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  1. Article ; Online: Tinkering with transcription factors uncovers plasticity of somatic cells.

    Azevedo, Judi L / Feldman, Ricardo A

    Genes & cancer

    2011  Volume 1, Issue 11, Page(s) 1089–1099

    Abstract: The advent of induced pluripotent stem cells (iPSCs) has brought the goal of using patient-derived cells for tissue repair closer to reality. However, the mechanisms involved in reprogramming to a pluripotent state are still not clear. It is understood ... ...

    Abstract The advent of induced pluripotent stem cells (iPSCs) has brought the goal of using patient-derived cells for tissue repair closer to reality. However, the mechanisms involved in reprogramming to a pluripotent state are still not clear. It is understood that reprogramming to pluripotency involves epigenetic remodeling and the reactivation of "core" pluripotency factors. However, little is known about the mechanisms involved in overcoming senescence while avoiding oncogenesis, the maintenance of self-renewal, and the regulation of the balance between pluripotency and differentiation. Here, we review recent advances in reprogramming technology and what is currently known about the mechanism of reprogramming to pluripotency. Work with patient-derived iPSCs is already providing new insights into the cellular and molecular mechanisms involved in human disease. Further advances in reprogramming technology should result in efficient methods to reprogram patient-derived cells into iPSCs for use in regenerative medicine.
    Language English
    Publishing date 2011-07-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2538519-7
    ISSN 1947-6027 ; 1947-6019
    ISSN (online) 1947-6027
    ISSN 1947-6019
    DOI 10.1177/1947601911401908
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease.

    Panicker, Leelamma M / Miller, Diana / Park, Tea Soon / Patel, Brijesh / Azevedo, Judi L / Awad, Ola / Masood, M Athar / Veenstra, Timothy D / Goldin, Ehud / Stubblefield, Barbara K / Tayebi, Nahid / Polumuri, Swamy K / Vogel, Stefanie N / Sidransky, Ellen / Zambidis, Elias T / Feldman, Ricardo A

    Proceedings of the National Academy of Sciences of the United States of America

    2012  Volume 109, Issue 44, Page(s) 18054–18059

    Abstract: Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid β-glucocerebrosidase gene. To model GD, we generated human induced pluripotent stem cells (hiPSC), by reprogramming skin fibroblasts from patients with type 1 (N370S/ ... ...

    Abstract Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid β-glucocerebrosidase gene. To model GD, we generated human induced pluripotent stem cells (hiPSC), by reprogramming skin fibroblasts from patients with type 1 (N370S/N370S), type 2 (L444P/RecNciI), and type 3 (L444P/L444P) GD. Pluripotency was demonstrated by the ability of GD hiPSC to differentiate to all three germ layers and to form teratomas in vivo. GD hiPSC differentiated efficiently to the cell types most affected in GD, i.e., macrophages and neuronal cells. GD hiPSC-macrophages expressed macrophage-specific markers, were phagocytic, and were capable of releasing inflammatory mediators in response to LPS. Moreover, GD hiPSC-macrophages recapitulated the phenotypic hallmarks of the disease. They exhibited low glucocerebrosidase (GC) enzymatic activity and accumulated sphingolipids, and their lysosomal functions were severely compromised. GD hiPSC-macrophages had a defect in their ability to clear phagocytosed RBC, a phenotype of tissue-infiltrating GD macrophages. The kinetics of RBC clearance by types 1, 2, and 3 GD hiPSC-macrophages correlated with the severity of the mutations. Incubation with recombinant GC completely reversed the delay in RBC clearance from all three types of GD hiPSC-macrophages, indicating that their functional defects were indeed caused by GC deficiency. However, treatment of induced macrophages with the chaperone isofagomine restored phagocytosed RBC clearance only partially, regardless of genotype. These findings are consistent with the known clinical efficacies of recombinant GC and isofagomine. We conclude that cell types derived from GD hiPSC can effectively recapitulate pathologic hallmarks of the disease.
    MeSH term(s) Cell Differentiation ; Cell Lineage ; Gaucher Disease/pathology ; Humans ; Macrophage Activation ; Models, Biological ; Pluripotent Stem Cells/cytology
    Language English
    Publishing date 2012-10-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1207889109
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease

    Panicker, Leelamma M. / Miller, Diana / Park, Tea Soon / Patel, Brijesh / Azevedo, Judi L. / Awad, Ola / Masood, M. Athar / Veenstra, Timothy D. / Goldin, Ehud / Stubblefield, Barbara K. / Tayebi, Nahid / Polumuri, Swamy K. / Vogel, Stefanie N. / Sidransky, Ellen / Zambidis, Elias T. / Feldman, Ricardo A.

    Proceedings of the National Academy of Sciences of the United States of America

    Volume v. 109,, Issue no. 4

    Abstract: Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid β-glucocerebrosidase gene. To model GD, we generated human induced pluripotent stem cells (hiPSC), by reprogramming skin fibroblasts from patients with type 1 (N370S/ ... ...

    Abstract Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid β-glucocerebrosidase gene. To model GD, we generated human induced pluripotent stem cells (hiPSC), by reprogramming skin fibroblasts from patients with type 1 (N370S/N370S), type 2 (L444P/Rec NciI), and type 3 (L444P/L444P) GD. Pluripotency was demonstrated by the ability of GD hiPSC to differentiate to all three germ layers and to form teratomas in vivo. GD hiPSC differentiated efficiently to the cell types most affected in GD, i.e., macrophages and neuronal cells. GD hiPSC-macrophages expressed macrophage-specific markers, were phagocytic, and were capable of releasing inflammatory mediators in response to LPS. Moreover, GD hiPSC-macrophages recapitulated the phenotypic hallmarks of the disease. They exhibited low glucocerebrosidase (GC) enzymatic activity and accumulated sphingolipids, and their lysosomal functions were severely compromised. GD hiPSC-macrophages had a defect in their ability to clear phagocytosed RBC, a phenotype of tissue-infiltrating GD macrophages. The kinetics of RBC clearance by types 1, 2, and 3 GD hiPSC-macrophages correlated with the severity of the mutations. Incubation with recombinant GC completely reversed the delay in RBC clearance from all three types of GD hiPSC-macrophages, indicating that their functional defects were indeed caused by GC deficiency. However, treatment of induced macrophages with the chaperone isofagomine restored phagocytosed RBC clearance only partially, regardless of genotype. These findings are consistent with the known clinical efficacies of recombinant GC and isofagomine. We conclude that cell types derived from GD hiPSC can effectively recapitulate pathologic hallmarks of the disease.
    Keywords genes ; mutation ; induced pluripotent stem cells ; phenotype ; genotype ; models ; erythrocytes ; patients ; sphingolipids ; fibroblasts ; enzyme activity ; genetic disorders ; macrophages ; neurons
    Language English
    Document type Article
    ISSN 0027-8424
    Database AGRIS - International Information System for the Agricultural Sciences and Technology

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