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Title: Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells

Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to prevent the development of liver fibrosis in a number of pre-clinical studies. Marked changes in liver histopathology and serological markers of liver function have been observed without a clear understanding of the therapeutic mechanism by which stem cells act. We sought to determine if MSCs could modulate the activity of resident liver cells, specifically hepatic stellate cells (SCs) by paracrine mechanisms using indirect cocultures. Indirect coculture of MSCs and activated SCs led to a significant decrease in collagen deposition and proliferation, while inducing apoptosis of activated SCs. The molecular mechanisms underlying the modulation of SC activity by MSCs were examined. IL-6 secretion from activated SCs induced IL-10 secretion from MSCs, suggesting a dynamic response of MSCs to the SCs in the microenvironment. Blockade of MSC-derived IL-10 and TNF-{alpha} abolished the inhibitory effects of MSCs on SC proliferation and collagen synthesis. In addition, release of HGF by MSCs was responsible for the marked induction of apoptosis in SCs as determined by antibody-neutralization studies. These findings demonstrate that MSCs can modulate the function of activated SCs via paracrine mechanisms provide a plausible explanation for the protective role of MSCs in liver inflammationmore » and fibrosis, which may also be relevant to other models of tissue fibrosis.« less
Authors:
 [1] ;  [2] ; ;  [1] ;  [3] ; ;  [1] ;  [1] ;  [4]
  1. Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, 51 Blossom Street, Boston, MA 02114 (United States)
  2. (United States)
  3. Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558 (Japan)
  4. (United States), E-mail: ireis@sbi.org
Publication Date:
OSTI Identifier:
21032969
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 363; Journal Issue: 2; Other Information: DOI: 10.1016/j.bbrc.2007.05.150; PII: S0006-291X(07)01137-0; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIBODIES; APOPTOSIS; BONE MARROW; COLLAGEN; DEOXYURIDINE; ENZYME IMMUNOASSAY; FIBROSIS; FLUORESCEIN; GROWTH FACTORS; INFLAMMATION; INJURIES; LIVER; LIVER CELLS; MUSCLES; PHOSPHATES; POLYMERASE CHAIN REACTION; RNA; SECRETION; STEM CELLS