Liver repopulation and long-term function of rat small hepatocyte transplantation as an alternative cell source for hepatocyte transplantation.

Hepatocyte transplantation (HT) is an attractive therapeutic modality for liver disease as an alternative for liver organ transplantation. Primary fresh hepatocytes (FHs) are the exclusive cell source that has been used for clinical HT. However, the use of FHs is limited due to a shortage of donor cells. Small hepatocytes (SHs) are hepatic progenitor cells and can be isolated not only from rodents but also from humans. SHs can proliferate in vitro and express liver functions, although conventional hepatocytes lose them within a short period after culture. SH functions in vivo have never been studied. We therefore investigated HT using SHs to evaluate cell engraftment and function compared to HT using FHs. The donor cell number in the SH group was smaller than that in the FH group at HT. The cell engraftment in the SH group was smaller in the liver and larger in the spleen than in the FH group. The cell engraftment in the liver increased after HT; however, that in the spleen decreased after HT in both groups. HT using SHs supported the serum albumin level in the NAR experiment as well as that using FH, and albumin mRNA was detectable in the recipients' tissues at 12 weeks after HT. In conclusion, HT using SHs showed hepatic repopulation similar to that using FHs. This suggests that both SHs and FHs can repopulate the liver as if they were hepatic stem cells. In addition, HT using SHs supported liver functions such as albumin correction at the same level as that using FHs. These observations strongly support the idea that SHs could be an alternative to primary FHs as a novel cell source for future HT.