Cell-autonomous decrease in proliferative competitiveness of the aged hepatocyte

Background & Aims The regenerative potential of the liver declines with age, this might be dependent on a decrease in the intensity of the stimulus and/or an increased refractoriness of the target. In the present study, we compared the in vivo growth capacity of young and old hepatocytes transplanted into the same host. Methods We utilized the retrorsine (RS)-based model for liver repopulation, which provides a specific and effective stimulus for transplanted hepatocytes. Rats of the dipeptidyl-peptidase type IV (DPP-IV)-deficient strain were given RS and were injected with a mix of hepatocytes isolated from either a 2-month old or an 18-month old donor. To follow the fate of transplanted cells, they were each identified through a specific tag: young hepatocytes expressed the green fluorescent protein (GFP+), while those from old donors were DPP-IV-positive. Results At 1 month post-transplantation, DPP-IV-positive clusters (derived from old donor) were consistently smaller than those GFP+ (young donor); the cross sectional area of clusters was decreased by 50%, while the mean volume was reduced to 1/3. Furthermore, when 2/3 partial hepatectomy (PH) was performed, the S-phase response of old hepatocyte-derived clusters was only 30-40% compared to that observed in cluster originating from young hepatocytes. No markers of cell senescence were expressed in clusters of transplanted hepatocytes. Conclusions This is the first direct evidence in vivo that hepatocytes in the aged liver express a cell-autonomous decline in their replicative capacity and in their regenerative response to PH compared to those from a young animal.