Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury

doi:10.1016/j.ajpath.2019.02.008

. 2019 Jun;189(6):1241-1255.

doi: 10.1016/j.ajpath.2019.02.008. Epub 2019 Mar 28.

Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury

Affiliations

¹ Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
² Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: duncana@pitt.edu.

PMID: 30928253
PMCID: PMC6547059
DOI: 10.1016/j.ajpath.2019.02.008

Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury

Patrick D Wilkinson et al. Am J Pathol. 2019 Jun.

. 2019 Jun;189(6):1241-1255.

doi: 10.1016/j.ajpath.2019.02.008. Epub 2019 Mar 28.

Affiliations

¹ Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
² Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: duncana@pitt.edu.

PMID: 30928253
PMCID: PMC6547059
DOI: 10.1016/j.ajpath.2019.02.008

Abstract

The liver contains diploid and polyploid hepatocytes (tetraploid, octaploid, etc.), with polyploids comprising ≥90% of the hepatocyte population in adult mice. Polyploid hepatocytes form multipolar spindles in mitosis, which lead to chromosome gains/losses and random aneuploidy. The effect of aneuploidy on liver function is unclear, and the degree of liver aneuploidy is debated, with reports showing aneuploidy affects 5% to 60% of hepatocytes. To study relationships among liver polyploidy, aneuploidy, and adaptation, mice lacking E2f7 and E2f8 in the liver (LKO), which have a polyploidization defect, were used. Polyploids were reduced fourfold in LKO livers, and LKO hepatocytes remained predominantly diploid after extensive proliferation. Moreover, nearly all LKO hepatocytes were euploid compared with control hepatocytes, suggesting polyploid hepatocytes are required for production of aneuploid progeny. To determine whether reduced polyploidy impairs adaptation, LKO mice were bred onto a tyrosinemia background, a disease model whereby the liver can develop disease-resistant, regenerative nodules. Although tyrosinemic LKO mice were more susceptible to morbidities and death associated with tyrosinemia-induced liver failure, they developed regenerating nodules similar to control mice. Analyses revealed that nodules in the tyrosinemic livers were generated by aneuploidy and inactivating mutations. In summary, we identified new roles for polyploid hepatocytes and demonstrated that they are required for the formation of aneuploid progeny and can facilitate adaptation to chronic liver disease.

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Figures

**Figure 1**
Diagram of the tyrosine catabolic pathway and experimental design. A: Loss of fumarylacetoacetate hydrolase (FAH) led to accumulation of fumarylacetoacetate and toxic metabolites. *Fah* deficiency was ameliorated by 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclo-hexanedione (NTBC) treatment or loss of homogentisate 1,2-dioxygenase (HGD). B: Schematic of experiments presented herein. HPD, 4-hydroxyphenylpyruvate dioxygenase; LKO, liver-specific *E2f7/E2f8* double knockout; MAI, maleylacetoacetate isomerase; TAT, tyrosine aminotransferase.

**Figure 2**
Diploid hepatocytes were increased and polyploid hepatocytes were depleted in *E2f7/E2f8*-deficient livers. A: Control mice contained floxed alleles of *E2f7/E2f8* and a Rosa26-*lacZ* reporter (*R26R^lacZ/lacZ*) but did not contain Cre recombinase. *E2f7/E2f8* liver-specific knockout mice (LKO) also contained Cre recombinase driven by the albumin promoter (Alb-Cre), a liver-specific driver of Cre, which deleted *E2f7/E2f8* and activated the reporter in the liver. Hepatocytes isolated from 2.5-month–old control and LKO livers were stained with X-gal, a substrate for β-galactosidase (blue). The presence of blue hepatocytes confirmed Cre expression in LKO livers. B: Hepatocytes isolated from control and LKO male mice were stained with the viability dye Fixable Viability Dye (FVD)–780 and the nuclear dye Hoechst. The distribution of live hepatic ploidy populations is shown for 4-month–old adult mice. The full gating strategy is shown in Supplemental Figure S1B. Diploid (2c), tetraploid (4c), and octaploid (8c) hepatocytes are indicated on representative flow cytometric plots (**left panels**), and the percentage of each population is summarized (**right panel**). Data are expressed as means ± SEM (B). n = 3 livers per genotype (A); n = 4 mice per genotype (B); ^∗∗∗∗P < 0.0001. Scale bar = 100 μm. FSC-W, forward scatter width.

