Inhibition of hepatic stellate cells by bone marrow-derived mesenchymal stem cells in hepatic fibrosis

BACKGROUND/AIMS: Therapies involving bone-marrow-derived mesenchymal stem cells (BM-MSCs) have considerable potential in the management of hepatic disease. BM-MSCs have been investigated in regenerative medicine due to their ability to secrete various growth factors and cytokines that regress hepatic fibrosis and enhance hepatocyte functionality. The aim of this study was to determine the antifibrosis effect of BM-MSCs on activated hepatic stellate cells (HSCs) and the mechanism underlying how BM-MSCs modulate the function of activated HSCs. METHODS: We used HSCs in both direct and indirect co-culture systems with BM-MSCs to evaluate the antifibrosis effect of BM-MSCs. The cell viability and apoptosis were evaluated by a direct co-culture system of activated HSCs with BM-MSCs. The activations of both HSCs alone and HSCs with BM-MSCs in the direct co-culture system were observed by immunocytochemistry for alpha-smooth muscle actin (alpha-SMA). The levels of growth factors and cytokines were evaluated by an indirect co-culture system of activated HSCs with BM-MSCs. RESULTS: The BM-MSCs in the direct co-culture system significantly decreased the production of alpha-SMA and the viability of activated HSCs, whereas they induced the apoptosis of activated HSCs. The BM-MSCs in the indirect co-culture system decreased the production of transforming growth factor-beta1 and interleukin (IL)-6, whereas they increased the production of hepatocyte growth factor and IL-10. These results confirmed that the juxtacrine and paracrine effects of BM-MSCs can inhibit the proliferative, fibrogenic function of activated HSCs and have the potential to reverse the fibrotic process by inhibiting the production of alpha-SMA and inducing the apoptosis of HSCs. CONCLUSIONS: These results have demonstrated that BM-MSCs may exert an antifibrosis effect by modulating the function of activated HSCs.

Transcriptional profiling and Wnt signaling activation in proliferation of human hepatic stellate cells induced by PDGF-BB / 대한간학회지

BACKGROUND/AIMS: This study aimed to better understand gene expression profiles of human hepatic stellate cell (HSC) activation and the relationship with the Wnt signaling pathway. METHODS: The global transcript levels in platelet derived growth factor-BB (PDGF-BB)-stimulated hTERT HSCs were analyzed using oligonucleotide microarrays. Oligonucleotide microarrays with 19K human oligo chips were performed to obtain gene expression profiles associated with proliferation in human hTERT HSCs. The microarray data was verified by real time quantitative PCR and expression of the components of Wnt signaling was analyzed by Western blot. RESULTS: Microarray data showed 243 up-regulated and 265 down-regulated genes in PDGF-BB-treated HSCs. The changes in expression of glypican3 and BH3 interacting domain death agonist (BID) mRNA in real time quantitative PCR, especially among the highly up- or down-regulated genes, were statistically consistent with the microarray data. The Wnt signaling pathway components, frizzled10 (FZD10) and calcium/calmodulin-dependent protein kinase II alpha (CAMK2A), showed increased expression in the short time course microarray and the up-regulation of FZD10 also occurred at the protein level. Our data showed various gene expression profiles during activation of human HSC. CONCLUSIONS: The up-regulated expression of FZD10 and CAMK2A suggests that the Wnt/Ca2+ signaling pathway is active in hTERT HSCs and may participate in HSC activation and proliferation