Recently, we showed that normal adult rat liver can be replaced by transplanting fetal
liver stem/progenitor cells (FLSPC). Liver repopulation occurs by cell competition
between transplanted FLSPC and host hepatocytes during which the former replace the
latter by inducing their apoptosis. In the present study, we compared the repopulation
potential of FLSPC after their transplantation into rats of different ages (2, 6,
14 mo.).
Embryonic day 14 (ED14) fetal liver cells from DPPIV+ F344 rats were transplanted
into mutant DPPIV– F344 rats and 6 mo. later, we observed 4.5% liver replacement by
transplanted FLSPC in 2 mo. old rats, but repopulation levels increased to 11.5% in
6 mo. old rats (P=0.002) and 22.6% in 14 mo. old rats (P<0.001).
The mechanism for increased hepatic replacement by transplanted FLSPC in older animals
was determined by measuring rates of proliferation and apoptosis in the liver of rats
at different ages. There was decreased proliferative activity and apoptotic rate in
hepatocytes of 6 or 14 mo. vs. 2 mo. old rats. We then measured proliferation and
apoptotic rates of cells in transplanted DPPIV+ clusters vs. surrounding DPPIV– host
liver in young rats (2 mo.) vs. older rats (14 mo.). The proliferative index of transplanted
cells was 3–5 fold higher than in host hepatocytes in both young and older rats; however,
apoptosis of host hepatocytes after transplanting FLSPC increased dramatically in
older rats compared to younger rats (0.7% vs. 0.23%, P<0.001).
The level of long-term tissue reconstitution obtained in older rats after transplantation
of FLSPC far exceeds that observed in younger rats in a normal hepatic environment,
and this increased repopulation by FLSPC appears to result from increased susceptibility
of host hepatocytes to apoptosis as a result of aging. Therefore, the potential use
of cell transplantation in such individuals has significant clinical implications
for the treatment of chronic liver diseases in the elderly.
