Nerve growth factor-mediated paracrine regulation of hepatic stellate cells by multipotent mesenchymal stromal cells.
OBJECTIVE
Multipotent mesenchymal stromal cells (MSC) have been reported to prevent the development of liver fibrosis and have emerged as a promising strategy for cell-based therapy. However, the underlying therapeutic mechanism remains unclear. Hepatic stellate cells (SC) activation is a pivotal event in the development of liver fibrosis.


METHODS
We hypothesized that MSC play an important role in regulating SC proliferation and apoptosis through paracrine mechanisms. To investigate the paracrine interactions between MSC and SC, a co-culture experimental model was developed using human MSC (hMSC) and human SC (hSC).


RESULTS
We demonstrate that hMSC and hSC both express nerve growth factor (NGF) receptor p75. Results acquired from transwell co-culture experiments using hSC and hMSC showed that hMSC secrete NGF, which enhances hSC apoptosis. Transcription factor nuclear factor kappa B (NF-KappaB) and B cell leukemia-xl (Bcl-xl) take part in the process.


CONCLUSIONS
These findings demonstrated that hMSC indirectly modulate activated hSC in vitro via NGF-mediated signaling cascades and provide a potential mechanism of how transplanted MSC are effective in treating liver fibrosis.
Lin
Nan
N
Department of Hepatobiliary Surgery, 3rd Affiliated Hospital, Sun Yat-Sen University, GuangZhou 510630, PR China.
Hu
Kunpeng
K
Chen
Si
S
Xie
Shujie
S
Tang
Zhaofeng
Z
Lin
Jizong
J
Xu
Ruiyun
R
D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003470:Culture Media; D005822:Genetic Vectors; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology*; D020800:Receptor, Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D003470:Culture Media; D020800:Receptor, Nerve Growth Factor; D011994:Recombinant Proteins; D020932:Nerve Growth Factor