Hepatocytes from fibrotic liver possess high growth potential in vivo.
Hepatocyte transplantation is effective for treating liver failure, but healthy donors as a source of hepatocytes are quite limited. The livers of patients with hepatic fibrosis could be an alternative source; however, few reports have examined the nature of hepatocytes from fibrotic livers (f-hepatocytes). In this study, we compared the growth of f-hepatocytes and hepatocytes from normal livers (n-hepatocytes). Hepatocytes were isolated from normal and CCl(4)-treated wild-type Fischer rats that express dipeptidyl dipeptidase IV (DPPIV) gene (DPPIV(+)). The n- and f-hepatocytes proliferated in culture at similar rates. Both types of hepatocytes were transplanted into DPPIV(-) mutant Fischer rats that had been treated with retrorsine to injure the liver and were partially hepatectomized (PHx) before transplantation. Both n- and f-DPPIV(+)-hepatocytes proliferated and formed colonies. The colony sizes of f-hepatocytes 21 days posttransplantation were approximately three times those of n-hepatocytes. The hepatocytes were analyzed using a fluorescence activated cell sorter (FACS). The FACS profile differed between f- and n-hepatocytes: f-hepatocytes were less granular, less autofluorescent, and smaller than n-hepatocytes. These characteristics of f-hepatocytes resembled those reported for small-sized n-hepatocytes (SHs), which are highly proliferative and preferentially express a unique set of 10 SH genes. However, f-hepatocytes preferentially expressed only five of the SH genes. The expression profile of f-hepatocytes was rather similar to that of proliferating n-hepatocytes in the regenerating liver after PHx. The f-hepatocytes were morphologically normal and did not show any preneoplastic phenotype. These normal and proliferative natures of f-hepatocytes in vivo suggest the fibrotic liver as a source of hepatocytes for transplantation.
Yoshizato Project, CLUSTER, Hiroshima Prefectural Institute of Industrial Science and Technology, Hiroshima 739-0046, Japan.
Manabu
M
Nishie
Chise
C
Tateno
Rie
R
Utoh
Toshihiko
T
Kohashi
Norio
N
Masumoto
Naoya
N
Kobayashi
Toshiyuki
T
Itamoto
Noriaki
N
Tanaka
Toshimasa
T
Asahara
Katsutoshi
K
Yoshizato
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D049109:Cell Proliferation; D017690:Cell Transplantation / Q000379:methods; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D008099:Liver / Q000166:cytology*; D008103:Liver Cirrhosis / Q000473:pathology*; D017114:Liver Failure, Acute / Q000139:chemically induced; D008297:Male; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D051381:Rats
D000972:Antineoplastic Agents, Phytogenic; D011763:Pyrrolizidine Alkaloids; D018819:Dipeptidyl Peptidase 4; C003300:retrorsine