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  • 1
    Online Resource
    Online Resource
    The Underlying Mechanism of Telomere Maintenance in Human Bone Marrow-Derived Mesenchymal Stem Cells.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 4252-4252
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4252-4252
    Abstract: Objective: Human bone marrow-derived mesenchymal stem cells(MSCs) are thought to be promising tools in cell and gene therapy. Unfortunately, the low frequency of MSCs in bone marrow and rapid aging in in vitro expansion, which profoundly compromise their proliferative capacity, give rise to a huge hindrance for their clinical use. Previous study indicated that MSCs would undergo quick telomere shortening as well as reduced replicative capacity during in vitro expansion. These findings suggested that MSCs’ telomere loss might be associated with their decreased proliferative and differentiative potentials. However, the mechanisms by which MSCs maintain their telomere homeostasis have not yet been fully addressed to date. In the present study, we compared the telomere length, the distribution pattern of telomeric repeat binding factor 1(TRF1) between MSCs and other telomerase-positive cells or telomerase-negative cells, detected extrachromosomal telomeric repeat DNA (ECTR DNA) in MSCs and the variation of telomerase activity during cell cycle progression in order to unveil the mystery of telomere regulation in MSCs. METHODS: MSCs were isolated from healthy human bone marrow (n=34) by the plastic adherence protocols and identified by flow cytometry with markers of CD14, CD45, CD44, HLA-DR, CD34, CD29 and CD166. Telomere length and ECTR DNA were detected with Southern hybridization. The TRF1 distribution were probed with immunofluorescence staining. Telomeric repeat amplification protocol (TRAP ) and/or semi-quantitive Western blot assay were performed to determine the telomerase activity in MSCs, MSCs-derived adipocytes and telomerase levels during cell cycle progression. MSCs were synchronized by serum starvation and Aphidicolin treatment for the aforementioned assay. RESULTS: The mean telomere restriction fragment (mTRF) in MSCs was 8.0 kbp( range, 2.7 kbp-18.0 kbp), similar to telomerase-positive HeLa cells 6.0 kbp (range, 2.7 kbp-8.6 kbp) and 293T cells 5.0 kbp(range, 2.7 kbp-8.6 kbp); while the mTRF in telomerase-negative cells WI-38–2RA was 21.2 kb (range 2.0 kbp- & gt;21.2 kbp). The results indicated that telomere length in MSCs and HeLa cells were shorter and relatively more homogeneous than WI-38–2RA cells. TRF1 did not coincide with promyelocytic leukemia (PML) nuclear body in MSCs and HeLa cells while it exclusively did in WI-38–2RA cells. ECTR DNA was negative in MSCs and HeLa cells but positive in WI-38–2RA cells. Detected by TRAP, telomerase activity in MSCs(n=34) was negative with relative telomerase activity (RTA) of 1.44%±0.77%, but it was positive in MSCs-derived adipocytes (n=3) with RTA of 11.80±2.52%(P & lt;0.001). Moreover, a cell cycle-dependent expression profile of telomerase was found in MSCs when they were synchronized by serum starvation and Aphidicolin treatment. Untreated MSCs expressed extremely low level of telomerase probed by Western blot with the 2C4 mAb, but the telomerase level had significantly increased when these cells were trapped in S phase. CONCLUSION: Since MSCs possessed similar features to telomerase-positive cells in telomere length, TRF1 localization pattern and ECTR DNA which were distinct from telomerase-negative ALT cells, and they had increased telomerase activity following differentiation into adipocytes and entrance into S phase, We postulated that the telomere in MSCs was maintained by telomerase pathway other than ALT pathway. The telomerase expression level of MSCs was tightly regulated with cell cycle progression.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.4252.4252
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Online Resource
    Abstract 664: BGB-10188, a highly selective PI3Kδ inhibitor with improved safety profile and superior anti-tumor activities in vivo
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 664-664
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 664-664