**Figure 3**
Hepatocytes from *E2f7/E2f8*-deficient livers were predominantly euploid. Hepatocytes isolated from control or liver-specific *E2f7/E2f8* double knockout (LKO) mice (male) were cultured briefly to stimulate cell division, proliferating hepatocytes were arrested in metaphase, and chromosomes from individual cells were identified by G-banding. A: Representative karyograms are shown for control and LKO hepatocytes. Chromosome name (ie, 1 to 19, X, and Y) and number (listed in parentheses) are indicated. Chromosome losses are marked in blue, and chromosome gains are shown in red. The example control hepatocyte was tetraploid and aneuploid with 80 chromosomes (four copies of most autosomes and two copies of each sex chromosome) but lost one copy of chromosomes 3 and 17 and gained one copy of chromosomes 5 and 13. The example LKO hepatocyte was diploid and euploid (two copies of all autosomes and one copy of each sex chromosome). B: Chromosome number is shown for control and LKO hepatocytes. Skewed chromosome counts (eg, hypodiploid, hypotetraploid, and hypertetraploid) were frequent in control but not LKO hepatocytes. C: Chromosome (Chr) gains and losses were summarized relative to the euploid number of homologous chromosomes. Every row marks an individual cell, and each column corresponds to a different chromosome. Detailed karyotypes are provided in Supplemental Tables S1 and S2. D: The percentage of aneuploid hepatocytes is indicated. Data are expressed as means ± SEM (D). n = 4 mice per genotype (B–D); n = 14 to 20 cells per mouse (B–D); n = 68 control hepatocytes (B–D); n = 80 LKO hepatocytes (**B–D**). ^∗∗∗P < 0.001.

**Figure 4**
Liver regeneration by control and liver-specific *E2f7/E2f8* double knockout (LKO) livers during tyrosinemia-induced chronic injury. A: Control and LKO mice were mated with *Hgd*^+/–*Fah*^–/– mice to generate tyrosinemia models: Tyrosinemia-control (T-control; *E2f7*^loxP/loxPE2f8^loxP/loxPR26R^lacZ/lacZHgd^+/–*Fah*^–/–) and Tyrosinemia-LKO (T-LKO; *E2f7*^loxP/loxPE2f8^loxP/loxPR26R^lacZ/lacZAlb-Cre^Tg/0Hgd^+/–*Fah*^–/–). B: Hepatocytes were isolated from T-control and T-LKO male mice and stained with the viability dye Fixable Viability Dye (FVD)–780 and the nuclear dye Hoechst. The distribution of live hepatic ploidy populations is shown for 4-month–old T-control and T-LKO mice. C: At 2.5 months of age, mice were cycled off/on 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclo-hexanedione (NTBC) three times, as indicated, to induce chronic injury and to promote liver regeneration by proliferation of disease-resistant hepatic clones. D: Overall survival during injury for T-control and T-LKO mice. E and F: Kaplan-Meier curve for harvested mice (E) and duration of injury before harvest (F) for T-control and T-LKO mice. G: Tyrosinemia-injured livers contained red macroscopic regenerating nodules. Representative images for T-control and T-LKO livers harvested after 37 and 42 days off NTBC, respectively. **Insets** depict magnified liver images. H and I: Microscopic nodules are visible by hematoxylin and eosin (H&E) staining (H; low magnification, **left column**; high magnification, **right column**) and presence of proliferating Ki-67⁺ hepatocytes (I, dark brown); the number of nodules is summarized. J: Mononucleate and binucleate hepatocytes were detected. β-catenin (green) marked cell membranes, Hoechst (blue) marked nuclei, and Ki-67 (red) marked proliferating hepatocytes within nodules. The percentage of binucleate cells within nodules and in the tissue adjacent to the nodules is indicated. **Dashed lines** in **H–J** indicate nodule boundaries. Data are expressed as means ± SEM (B, F, I, and J) or means only (D). n = 3 to 4 mice per genotype (B); n = 59 T-control mice (D); n = 47 T-LKO mice (D); n = 14 T-control mice (E and F); n = 6 T-LKO mice (E and F); n = 3 to 4 mice per genotype (I). ^∗P < 0.05, ^∗∗P < 0.01, and ^∗∗∗P < 0.001. Scale bars: 100 μm (**H–J**). 2c, diploid hepatocytes; 4c, tetraploid hepatocytes; 8c, octaploid hepatocytes.

