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Treatment with 2AAF blocks the SHPC regenerative response in retrorsine‐exposed rats

Liver regeneration after partial hepatectomy (PH) in retrorsine‐exposed rats is accomplished through proliferation and differentiation of small hepatocyte‐like progenitor cells (SHPC). The origin of SHPC is frequently debated and remains unknown. We have investigated the possibility that SHPC are derived from oval cells (OC), a known liver progenitor cell, by combining the retrorsine/PH (RP) model with 2‐acetamidofluorene (2AAF), an anti‐mitotic agent that elicits an oval cell response to liver deficit. Male Fischer 344 rats were treated twice (6 and 8 weeks of age) with retrorsine (30 mg/kg ip), with PH 5 weeks after the final treatment. 7 days prior to PH, a 50 mg 2AAF 21‐day time‐release pellet was inserted sc. Livers were harvested at 7 and 14 days post‐PH. H&E‐stained liver sections showed significant numbers of OC and absence of SHPC at 7 days post‐PH in animals treated with 2AAF/retrorsine/PH (2AAF/RP), while RP animals exhibit significant numbers of SHPC clusters and minimal OC reaction. At 14 days post‐PH new hepatocyte clusters appear in 2AAF/RP treated rats that represent the progeny of differentiating OC. These new hepatocytes in 2AAF/RP rats show minimal proliferation (1.4 ± 0.4% mitotic cells), while expanding SHPC in RP animals represent a regenerative population (6.0 ± 1.3% mitotic cells). The observation that SHPC do not respond to liver deficit in retrorsine‐exposed rats after 2AAF treatment strongly suggests that this progenitor cell population is unlikely to be derived from OC.