Table 1.
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.