Biochemical and Biophysical Research Communications
Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells☆
Section snippets
Materials and methods
Materials were purchased from Sigma–Aldrich, St. Louis, MO unless otherwise stated.
MSC isolation, ex vivo expansion and characterization. Human MSCs were isolated and cultured as previously reported [15]. The surface antigen profile as analyzed by flow cytometry (FACS Calibur, Becton Dickinson) was consistently CD14−, CD34−, CD45−, CD105+, CD106+ and CD44+. Cells were shown to have adipogenic and osteogenic differentiation potential (Suppl. Fig. 1) and were used during passages 4–7.
SC isolation
MSCs inhibit collagen synthesis in activated SCs
The reversal of experimental liver fibrosis in vivo has been highly correlated with a decrease in tissue collagen content [1]. A similar decrease in tissue collagen has been reported after MSC infusion into animals with fibrotic livers [13], [14]. We evaluated whether MSCs can reduce the secretion of procollagen type I C-peptipe (PIP) in SCs. Levels of PIP-secretion by activated SCs (101 ± 11 pg/106 cells/day) were significantly reduced at a MSC:SC coculture ratio of 1:10 (41 ± 18 pg/106 cells/day; p =
Discussion
Prior studies have shown that transplantation of a CD45− population of bone marrow cells prevented histopathological changes during chronic exposure to hepatotoxins [12], [13], [14]. These observations were correlated with a co-localization of transplanted cells and SCs, a reduction in the number of α-SMA+ cells, decreased tissue collagen content, and increased gelatinase gene expression. These in vivo findings provided a rationale for the therapeutic benefit of MSCs, although evidence
Acknowledgments
We thank Avrum Leeder, Pohun Chris Chen and Luke Selby for the isolation of cells from rat livers. We also acknowledge Robert Crowther’s assistance in cytological and histological preparations and Donald Poulsen’s contributions for medical illustrations. Imaging studies were made possible by the Special Shared Facility in Morphology at the Shriners Hospitals for Children. B.P. is supported by a National Science Foundation predoctoral fellowship. D.V.P. is supported by a fellowship from the
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Financial support: This work was partially supported by grants from the National Institutes of Health (F32 DK070496, K08 DK66040 and R01 DK43371) and the Shriners Hospitals for Children.
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These authors contributed equally to this work.