Identification of cytokines involved in hepatic differentiation of mBM-MSCs under liver-injury conditions.
OBJECTIVE
To identify the key cytokines involved in hepatic differentiation of mouse bone marrow mesenchymal stem cells (mBM-MSCs) under liver-injury conditions.


METHODS
Abdominal injection of CCl(4) was adopted to duplicate a mouse acute liver injury model. Global gene expression analysis was performed to evaluate the potential genes involved in hepatic commitment under liver-injury conditions. The cytokines involved in hepatic differentiation of mBM-MSCs was functionally examined by depletion experiment using specific antibodies, followed by rescue experiment and direct inducing assay. The hepatic differentiation was characterized by the expression of hepatic lineage genes and proteins, as well as functional features.


RESULTS
Cytokines potentially participating in hepatic fate commitment under liver-injury conditions were initially measured by microarray. Among the up-regulated genes determined, 18 cytokines known to closely relate to liver growth, repair and development, were selected for further identification. The fibroblast growth factor-4 (FGF-4), hepatocyte growth factor (HGF) and oncostatin M (OSM) were finally found to be involved in hepatic differentiation of mBM-MSCs under liver-injury conditions. Hepatic differentiation could be dramatically decreased after removing FGF-4, HGF and OSM from the liver-injury conditioned medium, and could be rescued by supplementing these cytokines. The FGF-4, HGF and OSM play different roles in the hepatic differentiation of mBM-MSCs, in which FGF-4 and HGF are essential for the initiation of hepatic differentiation, while OSM is critical for the maturation of hepatocytes.


CONCLUSIONS
FGF-4, HGF and OSM are the key cytokines involved in the liver-injury conditioned medium for the hepatic differentiation of mBM-MSCs.
Dong
Xue-Jun
XJ
Molecular Medicine Center of Shaoxing People's Hospital, Shaoxing 312000, Zhejiang Province, China.
Zhang
Hui
H
Pan
Ruo-Lang
RL
Xiang
Li-Xin
LX
Shao
Jian-Zhong
JZ
D000208:Acute Disease; D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D051519:Fibroblast Growth Factor 4 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D008099:Liver / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008813:Mice, Inbred ICR; D053683:Oncostatin M / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation
D016207:Cytokines; D017931:DNA Primers; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; C508352:Osm protein, mouse; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053683:Oncostatin M; D017228:Hepatocyte Growth Factor