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  1. Article: Shared gene expression patterns in mesenchymal progenitors derived from lung and epidermis in pulmonary arterial hypertension: identifying key pathways in pulmonary vascular disease.

    Gaskill, Christa / Marriott, Shennea / Pratap, Sidd / Menon, Swapna / Hedges, Lora K / Fessel, Joshua P / Kropski, Jonathan A / Ames, DeWayne / Wheeler, Lisa / Loyd, James E / Hemnes, Anna R / Roop, Dennis R / Klemm, Dwight J / Austin, Eric D / Majka, Susan M

    Pulmonary circulation

    2016  Volume 6, Issue 4, Page(s) 483–497

    Abstract: Rapid access to lung-derived cells from stable subjects is a major challenge in the pulmonary hypertension field, given the relative contraindication of lung biopsy. In these studies, we sought to demonstrate the importance of evaluating a cell type that ...

    Abstract Rapid access to lung-derived cells from stable subjects is a major challenge in the pulmonary hypertension field, given the relative contraindication of lung biopsy. In these studies, we sought to demonstrate the importance of evaluating a cell type that actively participates in disease processes, as well as the potential to translate these findings to vascular beds in other nonlung tissues, in this instance perivascular skin mesenchymal cells (MCs). We utilized posttransplant or autopsy lung explant-derived cells (ABCG2-expressing mesenchymal progenitor cells [MPCs], fibroblasts) and skin-derived MCs to test the hypothesis that perivascular ABCG2 MPCs derived from pulmonary arterial hypertension (PAH) patient lung and skin would express a gene profile reflective of ongoing vascular dysfunction. By analyzing the genetic signatures and pathways associated with abnormal ABCG2 lung MPC phenotypes during PAH and evaluating them in lung- and skin-derived MCs, we have identified potential predictor genes for detection of PAH as well as a targetable mechanism to restore MPCs and microvascular function. These studies are the first to explore the utility of expanding the study of ABCG2 MPC regulation of the pulmonary microvasculature to the epidermis, in order to identify potential markers for adult lung vascular disease, such as PAH.
    Language English
    Publishing date 2016-12-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2638089-4
    ISSN 2045-8940 ; 2045-8932
    ISSN (online) 2045-8940
    ISSN 2045-8932
    DOI 10.1086/688314
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling.

    Marriott, Shennea / Baskir, Rubin S / Gaskill, Christa / Menon, Swapna / Carrier, Erica J / Williams, Janice / Talati, Megha / Helm, Karen / Alford, Catherine E / Kropski, Jonathan A / Loyd, James / Wheeler, Lisa / Johnson, Joyce / Austin, Eric / Nozik-Grayck, Eva / Meyrick, Barbara / West, James D / Klemm, Dwight J / Majka, Susan M

    American journal of physiology. Cell physiology

    2014  Volume 307, Issue 8, Page(s) C684–98

    Abstract: Genesis of myofibroblasts is obligatory for the development of pathology in many adult lung diseases. Adult lung tissue contains a population of perivascular ABCG2(pos) mesenchymal stem cells (MSC) that are precursors of myofibroblasts and distinct from ... ...

    Abstract Genesis of myofibroblasts is obligatory for the development of pathology in many adult lung diseases. Adult lung tissue contains a population of perivascular ABCG2(pos) mesenchymal stem cells (MSC) that are precursors of myofibroblasts and distinct from NG2 pericytes. We hypothesized that these MSC participate in deleterious remodeling associated with pulmonary fibrosis (PF) and associated hypertension (PH). To test this hypothesis, resident lung MSC were quantified in lung samples from control subjects and PF patients. ABCG2(pos) cell numbers were decreased in human PF and interstitial lung disease compared with control samples. Genetic labeling of lung MSC in mice enabled determination of terminal lineage and localization of ABCG2 cells following intratracheal administration of bleomycin to elicit fibrotic lung injury. Fourteen days following bleomycin injury enhanced green fluorescent protein (eGFP)-labeled lung MSC-derived cells were increased in number and localized to interstitial areas of fibrotic and microvessel remodeling. Finally, gene expression analysis was evaluated to define the response of MSC to bleomycin injury in vivo using ABCG2(pos) MSC isolated during the inflammatory phase postinjury and in vitro bleomycin or transforming growth factor-β1 (TGF-β1)-treated cells. MSC responded to bleomycin treatment in vivo with a profibrotic gene program that was not recapitulated in vitro with bleomycin treatment. However, TGF-β1 treatment induced the appearance of a profibrotic myofibroblast phenotype in vitro. Additionally, when exposed to the profibrotic stimulus, TGF-β1, ABCG2, and NG2 pericytes demonstrated distinct responses. Our data highlight ABCG2(pos) lung MSC as a novel cell population that contributes to detrimental myofibroblast-mediated remodeling during PF.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters/metabolism ; Animals ; Cells, Cultured ; Humans ; Lung/blood supply ; Lung/pathology ; Mesenchymal Stem Cells/physiology ; Mice ; Myofibroblasts/physiology ; Neoplasm Proteins/metabolism ; Pericytes/physiology ; Pulmonary Fibrosis/metabolism ; Pulmonary Fibrosis/pathology ; Transforming Growth Factor beta1/physiology
    Chemical Substances ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters ; Neoplasm Proteins ; TGFB1 protein, human ; Transforming Growth Factor beta1
    Language English
    Publishing date 2014-10-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00114.2014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension.

    West, James D / Austin, Eric D / Gaskill, Christa / Marriott, Shennea / Baskir, Rubin / Bilousova, Ganna / Jean, Jyh-Chang / Hemnes, Anna R / Menon, Swapna / Bloodworth, Nathaniel C / Fessel, Joshua P / Kropski, Johnathan A / Irwin, David / Ware, Lorraine B / Wheeler, Lisa / Hong, Charles C / Meyrick, Barbara / Loyd, James E / Bowman, Aaron B /
    Ess, Kevin C / Klemm, Dwight J / Young, Pampee P / Merryman, W David / Kotton, Darrell / Majka, Susan M

    American journal of physiology. Cell physiology

    2014  Volume 307, Issue 5, Page(s) C415–30

    Abstract: Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by ... ...

    Abstract Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH.
    MeSH term(s) Cell Differentiation/genetics ; Cell Line ; Cells, Cultured ; Endothelial Cells/pathology ; Endothelial Cells/physiology ; Familial Primary Pulmonary Hypertension ; Humans ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/pathology ; Pluripotent Stem Cells/pathology ; Pluripotent Stem Cells/physiology ; Respiratory Mucosa/pathology ; Respiratory Mucosa/physiology ; Wnt Signaling Pathway/genetics
    Language English
    Publishing date 2014-05-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00057.2014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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