Activated hepatic stellate cells overexpress p75NTR after partial hepatectomy and undergo apoptosis on nerve growth factor stimulation.
BACKGROUND
Expression of neurotrophins (NTs) and their receptors is increased during hepatic regeneration, but their role is not well understood.


METHODS
NTs and their receptors were investigated by RT-PCR and immunostaining in regenerating livers after two-thirds hepatectomy (PH) and in hepatocytes and hepatic stellate cells (HSCs) isolated from regenerating livers in mice. Induction of apoptosis after treatment with NGF and the expression of alpha-smooth muscle actin (SMA), interleukin 6 (IL-6) and hepatocyte growth factor (HGF) were also investigated in regenerating HSCs.


RESULTS
Nerve growth factor (NGF) and p75 NT receptor (p75NTR) mRNA were elevated after PH, while other NTs and NT receptors showed no remarkable change. NGF was detected in regenerating hepatocytes, but not in normal hepatocytes. Regenerating HSCs expressed increased p75NTR and SMA in vivo and showed an activated phenotype and the high expression of HGF and IL-6 in vitro. Enhanced cell death was seen in HSCs, both from normal and regenerating liver, after treatment with NGF.


CONCLUSIONS
Although activated HSCs may produce the factors that regulate liver regeneration, the de novo NGF production by regenerating hepatocytes may induce the death of activated HSCs via p75NTR, leading to termination of hepatic regeneration.
Asai
Keiko
K
Department of Pathology, Asahikawa Medical College, Midorigaoka, Asahikawa, Japan.
Tamakawa
Susumu
S
Yamamoto
Masahiro
M
Yoshie
Masumi
M
Tokusashi
Yoshihiko
Y
Yaginuma
Yuji
Y
Kasai
Shinichi
S
Ogawa
Katsuhiro
K
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics; D022781:Hepatocytes; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology / Q000601:surgery; D008115:Liver Regeneration; D051379:Mice; D008815:Mice, Inbred Strains; D020932:Nerve Growth Factor / Q000235:genetics / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics*
D000199:Actins; D015850:Interleukin-6; C484065:NGFR protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D017228:Hepatocyte Growth Factor; D020932:Nerve Growth Factor