There are currently no approved antifibrotic therapies for liver cirrhosis. We used vitamin A-coupled liposomes to deliver small interfering RNA (siRNA) against gp46, the rat homolog of human heat shock protein 47, to hepatic stellate cells. Our approach exploits the key roles of these cells in both fibrogenesis as well as uptake and storage of vitamin A. Five treatments with the siRNA-bearing vitamin A-coupled liposomes almost completely resolved liver fibrosis and prolonged survival in rats with otherwise lethal dimethylnitrosamine-induced liver cirrhosis in a dose- and duration-dependent manner. Rescue was not related to off-target effects or associated with recruitment of innate immunity. Receptor-specific siRNA delivery was similarly effective in suppressing collagen secretion and treating fibrosis induced by CCl(4) or bile duct ligation. The efficacy of the approach using both acute and chronic models of liver fibrosis suggests its therapeutic potential for reversing human liver cirrhosis.

Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.

Iron is an essential metal for the body, while excess iron accumulation causes organ dysfunction through the production of reactive oxygen species. There is a sophisticated balance of body iron metabolism of storage and transport, which is regulated by several factors including the newly identified peptide hepcidin. As there is no passive excretory mechanism of iron, iron is easily accumulated when exogenous iron is loaded by hereditary factors, repeated transfusions, and other diseased conditions. The free irons, non-transferrin-bound iron, and labile plasma iron in the circulation, and the labile iron pool within the cells, are responsible for iron toxicity. The characteristic features of advanced iron overload are failure of vital organs such as liver and heart in addition to endocrine dysfunctions. For the estimation of body iron, there are direct and indirect methods available. Serum ferritin is the most convenient and widely available modality, even though its specificity is sometimes problematic. Recently, new physical detection methods using magnetic resonance imaging and superconducting quantum interference devices have become available to estimate iron concentration in liver and myocardium. The widely used application of iron chelators with high compliance will resolve the problems of organ dysfunction by excess iron and improve patient outcomes.

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Hepatic transdifferentiation of bone marrow cells has been previously demonstrated by intravenous administration of donor cells, which may recirculate to the liver after undergoing proliferation and differentiation in the recipient's bone marrow. In the present study, to elucidate which cellular components of human bone marrow more potently differentiate into hepatocytes, we fractionated human bone marrow cells into mesenchymal stem cells (MSCs) Schwartz et al 1 demonstrated that multipotent adult progenitor cells (MAPCs) 2,3 from the bone marrow of humans as well as mice and rats, when cultured with fibroblast growth factor-4 (FGF-4) and hepatocyte growth factor (HGF) in matrigel, secreted albumin, expressed P450, took up low-density lipoprotein (LDL), and stored glycogen. 3 Lee et al reported that mesenchymal stem cells (MSCs) from human bone marrow and umbilical cord blood differentiated into hepatocyte-like cells with the use of HGF and oncostatin M. 4,5 Most recently, Jang et al reported that hematopoietic stem cells (HSCs) from mice devoid of progenitors and selected for unique properties displayed a plasticity by which they became liver cells when cocultured with injured liver separated by a barrier. 6 Thus, the origin of cells which may undergo hepatic differentiation as revealed by in vitro experiments were quite diverse, reflecting the sources, human or rodent, and methods of isolation.,The differentiation of bone marrow or umbilical cord blood derived cells into hepatocytes has also been demonstrated by in vivo transplantation procedures. In most of these transplantation studies, either isolated 7-12 or clonally defined [13][14][15][16][17][18][19][20][21] HSCs of donor origin, though their characteristics were not equally specified in each study, were found to induce hepatocytes in recipient liver, suggesting the differentiation potency of HSCs.However, in these studies HSCs were generally introduced intravenously and were surmised to reside once in bone marrow where they may undergo proliferation and differentiation. Therefore, the cells distributed to the liver via bone marrow may not necessarily represent the original HSCs themselves.In fact, some recent studies have disclosed that hepatocytes with apparent donor characters were the result of fusion of donor myelomonocytic cells differentiated from HSCs with host hepatocytes. 20,22 Further, the results of these studies with HSCs do not exclude the possibility that other cell types in bone marrow such as MSCs are also capable of undergoing hepatic differentiation. Thus, issues still remained to be clarified as to which cellular component of bone marrow is most suitable to bring about hepatic regeneration in consideration of future clinical application. It also remains to be solved if any bone marrow components indeed differentiate in vivo without fusion.In the present investigation, we attempted to examine the differentiation ability of fractionated human bone marrow components-MSCs, CD34 ϩ cells, and non-MSCs/CD34 Ϫ cells-into hepatocytes in vivo ...