Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction
Year: 2017
Type: article
Abstract: Pulmonary vascular disease is characterized by remodeling and loss of microvessels and is typically attributed to pathological responses in vascular endothelium or abnormal smooth muscle cell phenotypes. We have challenged this understanding by defining an adult pulmonary mesenchymal progenitor cell (MPC) that regulates both microvascular function and angiogenesis. The current understanding of adult MPCs and their roles in homeostasis versus disease has been limited by a lack of genetic markers with which to lineage label multipotent mesenchyme and trace the differentiation of these MPCs into vascular lineages. Here, we have shown that lineage-labeled lung MPCs expressing the ATP-binding cassette protein ABCG2 (ABCG2+) are pericyte progenitors that participate in microvascular homeostasis as well as adaptive angiogenesis. Activation of Wnt/β-catenin signaling, either autonomously or downstream of decreased BMP receptor signaling, enhanced ABCG2+ MPC proliferation but suppressed MPC differentiation into a functional pericyte lineage. Thus, enhanced Wnt/β-catenin signaling in ABCG2+ MPCs drives a phenotype of persistent microvascular dysfunction, abnormal angiogenesis, and subsequent exacerbation of bleomycin-induced fibrosis. ABCG2+ MPCs may, therefore, account in part for the aberrant microvessel function and remodeling that are associated with chronic lung diseases.
DOI: 10.1172/jci88629
Authors: Christa F. Gaskill, Erica J. Carrier, Jonathan A. Kropski, Nathaniel C. Bloodworth, Swapna Menon, Robert F. Foronjy, M. Mark Taketo, Charles C. Hong, Eric D. Austin, James D. West, Anna L. Means, James E. Loyd, W. David Merryman, Anna R. Hemnes, Stijn De Langhe, Timothy S. Blackwell, Dwight J. Klemm, Susan M. Majka
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Vanderbilt University, Vanderbilt University Medical Center, Stanford Diabetes Research Center, National Institutes of Health, Cancer Center, University of Colorado, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1182793083, G1245004033, G1332742017, G1565180698, Mechanobiology of Cardiopulmonary Fibrosis, G175020261, G1837664201, G2308744219, G237282720, G3298087253, Role of Lung MSC in Emphysema, G3619590958, G3724712001, G3739529010, Hormonal, Metabolic and Signaling Interactions in PAH, G3980323395, G4107354744, G41815566, G4290769314, G4425699080, G4775142410, G5029337574, G560889077, G563474107, G5679716143, G5868276417, DNA-Damage Repair In Pulmonary Fibrosis, G614957503, G6263508347, G7653134492, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G9000001553, G9000033427, G9000043901, G9000099628, G9000300101, University of Colorado Cancer Center Support Grant, Interdisciplinary Training Program in Lung Research, G9001225491, G949362299, G959610197
OpenAlex ID: W2610273044