| 1. |
- Foo, Kylie S, et al.
(author)
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Human ISL1+ ventricular progenitors self-assemble into an in vivo functional heart patch and preserve cardiac function post infarction
- 2018
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In: Molecular Therapy. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 1525-0016. ; 26:7, s. 1644-1659
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Journal article (peer-reviewed)abstract
- The generation of human pluripotent stem cell (hPSC)-derived ventricular progenitors and their assembly into a 3-dimensional in vivo functional ventricular heart patch has remained an elusive goal. Herein, we report the generation of an enriched pool of hPSC-derived ventricular progenitors (HVPs), which can expand, differentiate, self-assemble, and mature into a functional ventricular patch in vivo without the aid of any gel or matrix. We documented a specific temporal window, in which the HVPs will engraft in vivo. On day 6 of differentiation, HVPs were enriched by depleting cells positive for pluripotency marker TRA-1-60 with magnetic-activated cell sorting (MACS), and 3 million sorted cells were sub-capsularly transplanted onto kidneys of NSG mice where, after 2 months, they formed a 7 mm x 3 mm x 4 mm myocardial patch resembling the ventricular wall. The graft acquired several features of maturation: expression of ventricular marker (MLC2v), desmosomes, appearance of T-tubule-like structures, and electrophysiological action potential signature consistent with maturation, all this in a non-cardiac environment. We further demonstrated that HVPs transplanted into un-injured hearts of NSG mice remain viable for up to 8 months. Moreover, transplantation of 2 million HVPs largely preserved myocardial contractile function following myocardial infarction. Taken together, our study reaffirms the promising idea of using progenitor cells for regenerative therapy. Correction in Mol Ther. 2021 Jan 6;29(1):409, DOI: 10.1016/j.ymthe.2020.11.015
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| 2. |
- Hagerstrand, Daniel, et al.
(author)
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Identification of a SOX2-dependent subset of tumor- and sphere-forming glioblastoma cells with a distinct tyrosine kinase inhibitor sensitivity profile
- 2011
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In: Neuro-Oncology. - : Oxford University Press (OUP). - 1522-8517 .- 1523-5866. ; 13:11, s. 1178-1191
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Journal article (peer-reviewed)abstract
- Putative cancer stem cells have been identified in glioblastomas and are associated with radio- and chemoresistance. Further knowledge about these cells is thus highly warranted for the development of better glioblastoma therapies. Gene expression analyses of 11 high-grade glioma cultures identified 2 subsets, designated type A and type B cultures. The type A cultures displayed high expression of CXCR4, SOX2, EAAT1, and GFAP and low expression of CNP, PDGFRB, CXCL12, and extracellular matrix proteins. Clinical significance of the 2 types was indicated by the expression of type A-and type B-defining genes in different clinical glioblastoma samples. Classification of glioblastomas with type A- and type B-defining genes generated 2 groups of tumors composed predominantly of the classical, neural, and/or proneural subsets and the mesenchymal subset, respectively. Furthermore, tumors with EGFR mutations were enriched in the group of type A samples. Type A cultures possessed a higher capacity to form xenograft tumors and neurospheres and displayed low or no sensitivity to monotreatment with PDGF-and IGF-1-receptor inhibitors but were efficiently growth inhibited by combination treatment with low doses of these 2 inhibitors. Furthermore, siRNA-induced downregulation of SOX2 reduced sphere formation of type A cultures, decreased expression of type A-defining genes, and conferred sensitivity to monotreatment with PDGF-and IGF-1receptor inhibitors. The present study thus describes a tumor-and neurosphere-forming SOX2-dependent subset of glioblastoma cultures characterized by a gene expression signature similar to that of the recently described classical, proneural, and/or neural subsets of glioblastoma. The findings that resistance to PDGF-and IGF-1-receptor inhibitors is related to SOX2 expression and can be overcome by combination treatment should be considered in ongoing efforts to develop novel stem cell-targeting therapies.
