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 ...

Recent studies have shown that chronic beta-adrenergic receptor (beta-AR) stimulation alters cardiac myocyte survival in a receptor subtype-specific manner. We examined the effect of selective beta(1)- and beta(2)-AR subtype stimulation on apoptosis induced by hypoxia or H(2)O(2) in rat neonatal cardiac myocytes. Although neither beta(1)- nor beta(2)-AR stimulation had any significant effect on the basal level of apoptosis, selective beta(2)-AR stimulation protected myocytes from apoptosis. beta(2)-AR stimulation markedly increased mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activation as well as phosphatidylinositol-3'-kinase (PI-3K) activity and Akt/protein kinase B phosphorylation. beta(1)-AR stimulation also markedly increased MAPK/ERK activation but only minimally activated PI-3K and Akt. Pretreatment with pertussis toxin blocked beta(2)-AR-mediated protection from apoptosis as well as the beta(2)-AR-stimulated changes in MAPK/ERK, PI-3K, and Akt/protein kinase B. The selective PI-3K inhibitor, LY 294002, also blocked beta(2)-AR-mediated protection, whereas inhibition of MAPK/ERK activation at an inhibitor concentration that blocked agonist-induced activation but not the basal level of activation had no effect on beta(2)-AR-mediated protection. These findings demonstrate that beta(2)-ARs activate a PI-3K-dependent, pertussis toxin-sensitive signaling pathway in cardiac myocytes that is required for protection from apoptosis-inducing stimuli often associated with ischemic stress.

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Summary Extracts from sea urchin intestine were screened for new anti-tumour drugs. Four glycolipids, 3'-sulphonoquinovosyl-1', 2'-diacylglyceride (A-4), 3'-sulphonoquinovosyl-1 '-monoacylglyceride (2'-Iyso A-4, A-5), NeuGca2-6GIcP1-1 ceramide (A-6) and HSO3-8NeuGca2-6Glcp1-1ceramide (A-7), were isolated from the intestine of sea urchin, Strongylocentrotus intermedius, and characterized by means of proton nuclear magnetic resonance spectroscopy and fast atom bombardment mass spectrometry. When tested for cytotoxic activity against tumour cells in vitro, A-5 showed significant activity, but A-4, -6 and -7 did not. In addition, the hydrophilic derivatives of A-4 or -5 had no cytotoxicity. Furthermore, the anti-tumour effects on nude mice bearing solid tumours of a human lung adenocarcinoma cell line A-549 were evaluated in vivo using A-4 and -5. As a result, A-5 was found to be significantly effective in suppressing the growth of solid tumours, whereas A-4 had no effect. Pathologically, the solid tumours showed haemorrhagic necrosis areas after treatment with A-5. In this study, we have demonstrated the anti-tumour effect of sulphonoquinovosyl-lysoglyceride (A-5), which provides important information that this sulpholipid could be a useful drug for cancer chemotherapy.