**Figure 5**
Approach to identify the origin of proliferating nodules. A:*Hgd*^+/–*Fah*^–/– tyrosinemic mice are sensitive to 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclo-hexanedione (NTBC) withdrawal. Hepatocytes that lose the *Hgd* wild-type (WT) allele become resistant to tyrosinemia and can proliferate during tyrosinemia-induced injury. Loss of the *Hgd* WT allele occurred by either loss of chromosome (Chr) 16, which contained the *Hgd* locus, or by inactivating mutations in the *Hgd* WT allele. B: Individual regenerating nodules were isolated by laser capture microdissection (LCM), and genomic DNA and RNA were prepared from each nodule for downstream analysis. **Dashed lines** indicate a representative nodule. C: The size of nodules in harvested Tyrosinemia-control (T-control) and Tyrosinemia–liver-specific *E2f7/E2f8* double knockout (T-LKO) livers subjected to LCM was equivalent. n = 4 mice per genotype; mixed sex (C). FAH, fumarylacetoacetate hydrolase; HGD, homogentisate 1,2-dioxygenase; KO, knockout.

**Figure 6**
The *Hgd* wild-type (WT) allele was lost by similar mechanisms in equal frequencies by regenerating nodules from Tyrosinemia-control (T-control) and Tyrosinemia–liver-specific *E2f7/E2f8* double knockout (T-LKO) livers. **A–C:** Genomic DNA analysis for each nodule. Strategy for detecting *Hgd* WT and knockout (KO) alleles in genomic DNA by PCR. Genomic DNA was amplified by PCR and was digested with restriction enzyme HpyCH4III (A). Tail tissue DNA isolated from *Hgd*^+/+, *Hgd*^–/–, and *Hgd*^+/– mice illustrate the WT (170 bp) and KO (290 bp) bands. The 120-bp WT band is not shown. Neg is a negative control that did not contain template DNA. Representative nodules from T-control and T-LKO livers depict WT + KO alleles (nodules 1 and 2) and KO alleles (nodules 3 and 4; B). Nearly 25% of regenerating nodules from T-control and T-LKO livers lost the *Hgd* WT allele and are effectively *Hgd*^–/– (C). **D–F:** Transcriptomic analysis of *Hgd* transcripts in each nodule. Strategy for detecting full-length (FL) transcript from the *Hgd* WT allele or splice variants (SVs) from the *Hgd* KO allele (D). Reverse transcription-PCR with the use of RNA from whole livers isolated from *Hgd*^+/+, *Hgd*^–/–, and *Hgd*^+/– mice illustrate FL and SV banding patterns. Neg is a negative control that did not contain template cDNA. Representative nodules from T-control and T-LKO livers depict FL + SV *Hgd* transcripts (nodules 1 and 2) and SV *Hgd* transcripts (nodules 3 and 4; E). The percentage of *Hgd* transcripts is indicated for nodules genotyped as *Hgd*^+/– and *Hgd*^–/–. *Hgd* transcripts were expressed similarly in nodules from T-control and T-LKO mice, and, consistent with loss of the WT *Hgd* allele, up to 80% of *Hgd*^–/– nodules contained *Hgd* SVs only (F). Data are expressed as means ± SEM (C) or means only (F). n = 57 nodules from 4 T-control mice; n = 54 nodules from 4 T-LKO mice. ^∗P < 0.05, ^∗∗P < 0.01.

**Figure 7**
Impact of hepatic polyploidy on liver function. A: Liver-specific *E2f7/E2f8* double knockout (LKO) mice with reduced polyploidy were mostly euploid and highly sensitive to tyrosinemia-induced chronic liver injury. In contrast, control hepatocytes were predominantly polyploid, enriched with aneuploid karyotypes, and were less sensitive to injury. B: Model summarizing unique capabilities of diploid and polyploid hepatocytes, incorporating current and recently published findings. **Solid arrows** indicate polyploidization. **Dashed arrows** indicate ploidy reversal. Polyploid hepatocytes are protected from tumorigenesis associated with tumor suppressor loss and, as demonstrated here, are essential for adaptation to chronic liver injury. In contrast, proliferation capacity was highest among diploid hepatocytes. 2n, 2 chromosome sets; 4n, 4 chromosome sets; 8n, 8 chromosome sets.

