Mesenchymal stem cells (MSCs), known for his or her capacity to proliferate indefinitely and differentiate into almost all types of cells, including hepatocytes, have provided the hope of cellular replacement therapy for liver failure. Research frontiers Mouse liver-injury conditioned IL18R1 antibody tradition medium dramatically facilitated the differentiation of mouse bone marrow MSCs (mBM-MSCs) into functional hepatic cells. and oncostatin M (OSM) were finally found out to be involved in hepatic differentiation of mBM-MSCs under liver-injury conditions. Hepatic differentiation could be dramatically decreased after removing FGF-4, HGF and OSM from the liver-injury conditioned medium, and could be rescued by supplementing these cytokines. The FGF-4, HGF and OSM play different functions in the hepatic differentiation of mBM-MSCs, in which FGF-4 and HGF are essential for the initiation of hepatic differentiation, while OSM is critical for the maturation of hepatocytes. CONCLUSION: FGF-4, HGF and OSM are the key cytokines involved in the liver-injury conditioned medium for the hepatic differentiation of mBM-MSCs. new functions under either metabolic or pathologic conditions, and their clinical therapy for tissue repair. In fact, several studies in animal models have suggested that endogenous MSCs may Balamapimod (MKI-833) naturally be involved in wound healing and tissue regeneration, and the engrafted exogenous MSCs have beneficial effects in tissue repair, including that of bone, myocardial tissue, skin, kidney and liver[9-19]. These may encourage further studies on the new insight into MSCs biology and the mechanisms underlying MSCs differentiation, which are still poorly comprehended at present. Recently, by an tracing technology, we have exhibited that BM-MSCs could be recruited from the bone Balamapimod (MKI-833) marrow into peripheral blood, and toward into the wounded sites in response to the injured-liver signals, which indicated a close relationship between BM-MSCs and liver repair. Balamapimod (MKI-833) Moreover, we have also found that the engrafted exogenous BM-MSCs could be recruited to the injured liver, and were able to differentiate into multiple hepatic-lineage cells, which greatly improved the wound healing, providing further insight into the relationship between BM-MSCs and injured liver. Our previous reports also support the idea that this liver-injury conditioned culture medium can induce the differentiation of BM-MSCs into functional hepatic cells in an experiment. These observations indicated that this hepatic differentiation of BM-MSCs may be induced by the cytokines secreted from the injured liver cells, since no cellular interactions existed in such cell-free cultural medium. However, which cytokines direct hepatic fate specification of BM-MSCs still remains unclear. In the present study, we identified the key cytokines that play a crucial role in the differentiation of mBM-MSCs in the liver-injury conditioned medium. We hope our obtaining will benefit the better understanding of the novel mechanisms underlying BM-MSCs involved liver repair and regeneration, and help improve the cytokine-based hepatic inducing strategy and provide a rich cellular resource from BM-MSCs for cytotherapy of acute liver diseases. MATERIALS AND METHODS Experimental animals Eight to ten-week-old male ICR mice obtained from the Laboratory Animal Unit of Zhejiang Academy of Medical Sciences (Hangzhou, China) were used in the experiments. Animals were housed under specified pathogen-free conditions. All animal experiments were done in accordance with a legal regulation, which includes approval by a local ethical committee. Isolation and culture of bone marrow MSCs The mouse bone marrow MSCs (mBM-MSCs) were prepared as described previously. Briefly, the bone marrow was extruded by clipping of the epiphysial ends of the bones and flushing with IMDM (Sigma, St. Louis, MO), supplemented with 10% fetal bovine serum (Hyclone, Rockville, MD), 1% penicillin/streptomycin (Medium A). After 3 d, non-adherent cells and debris were removed, and the adherent cells were cultured constantly. At Balamapimod (MKI-833) near confluence, the cells were replated at 5 104 cells/cm2. Osteogenic, chondrogenic and adipogenic differentiations were examined for functional identification. Preparation of acute liver-injury mouse model The acute liver-injury mouse model was prepared according to the method described previously. Briefly, the mice were treated with CCl4 (1.0 mL/kg body weight of Balamapimod (MKI-833) a 10% solution in mineral oil injected intraperitoneally) twice a day and then sacrificed by.
- This work was supported partly with the National Institutes of Health National Center for Advancing Translational Sciences Clinical and Translational Science Award towards the University of Florida UL1 TR000064 and National Institutes of Health National Environmental Health Sciences TCE/Health Ramifications of Chlorinated Compounds grant P42 ES07375
- Suppressed proteasomal degradation of HIF-1 and increased HIF-1 transcriptional activity occurs when HIF prolyl hydroxylase activity is usually inhibited by proline