Dual effects of adenovirus-mediated thrombopoietin gene transfer on hepatic oval cell proliferation and platelet counts.
Thrombopoietin (TPO) is the growth factor for megakaryocytes and platelets, however, it also acts as a potent regulator of stem cell proliferation. To examine the significance of TPO expression in proliferation of hepatic oval cells, the effect of adenovirus-mediated TPO gene transfer into livers of the Solt-Farber model, which mimics the condition where liver regeneration is impaired, was examined. Hepatic TPO mRNA peaked its expression at 2 days after gene transduction and then gradually decreased. The peripheral platelet number began to increase at 4 days (P<0.05) and reached its plateau at 9 days (P<0.01). Oval cells expressed c-Mpl, a receptor for TPO as well as immature hematopoietic and hepatocytic surface markers such as CD34 and AFP. The proliferating cell nuclear antigen-positive oval cells in rats into which adenovirus-TPO gene was transferred at 7 and 9 days were significantly greater than those in adenovirus-LacZ gene transferred (P<0.05, each), and the total numbers of oval cells in the adenovirus-TPO gene transferred at 9 and 13 days were also significantly greater than those in adenovirus-LacZ gene transferred (P<0.05, each). Expression of SCF protein was increased at 4, 7, and 9 days by TPO gene administration and that of c-Kit was increased at 4 and 7 days. These data suggest that adenovirus-mediated TPO gene transfer stimulated oval cell proliferation in liver as well as increasing peripheral platelet counts, emphasizing the significance of the TPO/c-Mpl system in proliferation of hepatic oval cells.
Ichiba
Miho
M
Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Japan.
Shimomura
Takashi
T
Murai
Rie
R
Hashiguchi
Koichi
K
Saeki
Toshiya
T
Yoshida
Yoko
Y
Kanbe
Takamasa
T
Tanabe
Naotada
N
Tsuchiya
Hiroyuki
H
Miura
Norimasa
N
Tajima
Fumihito
F
Kurimasa
Akihiro
A
Hamada
Hirofumi
H
Shiota
Goshi
G
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002455:Cell Division / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008099:Liver / Q000166:cytology*; D008115:Liver Regeneration; D008297:Male; D010976:Platelet Count; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D013926:Thrombopoietin / Q000235:genetics*
D012333:RNA, Messenger; D013926:Thrombopoietin; D019009:Proto-Oncogene Proteins c-kit