Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcitonin gene-related peptide (CGRP) has a beneficial effect in pulmonary hypertension and is a target for cardiovascular gene therapy. Marrow stromal cells (MSCs), also known as mesenchymal stem cells, hold promise for use in adult stem cell-based ex vivo gene therapy. To test the hypothesis that genetically engineered MSCs secreting CGRP can inhibit vascular smooth muscle cell proliferation, rat MSCs were isolated, ex vivo expanded, and transduced with adenovirus containing CGRP. Immunocytochemical analysis demonstrated that wild type rat MSCs express markers specific for stem cells, endothelial cells, and smooth muscle cells including Thy-1, c-Kit, von Willebrand Factor and alpha-smooth muscle actin. Immunocytochemistry confirmed the expression of CGRP by the transduced rat MSCs. The transduced rat MSCs released 10.3+/-1.3 pmol CGRP/1 x 10(6) cells/48 h (mean+/-S.E.M., n=3) into culture medium at MOI 300 and the CGRP-containing culture supernatant from the transduced cells inhibited the proliferation of rat pulmonary artery smooth muscle cells (PASMCs) and rat aortic smooth muscle cells (ASMCs) in culture. Co-culture of the transduced rat MSCs with rat PASMCs or rat ASMCs also inhibited smooth muscle cell proliferation. These findings suggest that this novel adult stem cell-based CGRP gene therapy has potential for the treatment of cardiovascular diseases including pulmonary hypertension.
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PMID:Inhibition of vascular smooth muscle cell proliferation in vitro by genetically engineered marrow stromal cells secreting calcitonin gene-related peptide. 1632 11

To analyze the mechanisms by which cancer cells escape from hosts' immune surveillance, we investigated the changes in immune status during the progression of leukemia induced by injecting mice with WEHI-3B cells. In the bone marrow (BM) of leukemic mice, only DX5(+)CD3(-) cells were continuously increased, despite the progression of leukemia. In addition, DX5(+)CD3(-) cells were rapidly increased in peripheral blood (PB) 20 days after inoculation. We also found that myeloid dendritic cells (DCs) expressing low levels of I-A(d) and having low allo-T cell stimulatory activity were markedly increased in PB and spleen. The increase in DX5(+) cells in BM was thought to be induced by soluble factors from leukemic cells. DX5(+) cells from leukemic mice were CD3(-), B220(-), Gr-1(-), CD14(-), CD94(-), Ly-49C/F(-), asialo GM1(+), CD25(+), CD122(+), Thy-1(bright), and c-kit(dim) and showed low killing activity against YAC-1 cells, suggesting that those DX5(+) cells were immature NK cells. NK cells from leukemic PB down-regulated the expression of I-A(d) on DCs, an effect mediated by TGF-beta. Moreover, these NK cells significantly suppressed the allo-T cell stimulatory activity of DCs, an effect requiring cell-to-cell contact between NK cells and DCs and thought to involve CD25. Importantly, NK cells from leukemic PB inhibited generation of autotumor-specific CTL induced by DCs in primary MLR or by DC immunization. In conclusion, we identified circulating immature NK cells with immunosuppressive activities. These cells may be important for understanding the involvement of the host immune system during the development of leukemia.
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PMID:Immature NK cells suppress dendritic cell functions during the development of leukemia in a mouse model. 1654 47

