Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction
Christa F. Gaskill, … , Dwight J. Klemm, Susan M. Majka
Christa F. Gaskill, … , Dwight J. Klemm, Susan M. Majka
Published May 2, 2017
Citation Information: J Clin Invest. 2017;127(6):2262-2276. https://doi.org/10.1172/JCI88629.
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Research Article Pulmonology

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.

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

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Figure 3

ABCG2+ lung MPCs regulate the contractility and function of microvessels.

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ABCG2+ lung MPCs regulate the contractility and function of microvessels...
(A and B) The murine strains indicated were induced with i.p. tamoxifen (0.5 mg total). Eighteen to twenty weeks after tamoxifen induction, a pressure transducer was placed into the jugular vein to the right heart to measure RVSP. Baseline pressures were measured, and epinephrine was injected i.v. into the femoral vessel (n = 5). P values in A were determined by by 1-way ANOVA followed by Tukey’s post-hoc test. (C) In vitro contractility of isolated primary murine lung MPCs and human control and PAH ABCG2+ MPCs was measured by plating cells onto collagen discs at time zero. The discs were photographed and the area calculated using ImageJ. Shown are representative collagen gel images from 2 independent replicates. Data are presented as the mean ± SEM. ***P < 0.001. P values in C were determined by by 1-way ANOVA followed by Tukey’s post-hoc test (for murine qRT-PCR) and a nonparametric Wilcoxon-Kruskal-Wallis test and χ2 approximation (for patients’ samples).