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| 3. |
- He, Xiaobing
(author)
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Stem cell signatures in glioma
- 2012
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Doctoral thesis (other academic/artistic)abstract
- Gliomas are the most common tumors of the central nervous system in adults. Glioblastoma, the most aggressive form, has a median survival of 15 months regardless of the standard treatment with surgery and temozolomide-based radiochemotherapy. Therefore, it is imperative to improve treatment options for patients with glioblastoma. It has been suggested that the putative tumor stem cells in brain tumors are responsible for glioma initiation, development and resistance to conventional therapy and therefore may be a potential target for novel therapy. By searching for stem cell gene expression signatures in human high-grade glioma cultures, two novel subsets (type A and type B) of glioblastoma cultures were identified with gene expression profiles similar to the recently described TCGA proneural/classical/neural and the mesenchymal subsets, respectively. The two subsets of cultures have different capacities in terms of tumorigenic potential, sphere forming ability and distinct tyrosine kinase inhibitor sensitivity profiles. The findings that the resistance of type A cultures to tyrosine kinase inhibitor mono-treatment is SOX2-dependent and can be overcome by a combination of treatments with PDGFR and IGF1-R inhibitors provide a novel strategy for tumor stem cell-targeting therapy. A set of markers defining neural stem cells and pluripotent embryonic stem cells were tested on a series of human glioma tissues. Results demonstrated that besides deregulated expression of neural and pluripotent stem cell regulatory proteins, high-grade gliomas also show expression of mesodermal- and endodermal-specific transcription factors together with neural proteins. In vivo xenograft experiments indicated that the presence of pluripotency markers is dependent on signals from the tumor microenvironment. An experimental mouse glioma model with human PDGFB overexpressed in astrocyte and astrocyte progenitor cells on a p53 null background was used for studying epigenetic changes in mouse brain tumors and in neural stem/progenitor cells during the pre-neoplastic stage. DNA hypomethylation and elevated Histone3 Lysine9 di-methylation (H3K9Me2) were detected not only in the tumors but also in samples of the adult frontal brain lateral ventricular wall (LVW) and in neurosphere cultures respectively, from the hGFAPpPDGFB/Trp53 null (B+p53-/-) brain during the pre-neoplastic stage. Thus, non-neoplastic but epigenetically disturbed LVW cells might be early targets of transformation in the development of glioblastoma. Taken together, this work provides some new insights into stem cell related mechanisms involved in glioma development. Therefore, targeting brain cancer stem cells presents a new and potentially more effective therapy for glioma.
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| 4. |
- Holmberg, Johan, et al.
(author)
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Activation of Neural and Pluripotent Stem Cell Signatures Correlates with Increased Malignancy in Human Glioma
- 2011
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3, s. e18454-
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Journal article (peer-reviewed)abstract
- The presence of stem cell characteristics in glioma cells raises the possibility that mechanisms promoting the maintenance and self-renewal of tissue specific stem cells have a similar function in tumor cells. Here we characterized human gliomas of various malignancy grades for the expression of stem cell regulatory proteins. We show that cells in high grade glioma co-express an array of markers defining neural stem cells (NSCs) and that these proteins can fulfill similar functions in tumor cells as in NSCs. However, in contrast to NSCs glioma cells co-express neural proteins together with pluripotent stem cell markers, including the transcription factors Oct4, Sox2, Nanog and Klf4. In line with this finding, in high grade gliomas mesodermal-and endodermal-specific transcription factors were detected together with neural proteins, a combination of lineage markers not normally present in the central nervous system. Persistent presence of pluripotent stem cell traits could only be detected in solid tumors, and observations based on in vitro studies and xenograft transplantations in mice imply that this presence is dependent on the combined activity of intrinsic and extrinsic regulatory cues. Together these results demonstrate a general deregulated expression of neural and pluripotent stem cell traits in malignant human gliomas, and indicate that stem cell regulatory factors may provide significant targets for therapeutic strategies.
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| 5. |
- Huang, Yajun, et al.
(author)
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Flame-retardant polyvinyl alcohol/cellulose nanofibers hybrid carbon aerogel by freeze drying with ultra-low phosphorus
- 2019
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In: Applied Surface Science. - : Elsevier BV. - 0169-4332. ; 497
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Journal article (peer-reviewed)abstract
- Polyvinyl alcohol/cellulose nanofibers hybrid aerogel was prepared under freeze drying method. To improve the aerogels' anti-combustion performance, 0.8 wt% microencapsulated ammonium polyphosphate (MCAPP) was loaded as the flame retardant. Aerogels with extremely low density (~0.06 g/cm3) and excellent mechanical performance (Young's modulus: 1.045 MPa) can be obtained. The resulted aerogel also exhibit considerable thermal insulation ability (thermal conductivity: ~0.04 W/m·K). Experimental results indicate that the value of limiting oxygen index increases from 19.5% to 37.5% when loading 0.8 wt% MCAPP. Accordingly, the aerogels' peak heat release rate decreased significantly from 222.44 to 107.84 kW/m2. The char residue rises when introducing MCAPP and the char's integrity improves a lot after combustion. The fire performance index and fire growth index increases and falls respectively, indicating improved anti-combustion performance. X-ray photoelectron spectroscopy results show C[dbnd]O bonds would be increased for the esterification of phosphoric acid from MCAPP. In addition, the production of carbonate can be prohibited while combustion when loading MCAPP.
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