Hepatic stem cells can be identified by the expression of putative markers such as CD117 (c-kit), CD90 (Thy-1), CD34, and HLA-DR. We have identified populations expressing these markers in both fetal and tumoral human liver by flow cytometry, using monoclonal antibodies against CD90, CD117, CD34, and HLA-DR. In tumoral liver CD117+/CD90+ cells were found in decreasing number from the neoplastic (2.48 +/- 0.67) and peritumoral region (0.88 +/- 0.12) to the area of para-tumoral (normal) parenchyma (0.13 +/- 0.04). The CD117+/CD34+ cells showed the following distribution: 0.35 +/- 0.05% in the tumoral region, 1.01 +/- 0.23% in the peritumoral region and 0.35 +/- 0.01 in the para-tumoral region. Using the same markers on fetal liver cells we have also identified small populations of CD117+/CD90+ cells (0.28 +/- 0.07%) and CD117+/CD34+ cells (1.13 +/- 0.24%), presumably resident stem cells or hematopoietic stem cells. Immunomagnetic negative separation was then performed on fetal liver cells using monoclonal antibodies against specific markers of hematopoietic lineages such as CD3, 14, 16, 19, 22, and CD56 to eliminate this population. The remaining cells were then incubated with fluorescently labeled monoclonal antibodies against CD90 and CD117 and analyzed using fluorescence microscopy. As expected these markers were expressed on the majority of the selected cells (89.28 +/- 9.56%). Isolation using appropriate markers and initiation of primary cultures is a first step to the therapeutic use of fetal stem cells and for the study of adult liver stem cells involvement in carcinogenesis.
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PMID:[Expression of stem cell markers on fetal and tumoral human liver cells in primary culture]. 1660 35

Hepatic progenitor cells (called oval cells in rodents) proliferate during chronic liver injury. They have been suggested as targets of malignant transformation in chronic liver diseases, including chronic hepatitis C. Interferon alpha therapy reduces the risk of hepatocellular carcinoma (HCC) in chronic hepatitis C regardless of viral clearance. The aim of this study was to determine whether interferon alpha could reduce the risk of HCC by modifying preneoplastic events in the hepatic progenitor cell population. Pre- and post-treatment liver biopsies were evaluated for changes in t he hepaticprogenitor cell population in 16 patients with non-responding chronic hepatitis C Interferon alpha-based treatment significantly reduced the numbers of c-kit-positive hepatic progenitor cells by 50%. To determine the mechanism of cell number reduction, the effects of interferon alpha on murinehepatic progenitor cells were studied in vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) proliferation assay and proliferating cell nuclear antigen staining showed that interferon alpha had a dose-dependent, anti-proliferative effect Interferon alpha stimulated hepatocytic and biliary differentiation of the oval cell lines reflected by increased expression of albumin and cytokeratin19 accompanied by decreased expression of alphafetoprotein and Thy-1. To validatethese results in vivo, mice were placed on the choline-deficient, ethionine-supplemented diet to induce liver injury and oval cell proliferation and treated with pegylated interferon alpha 2b for 2 weeks. This resulted in a significant four-fold reduction in the number of oval cells (P < .05). In conclusion, interferon alpha-based treatment reduced the number of hepatic progenitor cells in chronic liver injury by modulating apoptosis, proliferation, and differentiation. Supplementay material for this article can
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PMID:Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo. 1662 47

Few studies on the long-term culture of postnatal mouse hepatic stem/progenitor cells have been reported. We successfully adapted a serum-free culture system that we employed previously to expand fetal mouse hepatic stem/progenitor cells and maintained them in culture over long periods. The expanded postnatal cells contained immature alpha-fetoprotein-positive cells along with hepatocytic and cholangiocytic lineage-committed cells. These cells expressed CD49f but not CD45, CD34, Thy-1, c-kit, CD31, or flk-1, and oncostatin M induced their differentiation. This heterogeneous population contained side population (SP) cells, which express the ATP-binding cassette transporter ABCG2, and sca-1+ cells. As mice aged, the frequency of SP and sca-1+ cells decreased along with the ability of cultured cells to expand. Approximately 20%-40% of the SP cells expressed sca-1, but only a few sca-1+ cells were also SP cells. Analysis of colonies derived from single SP or sca-1+ cells revealed that, although both cells had dual differentiation potential and self-renewal ability, SP cells formed colonies more efficiently and gave rise to SP and sca-1+ cells, whereas sca-1+ cells generated only sca-1+ progeny. Thus, SP cells are more characteristic of stem cells than are sca-1+ cells. In regenerating livers, ABCG2+ cells and sca-1+ cells were detected around or in the portal area (the putative hepatic stem cell niche). The expanded cells share many features of fetal hepatic stem/progenitor cells or oval cells and may be useful in determining the mechanisms whereby hepatic stem cells self-renew and differentiate.
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PMID:Long-term culture of postnatal mouse hepatic stem/progenitor cells and their relative developmental hierarchy. 1721 96

