Homing of bone marrow mesenchymal stem cells mediated by sphingosine 1-phosphate contributes to liver fibrosis.
OBJECTIVE
Myofibroblasts play a central role in the pathogenesis of liver fibrosis. Myofibroblasts of bone marrow (BM) origin have recently been identified in fibrotic liver. However, little is known about the mechanism that controls their mobilization in vivo. Here we confirmed that BM mesenchymal stem cells (BMSCs) can migrate to the damaged liver and differentiate into myofibroblasts. We also investigated the mechanism underlying the homing of BMSCs after liver injury.


METHODS
ICR mice were lethally irradiated and received BM transplants from enhanced green fluorescent protein transgenic mice. Carbon tetrachloride or bile duct ligation was used to induce liver fibrosis. The fibrotic liver tissue was examined by immunofluorescent staining to identify BM-derived myofibroblasts.


RESULTS
BMSCs contributed significantly to myofibroblast population in fibrotic liver. Moreover, analysis in vivo and in vitro suggested that homing of BMSCs to the damaged liver was in response to sphingosine 1-phosphate (S1P) gradient between liver and BM. Furthermore, S1P receptor type 3 (S1P3) was required for migration of BMSCs triggered by S1P.


CONCLUSIONS
S1P mediates liver fibrogenesis through homing of BMSCs via S1P3 receptor, which may represent a novel therapeutic target in liver fibrosis through inhibiting S1P formation and/or receptor activation.
Li
Changyong
C
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, China.
Kong
Yaxian
Y
Wang
Hong
H
Wang
Shuling
S
Yu
Hao
H
Liu
Xin
X
Yang
Lin
L
Jiang
Xiangming
X
Li
Lingsong
L
Li
Liying
L
D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013498:Suramin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D000099157:Sphingosine Kinase
D017931:DNA Primers; D049452:Green Fluorescent Proteins; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D011994:Recombinant Proteins; D013110:Sphingosine; D013498:Suramin; D053773:Transforming Growth Factor beta1; D000099157:Sphingosine Kinase; C485184:enhanced green fluorescent protein; C060506:sphingosine 1-phosphate