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Mesenchymal Regulation of the Microvascular Niche in Chronic Lung Diseases

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Abstract

The adult lung is comprised of diverse vascular, epithelial, and mesenchymal progenitor cell populations that reside in distinct niches. Mesenchymal progenitor cells (MPCs) are intimately associated with both the epithelium and the vasculature, and new evidence is emerging to describe their functional roles in these niches. Also emerging, following lineage analysis and single cell sequencing, is a new understanding of the diversity of mesenchymal cell subpopulations in the lung. However, several gaps in knowledge remain, including how newly defined MPC lineages interact with cells in the vascular niche and the role of adult lung MPCs during lung repair and regeneration following injury, especially in chronic lung diseases. Here we summarize how the current evidence on MPC regulation of the microvasculature during tissue homeostasis and injury may inform studies on understanding their role in chronic lung disease pathogenesis or repair. © 2019 American Physiological Society. Compr Physiol 9:1431‐1441, 2019.

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Figure 1. Figure 1. The pulmonary microvascular niche. During tissue homeostasis, cells that comprise the microvascular niche are intimately associated and include microvascular endothelial cells (MVECs, pink), pericyte/vascular smooth muscle cells (vSMCs, red), mesenchymal progenitor cells (MPCs, green), fibroblasts (FB, purple), and alveolar epithelial cells (AECs, yellow). Dysfunction in one or more of these cell types, here specifically MPCs, impacts vascular homeostasis and remodeling. Following injury or during disease remodeling is also complex and may be described as (1) involving MVEC, SMC, or fibroblast proliferation; (2) loss of differentiated SMC phenotypes with mesenchymal proliferation; and/or (3) loss of microvessel structures or rarefaction.
Figure 2. Figure 2. A comparison of MPC, pericytes, and fibroblasts.
Figure 3. Figure 3. Summary of common gene expression signatures associated with Wnt signaling and angiogenesis in ABCG2pos MPC from COPD, IPF, and PAH patients.


Figure 1. The pulmonary microvascular niche. During tissue homeostasis, cells that comprise the microvascular niche are intimately associated and include microvascular endothelial cells (MVECs, pink), pericyte/vascular smooth muscle cells (vSMCs, red), mesenchymal progenitor cells (MPCs, green), fibroblasts (FB, purple), and alveolar epithelial cells (AECs, yellow). Dysfunction in one or more of these cell types, here specifically MPCs, impacts vascular homeostasis and remodeling. Following injury or during disease remodeling is also complex and may be described as (1) involving MVEC, SMC, or fibroblast proliferation; (2) loss of differentiated SMC phenotypes with mesenchymal proliferation; and/or (3) loss of microvessel structures or rarefaction.


Figure 2. A comparison of MPC, pericytes, and fibroblasts.


Figure 3. Summary of common gene expression signatures associated with Wnt signaling and angiogenesis in ABCG2pos MPC from COPD, IPF, and PAH patients.
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Teaching Material

S. M. Majka, M. Rojas, I. Petrache, R. F. Foronjy. Mesenchymal Regulation of the Microvascular Niche in Chronic Lung Diseases. Compr Physiol 9: 2019, 1431-1441.

Didactic Synopsis

Major Teaching Points:

  • Understand the importance of bone-marrow-derived and resident lung mesenchymal progenitors (MPCs) in the pulmonary vasculature during tissue homeostasis and disease states.
  • Much of our understanding of lung MPCs is from studies performed using bone-marrow MPCs (BM-MPCs) as a therapeutic to ameliorate lung injury or disease. However, recent studies and novel models currently allow the study of resident lung MPCs.
  • MPCs are intimately associated with the microvasculature in both BM and lung tissues.

-MPCs express markers common to both vascular smooth muscle and pericytes.

-However, the role MPCs play in terms of microvascular regulation is less clear at this time.

  • Age and senescence of MPCs influence inflammation and the severity of lung injury in murine models.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1 Teaching points: During pulmonary tissue homeostasis, cells that comprise the microvascular niche are intimately associated and include microvascular endothelial cells (MVECs, pink), pericyte/vascular smooth muscle cells (vSMCs, red), mesenchymal progenitor cells (MPCs, green), fibroblasts (FB, purple), and alveolar epithelial cells (AECs, yellow). Dysfunction in one or more of these cell types, here specifically MPCs, impacts vascular homeostasis and remodeling. Following injury or during disease remodeling is also complex and may be described as (1) involving MVEC, SMC, or fibroblast proliferation; (2) loss of differentiated SMC phenotypes with mesenchymal proliferation; and /or (3) loss of microvessel structures or rarefaction. Additional components of the niche, which may influence these processes, are immune cells, such as T-cells and macrophages.

Figure 2 Teaching points: When making a comparison between mesenchymal progenitor cells (MPCs), fibroblasts, and pericytes, there is a significant overlap in cell surface marker expression; however, the phenotypes differ in their contractile profiles/function as well as the ability to form clonal colonies (CFU-F).

Figure 3 Teaching points: Primary MPCs isolated from PAH, COPD, and IPF patient lung tissue explants exhibit common transcriptional signatures of deregulated Wnt signaling, which affects both microvascular barrier function and angiogenesis.

 


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How to Cite

Susan M. Majka, Mauricio Rojas, Irina Petrache, Robert F. Foronjy. Mesenchymal Regulation of the Microvascular Niche in Chronic Lung Diseases. Compr Physiol 2019, 9: 1431-1441. doi: 10.1002/cphy.c180043