With help of a hCD25 reporter controlled by pre-T cell receptor alpha (Ptcra) regulatory elements, T cell precursors were identified in peripheral blood. Sca-1(+)IL-7Ralpha(+)Flt3(-) precursors that were c-kit(lo)Thy-1(hi) generated T lineage cells when cultured on OP9-DL1 stromal cells and upon transfer into Rag2(-/-)Il2rg(-/-) mice. No B cells were generated in vivo and only few in vitro. These cells, which we call circulating T cell progenitors (CTP), were found at the same frequency in Foxn1(nu/nu) thymus-deficient mice and wild-type mice, indicating that they were pre- rather than postthymic. Inhibition of Notch-dependent transcription in vivo reduced the frequency of intrathymic early T cell progenitors (ETP), but not CTP, indicating that the latter are less Notch dependent. Thus, CTP represent T lineage-committed T cell precursors linking extrathymic with intrathymic lymphopoiesis in adult mice.
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PMID:Identification of a T lineage-committed progenitor in adult blood. 1724 55

Tissue stem cells participate in the repopulation of tissue after injury. Tissue injury stimulates the normally quiescent tissue stem cells to differentiate and proliferate, in the process of replacing and/or repairing the damaged cells, and hence effecting tissue regeneration. The salivary glands retain the ability for frequent regeneration. Previously, we isolated progenitor cells from the injured salivary glands of mice and rats that differentiated into hepatic and pancreatic lineages. The isolated progenitors were CD49f-positive and intracellular laminin-positive, and proliferated on type I collagen while maintaining their multipotency. In this study, we analyzed the tissue stem cells induced by ligating the main excretory duct of the salivary gland in swine. After duct ligation of the gland, acinar cells receded due to apoptosis, and epithelial cells subsequently proliferated. We cultured cells obtained from the duct-ligated salivary gland and purified the cells by limited dilution. The isolated cells were positive for CD29, CD49f, intracellular laminin, AFP, CK19, CK18, and Thy-1(CD90), and weakly positive for c-Kit (CD117). After three-dimensional formation, the cells expressed insulin and albumin. We designated the cells as swine salivary gland-derived progenitor cells. Gene expression of insulin and albumin was significantly increased (five-fold) and that of insulin was also increased (3.8-fold) with differentiation medium with nicotinamide and/or GLP-1 treatment in spherical culture. The expressions of albumin and insulin were 1/10-fold and 1/4-fold compared to porcine hepatocytes and pancreatic endocrine cells. The differentiated SGP cells could release insulin, which were stimulated by glucose and potassium. These results indicate that swine SGP cells could differentiate into hepatocytes and beta-cells, functionally. Swine SGP cells were useful tools for therapy and analyzing endodermal regenerative models in large animals.
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PMID:Isolation of tissue progenitor cells from duct-ligated salivary glands of swine. 1757 51

The MHB-2 cell line, established from a mouse hepatoblastoma (HB), was subjected to the reverse transcriptase-polymerase chain reaction (RT-PCR) for evaluation of gene expression related to cell differentiation. RNAs for c-kit, CD34, thy-1, albumin, cytokeratin (CK) 8, 18 and 19 could be detected, but expression of alpha-fetoprotein, glucose-6-phosphatase, tyrosine aminotransferase and CK7 was not observed. MHB-2 cells were positive for CK8/18 but negative for c-kit, CD34, thy-1 and albumin on protein level. Immunohistochemical staining of the HB in vivo revealed diffusely expressed c-kit. Thy-1-positive HB cells were sparsely observed, but the tumor was negative for CD34 and rarely positive for CK8/18. By in situ hybridization, the HB was positive for CK18 but negative for CK19. Slight expression of albumin, but the lack of immature hepatocytic marker suggested some heterogeneous hepatocyte or an undifferentiated cell from other origin. Furthermore, positive expression of CK19 as well as CK8 and CK18 in culture strongly suggested the differentiation into a biliary lineage or the bidirectional state. In conclusion, the present study indicated the mouse HB to have de-differentiated, bipotent, or biliary-like cell characteristics, and considering the histological difference between HB and biliary tumors, it suggests the mouse HB cells are closely like some sort of hepatic undifferentiated cells.
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PMID:Evaluation of gene expression related to hepatic cell maturation and differentiation in a chemically induced mouse hepatoblastoma cell line. 1763 80

