Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors.
OBJECTIVE
In liver fibrosis, alterations within the space of Disse microenvironment occur and facilitate further progression of chronic liver disease. The normal basement membrane-like matrix present within the space of Disse converts to a matrix rich in fibril-forming collagens during fibrosis.


METHODS
To further understand the pathogenesis of liver fibrosis, we modified an in vitro Boyden chamber system to partially mimic in vivo conditions of hepatic stellate cells (HSCs) during health and disease.


RESULTS
Stimulation of HSCs with platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta1, and/or epithelial growth factor (EGF) resulted in an increase in their migratory capacity and up-regulated matrix metalloproteinase (MMP)-2 activity. Migration induced by PDGF-BB was associated with increased proliferation, whereas TGF-beta1/EGF-induced migration was proliferation independent. COL-3, an inhibitor of MMP-2 and MMP-9, inhibited migration of HSCs induced by direct activation of PDGF-BB or TGF-beta1 but had no effect on migration induced by chemotactic stimuli without direct contact, suggesting 2 distinct MMP-dependent and MMP-independent mechanisms of PDGF-BB- or TGF-beta1-induced migration. Additionally, we show that type I collagen by itself induced migration of HSCs. Migration induced by PDGF-BB, TGF-beta1, and collagen I could be inhibited by alpha(1)- and/or alpha(2)-integrin blocking antibodies, collectively suggesting an integrin-dependent, MMP-2-mediated migration of HSCs.


CONCLUSIONS
Basement membrane matrix integrity, composition, and cell-matrix interactions play an important role in anchoring HSCs and preventing them from spreading within the space of Disse and potentially elsewhere in the liver. Additionally, our data provide strong evidence for MMPs in regulation of HSCs migration.
Yang
Changqing
C
Program in Matrix Biology, Gastroenterology and Renal Divisions, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
Zeisberg
Michael
M
Mosterman
Barbara
B
Sudhakar
Akulapalli
A
Yerramalla
Udaya
U
Holthaus
Kathryn
K
Xu
Lieming
L
Eng
Francis
F
Afdhal
Nezam
N
Kalluri
Raghu
R
D000818:Animals; D000077214:Becaplermin; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002630:Chemotactic Factors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005109:Extracellular Matrix / Q000502:physiology*; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D039001:Integrin alpha Chains / Q000502:physiology; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000473:pathology / Q000503:physiopathology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D002630:Chemotactic Factors; D006133:Growth Substances; D039001:Integrin alpha Chains; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000077214:Becaplermin; D004815:Epidermal Growth Factor