**Supplemental Figure S1**
Diploid hepatocytes were increased and polyploid hepatocytes were depleted in *E2f7/E2f8*-deficient livers. A: Single cell suspensions of liver-specific *E2f7/E2f8* double knockout (LKO) and control hepatocytes were stained with Fixable Viability Dye (FVD)–780 (a viability dye) + Hoechst dye and analyzed by flow cytometry. The distribution of live hepatic ploidy populations is shown for 3- to 4-week–old mice. Diploid (2c), tetraploid (4c), and octaploid (8c) hepatocytes are indicated on representative flow cytometry plots (**left panels**), and the percentage of each population is summarized (**right panel**). B: The fluorescence-activated cell sorting (FACS) gating strategy for identification of hepatic ploidy populations is shown. Cells were gated on the basis of size/granularity and viability. Subsequently, single cells were selected and cellular debris removed. Hepatic ploidy populations were determined by separating the cells based on incorporation of Hoechst, using the Hoechst-blue channel. Ploidy populations are marked with chromatid number c because they contain a mixture of cycling and quiescent cells (although >99% are quiescent). Representative FACS plots are shown for a 4-month–old LKO mouse. Data are expressed as means ± SEM (A). n = 4 to 7 mice per genotype (A). ^∗∗∗∗P < 0.0001. FSC-A, forward scatter area; FSC-W, forward scatter width; SSC-A, side scatter area; SSC-W, side scatter width.

**Supplemental Figure S2**
Hepatocytes from *E2f7/E2f8*-deficient livers remained predominantly diploid during extensive *in vivo* proliferation. A: Approximately 300,000 hepatocytes from control and liver-specific *E2f7/E2f8* double knockout (LKO) mice (males, 4 months old) were transplanted into FRGN (*Fah*^–/–*Rag2*^–/– IL-2 common γ chain^–/– Nod background) recipient mice (females, 2 months old) and subjected to 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclo-hexanedione (NTBC) cycling to promote liver repopulation by transplanted donor cells. After completed repopulation, livers that contained a mixture of fumarylacetoacetate hydrolase positive (FAH⁺) donor hepatocytes and FAH^– host hepatocytes were isolated and stained with Fixable Viability Dye (FVD)–780, Hoechst, and FAH antibody (donor marker). B: Cells were first gated on the basis of size/granularity and viability. Single cells were then selected and cellular debris was removed. Donor-derived cells (FAH⁺) were selected and hepatic ploidy populations was determined. Representative fluorescence-activated cell sorting (FACS) plots are shown for an FRGN mouse repopulated by LKO hepatocytes. C: The distribution of hepatic ploidy populations of live FAH⁺ donor-derived hepatocytes from mice repopulated with control or LKO hepatocytes are shown in representative flow cytometric plots and summarized in the graph. Data are expressed as means ± SEM (C). n = 4 mice repopulated with control hepatocytes (C); n = 4 mice repopulated with LKO hepatocytes (C). ^∗P < 0.05, ^∗∗∗∗P < 0.0001. 2c, diploid hepatocytes; 4c, tetraploid hepatocytes; 8c, octaploid hepatocytes; FSC-A, forward scatter area; FSC-W, forward scatter width; SSC-A, side scatter area; SSC-W, side scatter width.

