The prognosis of patients with malignant glioma is extremely poor, despite the extensive surgical treatment that they receive and recent improvements in adjuvant radio-and chemotherapy. In the present study, we propose the use of gene-modified mesenchymal stem cells (MSCs) as a new tool for gene therapy of malignant brain neoplasms. Primary MSCs isolated from Fischer 344 rats possessed excellent migratory ability and exerted inhibitory effects on the proliferation of 9L glioma cell in vitro. We also confirmed the migratory capacity of MSCs in vivo and showed that when they were inoculated into the contralateral hemisphere, they migrated towards 9L glioma cells through the corpus callosum. MSCs implanted directly into the tumor localized mainly at the border between the 9L tumor cells and normal brain parenchyma, and also infiltrated into the tumor bed. Intratumoral injection of MSCs caused significant inhibition of 9L tumor growth and increased the survival of 9L glioma-bearing rats. Gene-modification of MSCs by infection with an adenoviral vector encoding human interleukin-2 (IL-2) clearly augmented the antitumor effect and further prolonged the survival of tumor-bearing rats. Thus, gene therapy employing MSCs as a targeting vehicle would be promising as a new therapeutic approach for refractory brain tumor.

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 ...

AbstractAllogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for various hematologic disorders. Graft-versus-host disease (GVHD) and infections are the major complications of SCT, and their close relationship has been suggested. In this study, we evaluated a link between 2 complications in mouse models. The intestinal microbial communities are actively regulated by Paneth cells through their secretion of antimicrobial peptides, α-defensins. We discovered that Paneth cells are targeted by GVHD, resulting in marked reduction in the expression of α-defensins, which selectively kill noncommensals, while preserving commensals. Molecular profiling of intestinal microbial communities showed loss of physiologic diversity among the microflora and the overwhelming expansion of otherwise rare bacteria Escherichia coli, which caused septicemia. These changes occurred only in mice with GVHD, independently on conditioning-induced intestinal injury, and there was a significant correlation between alteration in the intestinal microbiota and GVHD severity. Oral administration of polymyxin B inhibited outgrowth of E coli and ameliorated GVHD. These results reveal the novel mechanism responsible for shift in the gut flora from commensals toward the widespread prevalence of pathogens and the previously unrecognized association between GVHD and infection after allogeneic SCT.

Mesenchymal stem cells (MSC) were reported to ameliorate functional deficits after stroke in rats, with some of this improvement possibly resulting from the action of cytokines secreted by these cells. To enhance such cytokine effects, we previously transfected the telomerized human MSC with the BDNF gene using a fiber-mutant adenovirus vector and reported that such treatment contributed to improved ischemic recovery in a rat transient middle cerebral artery occlusion (MCAO) model. In the present study, we investigated whether other cytokines in addition to BDNF, i.e., GDNF, CNTF, or NT3, might have a similar or greater effect in this model. Rats that received MSC-BDNF (P < 0.05) or MSC-GDNF (P < 0.05) showed significantly more functional recovery as demonstrated by improved behavioral test results and reduced ischemic damage on MRI than did control rats 7 and 14 days following MCAO. On the other hand, rats that received MSC-CNTF or MSC-NT3 showed neither functional recovery nor ischemic damage reduction compared to control rats. Thus, MSC transfected with the BDNF or GDNF gene resulted in improved function and reduced ischemic damage in a rat model of MCAO. These data suggest that gene-modified cell therapy may be a useful approach for the treatment of stroke.