@article{0ed6af9c8b124fb683bf7d68e5436093,
title = "Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction",
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.",
author = "Gaskill, {Christa F.} and Carrier, {Erica J.} and Kropski, {Jonathan A.} and Bloodworth, {Nathaniel C.} and Swapna Menon and Foronjy, {Robert F.} and Taketo, {M. Mark} and Hong, {Charles C.} and Austin, {Eric D.} and West, {James D.} and Means, {Anna L.} and Loyd, {James E.} and Merryman, {W. David} and Hemnes, {Anna R.} and {De Langhe}, Stijn and Blackwell, {Timothy S.} and Klemm, {Dwight J.} and Majka, {Susan M.}",
note = "Funding Information: The authors would like to express their appreciation to Dr. J. Fessel (Vanderbilt University Medical Center) for discussions. The authors also acknowledge the expert technical assistance provided by S. Marriott, S. Majka, Lora Hedges, S. Shay, N. Penner, and Laura Hoaglin of the University of Colorado Cancer Center (UCCC) Skin Disease Research Center (SDRC) Morphology and Phenotyping Core (P30 AR 057212); Catherine E. Alford and the members of the Research Flow Cytometry Laboratory at the Nashville VA Medical Center; and Karen Helm at the University of Colorado Cancer Center's Flow Cytometry Shared Resource (P30-CA046934 NCI). This work was funded by grants to S.M. Majka from the NIH (R01HL091105 and NIH R01HL11659701). Additional funding was also provided by the NIH (PPG-5P01HL108800-04, to JEL, principal investigator). The experiments were performed at the University of Colorado's Cancer Center Microarray core facility (NCI P30 CA 46934-14). The project was supported in part by the National Center for Research Resources (UL1 RR024975-01) and is now at the National Center for Advancing Translational Sciences (2 UL1 TR000445-06). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.",
year = "2017",
month = jun,
day = "1",
doi = "10.1172/JCI88629",
language = "English (US)",
volume = "127",
pages = "2262--2276",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",
}