Partial hepatectomy is a surgical procedure in which specific liver lobes are removed intact without damage to the lobes left behind. The process has been extensively studied and is the subject of several excellent reviews.14–16
The excised liver lobes never grow back, but the remaining lobes grow to compensate for the mass of the resected tissue. Reconstitution of the entire liver mass, which is complete within 5–7 days in rodents, is mediated by mature cell types (ie, without stem cells). Classic thymidine labeling studies showed that virtually all rodent hepatocytes in the remaining liver divided once or twice to restore the original cell number within 3–4 days.17,18
The earliest labeled hepatocytes are seen 24 hours after partial hepatectomy; the peak of thymidine incorporation occurs after 24–48 hours. Following hepatocyte division, the other hepatic cell types also undergo a wave of mitosis, thereby restoring the original number of all liver cells within 1 week.
The regenerative response after partial hepatectomy is mediated by a number of factors. The most important signals are hepatocyte growth factor,19
interleukin-6, tumor necrosis factor α
, transforming growth factor α
, and epidermal growth factor. Nonpeptide hormones, including triiodothyronine20
can stimulate hepatocyte replication in vivo. Much less is known about how liver regeneration is terminated once the appropriate liver mass is restored. Although the exogenous factors (endocrine, paracrine, or autocrine) that sense overall liver size are not known, several intracellular signals have been identified. For example, some evidence suggests that transforming growth factor β
1 is important in termination of liver regeneration.22
Recent work strongly implicates the detection of blood bile acid levels by nuclear receptors, including FXR, as a regulator of liver growth.23
In addition, mammalian genes comparable to those in the Drosophila
Hippo kinase signaling cascade, which regulates wing mass during development, can also control hepatocyte proliferation.24
When YAP, the mammalian counterpart to Yorki, the last gene in the Drosophila
Hippo kinase cascade, is overexpressed in a transgenic mouse model, hepatocyte proliferation becomes unchecked and there is massive liver hyperplasia and hepatic carcinogenesis. When YAP hyperexpression is turned off or blocked, liver size returns to normal. It is therefore possible that the Hippo kinase pathway has a decisive role in determining overall liver size. Whether any of these intracellular signals are also important for progenitor-dependent liver regeneration or engraftment is unknown.