    Abstract: Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes capable of phosphorylating phosphatidylinositol to phosphoinositides, which are important secondary messengers involved in various cell signaling and functions. PI3Kδ is one of four isoforms (PI3Kα, β, δ and γ) of the PI3K class I family. It is restrictively expressed in leukocytes. PI3Kδ is a key signal transduction component for normal and malignant B cells and also important for the homeostasis and function of T-regulatory cells (Treg), making it a promising target for treatment of both hematologic malignancies and solid tumors. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing no significant inhibition over 376 protein kinases and 17 lipid kinases, and more than three-thousand folds selectivity over PI3Kα, PI3Kβ, and PI3Kγ. BGB-10188 potently inhibited PI3Kδ in biochemical, cellular and human whole blood assays with IC50s ranging from 1.7-16 nM. It also showed a long-lasting and strong target inhibition activity in mouse pharmacodynamics (PD) studies at doses as low as 10mg/kg. The elimination half-life (t1/2) of BGB-10188 in plasma was 12.6 hours and 10.4 hours in rats and dogs, respectively. BGB-10188 showed significant antitumor effects in different types of B cell Lymphoma xenograft models. The liver toxicities of BGB-10188 were evaluated in mice and significantly improved safety margin was observed for BGB-10188 in comparison with other PI3Kδ inhibitors. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is promising and warrants the testing of the compound in human. Citation Format: Xiao Yang, Xiaolong Yang, Xinxin Cui, Dan Su, Yue Wu, Xuebing Sun, Jingyuan Wang, Huichen Bai, Wei Wei, Jing Li, Xi Yuan, Ye Liu, Fan Wang, Zhiwei Wang, Lai Wang, Xuesong Liu, Xiaomin Song. BGB-10188, a highly selective PI3Kδ inhibitor with improved safety profile and superior anti-tumor activities in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 664.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-664
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 3
    Online Resource
    Online Resource
    Study on Telomerase Activity of Human Bone Marrow Mesenchymal Stem Cells.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 4255-4255
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 4255-4255
    Abstract: Human mesenchymal stem cells(hMSCs) have multiple differentiate potential, and it can differentiate into adipocytes, osteogenic cells, chondrocyte and neural cells et al. It has been reported that telomerase activity in hMSCs is negative, but it is still controversial and telomerase activity in hMSCs-derived adipocytes has not been reported. We investigate the telomerase activity in hMSCs before and after their committed differentiation into adipocytes in vitro and cryopreservation. hMSCs were isolated from normal human bone marrow fellowed by cell culture in DMEM with low glucose containing 10% FBS. The FACS was performed to examine the expression of cell surface molecules and analyze cell cycle of primary hMSCs.Then some of hMSCs were induced to differentiate into adipocytes in vitro by being treated with adipocytic medium fellowed by being stained with oil red O, and the others were cryopreserved in liguid nitrogon for three months. TRAP assay(telomerase repeat amplification protocol assay)was employed to detect telomerase activity in those hMSCs. T293 cells and α-Interferon were analyzed with each test as an additional positive control and negative control respectively. Telomerase activity was expressed as a percentage of the relative telomerase activity (RTA) of the hMSCs relative to the RTA of T293 cells. The results indicated the cells were positive for SH2, SH3, CD90 and negative for CD34, CD45, AC133. It was showed that the majority of primary hMSCs(85%) was at cell cycle of G0/G1 phase and the minority of hMSCs was at S, G2 or M phase. 80% hMSCs was orange adipocytes after they were treated with adipocytic medium for 3–4weeks. Telomerase activity was negative in hMSCs both at the beginning of culture and at the later stages during cell expansion,telomerase activity in hMSCs-passage 1–3(n=10) and hMSCs-passage 4–7(n=9) made no significant difference(1.46±0.83% vs 1.46±0.67%, p=0.99). Cryopreservation did not affect the telomerase activity in hMSCs. Telomerase activity in fresh hMSCs(n=13) and frozen hMSCs(n=6) made no significant difference(1.41±0.44% vs 1.51±1.07%, p=0.64). Telomerase activity in hMSCs-derived adipocytes(n=3) was significantly higher than in hMSCs(n=19)( 11.8±2.52% vs 1.46. ±0.67%, p & lt;0.00001). It is concluded that hMSCs are telomerase-negative, and the stage of culture or cryopreservation does not affect their telomerase activity. After being induced to differentiated into adipocytes, hMSCs telomerase activity is upregulated.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.4255.4255
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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