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. 2023 Apr 24;5(8):100779. doi: 10.1016/j.jhepr.2023.100779

Table 1.

Highlights of recent hepatocyte lineage-tracing results in the mouse liver.

Tracing method Hepatocytes labelled at start of tracing Hepatocytes labelled at end of tracing period in homeostasis or regeneration Ref.
Sox9-CreERT2 Zone 1 (SOX9+, next to bile ducts) Regeneration: Large clones spanning zones 1-3 (12x CCl4) 60
Mfsd2a-CreERT2 Zone 1, ∼40% of parenchyma Homeostasis: Reduction in by half to ∼20% of lobule (6- to 20-week-old mice, no change 20 to 36 week)
Regeneration: Expansion from zones 1 to 2 (PHx and 1x CCl4) and to zone 3 covering nearly all of lobule (10x CCl4)
84
Gls2-CreERT2 Zone 1 + ∼1/4 zone 2, ∼60% of lobule Homeostasis: Zone 1, ∼40% of lobule (12 months)
Regeneration: Zones 1-3, ∼99% of lobule (12x CCl4)
86
Agr1.2-CreERT2 Zone 1 + zone 2, 78% of lobule Homeostasis: Zone 1 + zone 2 + some of zone 3, 94% of lobule (12 months)
Regeneration: Zones 1-3, ∼99% of lobule (12x CCl4)
86
Agr1.1-CreERT2 Zones 1-3 except cells next to CV, 94% of lobule Homeostasis: Zone 1 + zone 2 + zone 3 except cells next to CV, 96% of lobule (12 months) 86
Cyp1a2-CreERT2 ∼2/3 of zone 2 + zone 3, ∼60% of lobule Homeostasis: Some of zone 1 + zone 2 + zone 3, ∼80% of lobule (12 months)
Regeneration: Zones 1-3, ∼67% of lobule (6 weeks DDC)
86
Oat-CreERT2 ∼1/4 of zone 2 + zone 3, 46% of lobule Homeostasis: Some of zone 1 + zone 2 + zone 3; 54% of lobule labelled (6 months) 86
Axin2-CreERT2 (endogenous locus) Zone 3 (AXIN2+ subset) Homeostasis: Large clones spanning zones 3 to 2, sometimes to zone 1 (1 year) 49
Axin2-CreERT2 (BAC transgenic) Zone 3 (AXIN2+ subset) Homeostasis: Zone 3 only (10 months)
Regeneration: Zone 3 + modest expansion to zone 2 (PHx). Upregulation of Axin2 and labelling of regenerating hepatocytes across zones in zonal injury model
85
Lgr5-CreERT2 (endogenous locus) Zone 3 (sparse LGR5+ subset) Homeostasis: Zone 3 only (18 months)
Regeneration: Similar Ki67 positivity as zone 2 hepatocytes (48 h post PHx)
44
Lgr5-rtTA-IRES-GFP; TetO-Cre Zone 3 (LGR5+ subset) Homeostasis: Zone 3 only (18 months) 50
GS-CreERT2 Zone 3 (GS+, next to CV), 9.4% of lobule Homeostasis: Zone 3 next to CV, 9.9% of lobule (12 months)
Regeneration: Zone 3, ∼15% of parenchyma (6 weeks DDC)
86
Axin2-CreERT2 (endogenous locus) Zone 3 and neighbouring zone 2, and sparsely in zone 1 (7 days after tamoxifen) Homeostasis: Similar pattern between 7 days and 365 days tracing 87
Lgr4-CreERT2 (endogenous locus) Sparse hepatocytes throughout zones 1-3 Homeostasis: Throughout lobule with no reported zonal dominance (10 months) 44
Tert-CreERT2 (knocked into exon 1) Sparse hepatocytes in zones 1-3 expressing high Tert, 2.8% of parenchyma Homeostasis: 30% of parenchyma in 1 year
Regeneration: 38% of parenchyma (1-month DDC)
89
Tert-CreERT2 (knocked into 3’UTR) Sparse hepatocytes throughout lobule, more in zones 2 and 3 than 1 Homeostasis: Hepatocytes distributed in all zones, primarily in zone 2 in (7 and 21 days) 86
AAV8-TBG-Cre Individual hepatocyte clones (differentiated with multicolour R26-Rainbow reporter), zones 1-3 Homeostasis: Broadly distributed hepatocyte division in all zones, more proliferation in zone 2, but no particularly large clones (13 months)
Regeneration: Hepatocyte division detected in all uninjured zones (1 to 12x CCl4 and AA)
88
Hamp2-CreERT2 Sparse hepatocytes throughout lobule, more in zone 2 than 1 and 3, ∼10% of parenchyma Homeostasis: Hepatocytes throughout lobule, more in zone 2 than 1 and 3, ∼25% of parenchyma (12 months)
Regeneration: Large hepatocyte clusters primarily in zone 2, ∼17% of parenchyma (6 weeks DDC). Large hepatocyte clusters primarily in zone 2, 13% (12x CCl4).
86
Mup3-CreERT2 Very sparse hepatocytes throughout lobule, more in zones 1 and 2 than zone 3, 0.06% of parenchyma Homeostasis: Very sparse hepatocytes throughout lobule, 0.85% of parenchyma (6 months) Regeneration: Hepatocyte clusters in zones 2 and 3, ∼2.8% of parenchyma (12x CCl4). 86
Ki67-Cre-rox-ERT2-rox
Activated in hepatocytes though Alb-DreERT2 or AAV8-TBG-Dre
Proliferating hepatocytes throughout lobule Homeostasis: Hepatocytes in zones 1-3, but most frequently in zone 2, less in zone 1 and very little in zone 3
Regeneration: Hepatocytes in zones 1-3, with earlier proliferation zones 1 and 2 (PHx)
75

AAV8-TBG-Cre and AAV8-TBG-Dre are adeno-associated viral vectors expressing Cre or Dre recombinase, respectively. All other lineage-tracing methods employ transgenic mouse lines expressing Cre from the indicated promoters. “∼X%” are numbers estimated from graphs in figures of the respective study when numbers were not provided.

AA, allyl alcohol; CCl4, carbon tetrachloride, DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet, PHx, 2/3 partial hepatectomy.