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Extracellular Matrix Stiffness in Lung Health and Disease

Ting Guo, Chao He, Aida Venado, Yong Zhou

10.1002/cphy.c210032

Source: Volume 12, Issue 3, July 2022

Published online: June 2022

Full Article on Wiley Online Library



Abstract

The extracellular matrix (ECM) provides structural support and imparts a wide variety of environmental cues to cells. In the past decade, a growing body of work revealed that the mechanical properties of the ECM, commonly known as matrix stiffness, regulate the fundamental cellular processes of the lung. There is growing appreciation that mechanical interplays between cells and associated ECM are essential to maintain lung homeostasis. Dysregulation of ECM‐derived mechanical signaling via altered mechanosensing and mechanotransduction pathways is associated with many common lung diseases. Matrix stiffening is a hallmark of lung fibrosis. The stiffened ECM is not merely a sequelae of lung fibrosis but can actively drive the progression of fibrotic lung disease. In this article, we provide a comprehensive view on the role of matrix stiffness in lung health and disease. We begin by summarizing the effects of matrix stiffness on the function and behavior of various lung cell types and on regulation of biomolecule activity and key physiological processes, including host immune response and cellular metabolism. We discuss the potential mechanisms by which cells probe matrix stiffness and convert mechanical signals to regulate gene expression. We highlight the factors that govern matrix stiffness and outline the role of matrix stiffness in lung development and the pathogenesis of pulmonary fibrosis, pulmonary hypertension, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. We envision targeting of deleterious matrix mechanical cues for treatment of fibrotic lung disease. Advances in technologies for matrix stiffness measurements and design of stiffness‐tunable matrix substrates are also explored. © 2022 American Physiological Society. Compr Physiol 12:3523‐3558, 2022.

Figure 1. Figure 1. A scheme of matrix stiffness‐mediated mechanosensing and mechanotransduction pathways. ECM‐derived mechanical cues are sensed by cell surface receptors, including integrin‐containing FAs, GPCRs, and TRPV4. Mechanoactivation of RhoA and ROCK promotes G‐actin polymerization into F‐actin, resulting in the release of MKL1 and its nuclear translocation. RhoA/ROCK activation and the remodeling of actin cytoskeleton can also activate YAP/TAZ and promote their nuclear translocation, whereas the canonical Hippo signaling phosphorylates YAP/TAZ and inhibits their nuclear translocation. In the nucleus, MKL1 interacts with SRF to activate the transcription of target genes, including αSMA and BCL2. MKL1 binds to YAP, which regulates CCN1 gene expression. In contrast, MKL1 and TAZ appear to antagonize each other for the cytoplasmic‐nuclear shuttling and the binding of gene promoter. MKL1 also regulates histone modifications through binding to H3K4 methyltransferase. Other mechanosensitive transcription factors include NF‐κB, β‐catenin, c‐Fos/c‐Jun, STAT3, ZNF416, and ELK1. Furthermore, the contractile cytoskeleton pulling on a stiffened ECM may change the conformation of latent TGF‐β complex, leading to the release or exposure of active TGF‐β.
Figure 2. Figure 2. Mechanical testing of normal and fibrotic mouse lung tissues by AFM microindentation. (A) A MFP‐3D‐BIO atomic force microscope (Asylum Research) mounted on a Nikon eclipse Ti2 microscope. (B) A typical force‐distance curve generated by AFM on mouse lung tissues. (C to E) C57BL/6 mice were administered 1.5 U/kg body weight bleomycin intratracheally to induce lung fibrosis. Control mice were given an equal volume (50 μL) of saline. Lung tissues were harvested at 28 d. Mechanical testing of unfixed native mouse lung tissues was performed by AFM microindentation. Tissue sections were stained with a collagen‐Col‐F collagen‐binding reagent to facilitate localization of specific lung areas (e.g., the alveolar wall and collagen‐enriched fibrotic area) and positioning of the cantilever tip (C). Heat maps show the elastic moduli (Young's moduli) of the alveolar wall in the saline‐treated lungs and the fibrotic area in bleomycin‐treated lungs (D). Bar graphs show the distribution of stiffness in saline‐ and bleomycin‐treated mouse lungs (E). Scale bars = 100 μm. (Panels C‐E: Reused, with permission, from Sato S, et al., 2021, 332)


Figure 1. A scheme of matrix stiffness‐mediated mechanosensing and mechanotransduction pathways. ECM‐derived mechanical cues are sensed by cell surface receptors, including integrin‐containing FAs, GPCRs, and TRPV4. Mechanoactivation of RhoA and ROCK promotes G‐actin polymerization into F‐actin, resulting in the release of MKL1 and its nuclear translocation. RhoA/ROCK activation and the remodeling of actin cytoskeleton can also activate YAP/TAZ and promote their nuclear translocation, whereas the canonical Hippo signaling phosphorylates YAP/TAZ and inhibits their nuclear translocation. In the nucleus, MKL1 interacts with SRF to activate the transcription of target genes, including αSMA and BCL2. MKL1 binds to YAP, which regulates CCN1 gene expression. In contrast, MKL1 and TAZ appear to antagonize each other for the cytoplasmic‐nuclear shuttling and the binding of gene promoter. MKL1 also regulates histone modifications through binding to H3K4 methyltransferase. Other mechanosensitive transcription factors include NF‐κB, β‐catenin, c‐Fos/c‐Jun, STAT3, ZNF416, and ELK1. Furthermore, the contractile cytoskeleton pulling on a stiffened ECM may change the conformation of latent TGF‐β complex, leading to the release or exposure of active TGF‐β.


Figure 2. Mechanical testing of normal and fibrotic mouse lung tissues by AFM microindentation. (A) A MFP‐3D‐BIO atomic force microscope (Asylum Research) mounted on a Nikon eclipse Ti2 microscope. (B) A typical force‐distance curve generated by AFM on mouse lung tissues. (C to E) C57BL/6 mice were administered 1.5 U/kg body weight bleomycin intratracheally to induce lung fibrosis. Control mice were given an equal volume (50 μL) of saline. Lung tissues were harvested at 28 d. Mechanical testing of unfixed native mouse lung tissues was performed by AFM microindentation. Tissue sections were stained with a collagen‐Col‐F collagen‐binding reagent to facilitate localization of specific lung areas (e.g., the alveolar wall and collagen‐enriched fibrotic area) and positioning of the cantilever tip (C). Heat maps show the elastic moduli (Young's moduli) of the alveolar wall in the saline‐treated lungs and the fibrotic area in bleomycin‐treated lungs (D). Bar graphs show the distribution of stiffness in saline‐ and bleomycin‐treated mouse lungs (E). Scale bars = 100 μm. (Panels C‐E: Reused, with permission, from Sato S, et al., 2021, 332)
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Article Title: Extracellular Matrix Stiffness in Lung Health and Disease
 

How to Cite

Ting Guo, Chao He, Aida Venado, Yong Zhou. Extracellular Matrix Stiffness in Lung Health and Disease. Compr Physiol 2022, 12: 3523-3558. doi: 10.1002/cphy.c210032