**Supplemental Figure S3**
Liver-specific *E2f7/E2f8* double knockout (LKO) hepatocytes remained predominantly euploid after repopulation of FRGN (*Fah*^–/–*Rag2*^–/– IL-2 common γ chain^–/– Nod background) livers. A: Approximately 300,000 hepatocytes from LKO mice (males, 4 months old) were transplanted into FRGN recipient mice (females, 2 months old) and subjected to 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclo-hexanedione (NTBC) cycling to promote liver repopulation by transplanted donor cells. After completed repopulation, livers that contained a mixture of fumarylacetoacetate hydrolase positive (FAH⁺) donor hepatocytes and FAH^– host hepatocytes were isolated. Hepatocytes were cultured briefly to stimulate cell division, proliferating hepatocytes were arrested in metaphase, and chromosomes from individual cells were identified by G-banding. Karyotypes were determined for donor-derived, male LKO hepatocytes that were Y chromosome⁺. B: Chromosome number is shown for LKO-derived hepatocytes. Skewed chromosome counts (eg, hypodiploid, hypotetraploid) were infrequent. C: Chromosome (Chr) gains and losses were summarized relative to the euploid number of homologous chromosomes. Every row marks an individual cell, and each column corresponds to a different chromosome. Detailed karyotypes are provided in Supplemental Table S3. D: The percentage of aneuploid LKO hepatocytes was compared with the degree of aneuploidy in freshly isolated 4-month–old adult control and LKO hepatocytes, which were originally reported in Figure 3D. Data are expressed as means ± SEM (D). n = 4 mice; 20 cells karyotyped per mouse (A); n = 80 LKO-derived hepatocytes (B). ^∗∗P < 0.01, ^∗∗∗P < 0.001.

**Supplemental Figure S4**
The size of macroscopic regenerating nodules in tyrosinemia-injured livers was independent of the length of injury. Tyrosinemia-control (T-control) and Tyrosinemia–liver-specific *E2f7/E2f8* double knockout (T-LKO) livers were cycled off/on 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclo-hexanedione (NTBC) as described in Figure 4C. Most livers contained macroscopic regenerating nodules, but nodule size and number varied. Representative images depict liver heterogeneity from T-control and T-LKO livers that were harvested. Livers are arranged from least (left) to most (right) nodules, and the duration of tyrosinemia-induced liver injury (caused by NTBC withdrawal) is indicated beneath each image.

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References

1. Gentric G., Desdouets C. Polyploidization in liver tissue. Am J Pathol. 2014;184:322–331. - PubMed
1. Pandit S.K., Westendorp B., de Bruin A. Physiological significance of polyploidization in mammalian cells. Trends Cell Biol. 2013;23:556–566. - PubMed
1. Celton-Morizur S., Merlen G., Couton D., Margall-Ducos G., Desdouets C. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest. 2009;119:1880–1887. - PMC - PubMed
1. Duncan A.W. Aneuploidy, polyploidy and ploidy reversal in the liver. Semin Cell Dev Biol. 2013;24:347–356. - PubMed
1. Margall-Ducos G., Celton-Morizur S., Couton D., Bregerie O., Desdouets C. Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Sci. 2007;120:3633–3639. - PubMed

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[1] Gentric G., Desdouets C. Polyploidization in liver tissue. Am J Pathol. 2014;184:322–331. - PubMed

[2] Gentric G., Desdouets C. Polyploidization in liver tissue. Am J Pathol. 2014;184:322–331. - PubMed

[3] Pandit S.K., Westendorp B., de Bruin A. Physiological significance of polyploidization in mammalian cells. Trends Cell Biol. 2013;23:556–566. - PubMed

[4] Pandit S.K., Westendorp B., de Bruin A. Physiological significance of polyploidization in mammalian cells. Trends Cell Biol. 2013;23:556–566. - PubMed

[5] Celton-Morizur S., Merlen G., Couton D., Margall-Ducos G., Desdouets C. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest. 2009;119:1880–1887. - PMC - PubMed

[6] Celton-Morizur S., Merlen G., Couton D., Margall-Ducos G., Desdouets C. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest. 2009;119:1880–1887. - PMC - PubMed

[7] Duncan A.W. Aneuploidy, polyploidy and ploidy reversal in the liver. Semin Cell Dev Biol. 2013;24:347–356. - PubMed

[8] Duncan A.W. Aneuploidy, polyploidy and ploidy reversal in the liver. Semin Cell Dev Biol. 2013;24:347–356. - PubMed

[9] Margall-Ducos G., Celton-Morizur S., Couton D., Bregerie O., Desdouets C. Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Sci. 2007;120:3633–3639. - PubMed

[10] Margall-Ducos G., Celton-Morizur S., Couton D., Bregerie O., Desdouets C. Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Sci. 2007;120:3633–3639. - PubMed

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Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury

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Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury

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