successful cytokinesis in >90% of proliferation events [21]. Hence, the aged liver contains hepatocytes of all ploidy states reaching up to 16 copies in the wild type mouse [9,15].…”

“…This effect, however, is equaled out with age and ploidy is rather equally distributed across the lobule in the adult human liver [17][18][19]. Studied in the mouse, homeostatic proliferation is most frequently observed in zone 2, as observed in inducible Ki67-Cre or Hamp2-Cre reporter mice [20,21]. In addition to zone 2, also diploid pericentral (zone 3) hepatocytes contribute to liver homeostasis [22] although the importance of this population is unclear [23].…”

“…Drug and diet induced liver injury primarily affect the periportal (zone 1) and pericentral (zone 3) hepatocyte populations (Figure 2). Two recent studies show that zone 2 hepatocytes can regenerate the liver upon such types of zonal injury as this hepatocyte population is shielded from the insult [20,21]. Upon partial hepatectomy, a type of injury that induces regeneration without a zonal bias, a wave-like propagation of proliferation from the periportal vein (zone 1) to the central vein (zone 3) can be detected [21,24].…”

Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis

“…However, several recent studies have presented evidence against this study and demonstrated that all hepatocytes have similar proliferative potential, regardless of their location [6,[9][10][11][12]. Furthermore, very recent two studies showed that zone 2 is the region J o u r n a l P r e -p r o o f with the highest homeostatic hepatocyte proliferation [13,14]. Therefore, the mechanism of liver regeneration, including repair responses to liver injury, is still a matter of debate.…”

The Liver–Immunity Nexus and Cancer Immunotherapy

“…Also uniquely amongst organs, the liver is able to regenerate up to 90% of its volume and is able to scale to body size (2). This compensatory hyperplasia is not due to a specialized stem cell population as in the gut, skin or bone marrow but is present in midzone hepatocytes and can be activated following infection, injury or hepatectomy (3,4).…”