The intrahepatic bile duct has been suggested to be a source of hepatic progenitor cells in the severely damaged liver. In contrast, little attention has been paid to the question of whether hepatic progenitor cells exist in the extrahepatic bile duct (EHBD). In the present study, we examined the phenotypic changes of the mouse EHBD following bile duct ligation. After bile duct ligation, the number of c-Kit-positive epithelial cells increased in the EHBD. The ligated EHBD expressed mRNA for hepatic progenitor cell markers, including c-Kit and Thy-1. Hepatocyte markers such as albumin and cytochrome P450 7a1 were also transiently detected in the EHBD after a bile duct ligation. In a culture of EHBD cells, we detected hepatic progenitor cells that were positive for both staining with anti-albumin antibodies and Dolichos biflorus agglutinin, a biliary epithelial cell-specific lectin. Furthermore, hepatic progenitor cells positive for both c-Kit and albumin were found in the cultured EHBD population. Additionally EHBD-derived hepatocyte-like cells were also observed in the culture. A transplantation study revealed that EHBD cells integrate into the parenchyma and are albumin positive. These data suggest that hepatic progenitor cells emerge in the EHBD following bile duct ligation, that subsequently give rise to hepatocyte-like cells. We also observed that the gall bladder transiently expressed hepatocyte markers after bile duct ligation. Our results suggest a potential of the EHBD and gall bladder as useful transplantable sources for liver injury.
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PMID:Hepatic progenitor cells in the mouse extrahepatic bile duct after a bile duct ligation. 1800 41

The "in vitro" establishment of a physiological model of bipotential liver progenitors would be useful for analyzing the molecular mechanisms involved in regulating growth and differentiation, as well as studying their potential role/s in liver physiology and pathology. The transforming growth factor-beta (TGF-beta) induces de-differentiation of fetal rat hepatocytes (FH), concomitant with changes in morphology. The aim of this work was to isolate and characterize this population of TGF-beta-treated fetal hepatocytes (TbetaT-FH) and test whether they can behave as liver progenitors. The TbetaT-FH isolated cell lines show high expression of Thy-1 and low expression of c-Kit. They express liver-specific proteins, such as albumin and alpha-fetoprotein, and mesenchymal markers, such as vimentin. TbetaT-FH maintain expression of the hnf3beta gene, but lose expression of hnf1beta, hnf4, and hnf6. They express c-met and show an increase in proliferation in response to HGF. Interestingly, the transdifferentiation process is coincident with changes in the expression of genes related to the oxidative metabolism. TbetaT-FH cultured in the presence of EGF + DMSO change morphology, towards epithelial cells, gaining expression of CK19 and c-Kit, markers found in hepatoblasts and bile duct cells. Furthermore, TbetaT-FH form duct-like structures when cultured on Matrigel. TbetaT-FH show also potential to revert to an hepatocyte phenotype when submitted to a long-term "in vitro" differentiation protocol towards hepatocytic lineage. In summary, our results support the hypothesis that hepatocytes can function as facultative liver stem cells and demonstrate that TGF-beta might play an essential role in the transdifferentiation process.
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PMID:Isolation and characterization of a putative liver progenitor population after treatment of fetal rat hepatocytes with TGF-beta. 1828 37


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