Matrix, Mesenchyme, and Mechanotransduction

Abstract

The extracellular matrix (ECM) of the lung serves as both a scaffold for resident cells and a mechanical support for respiratory function. The ECM is deposited during development and undergoes continuous turnover and maintenance during organ growth and homeostasis. Cells of the mesenchyme, including the tissue resident fibroblast, take a leading role in depositing and organizing the matrix and do so in an anatomically distinct fashion, with differing composition, organization, and mechanical properties within the airways, vessels, and alveoli of the lung. Recent technological advancements have allowed the lung's ECM biochemical composition and mechanical properties to be studied with improved resolution, thereby identifying novel disease-related changes in ECM characteristics. In parallel, efforts to study cells seeded on normal and disease-derived matrices have illustrated the powerful role the ECM can play in altering key functions of lung resident cells. The mechanical properties of the matrix have been identified as an important modifier of cell-matrix adhesions, with matrices of pathologic stiffness promoting profibrotic signaling and cell function. Ongoing work is identifying both mechanically activated pathways in mesenchymal cells and diseaserelated ECM molecules that biochemically regulate cell function. Uncovering the control systems by which cells respond to and regulate the matrix, and the failures in these systems that underlie aberrant repair, remains a major challenge. Progress in this area will be an essential element in efforts to engineer functional lung tissue for regenerative approaches and will be key to identifying new therapeutic strategies for lung diseases characterized by disturbed matrix architecture.

Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension

“…Despite advances in our understanding of large vessel stiffening (24), much less is known about the micromechanical environment in PH and how the stiffness of the local cellular environment may regulate fundamental aspects of vascular biology. Alterations in tissue stiffness have long been regarded as sequelae of disease; however, emerging studies suggest that the mechanical properties of the matrix may alter cellular activation and promote pathologic tissue remodeling (13, 14, 25). Changes in the matrix mechanical environment have been shown to dramatically influence cellular morphology, cytoskeletal organization, expression of adhesion molecules, migration, proliferation, and differentiation (26, 27) in a number of cell types, including epithelial cells (28), fibroblasts (13, 14, 28), stem cells (29–32), tumor cells (33, 34), and smooth muscle cells (35–37).…”

Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic?

“…Examples include increased stiffness and stretch-induced activation of TGFβ by the remodelled lung. 77–79 Remodelling of lung tissue in patients with IPF alters expression of multiple matrix molecules, 80 many of which can activate profibrotic-signalling pathways in the mesenchymal cells that engage them. 78 These IPF fibroblasts, which are potentially metabolically aberrant, 81 can acquire destructive properties, such as the ability to invade matrix, which could contribute to chronic remodelling.…”

“…Because these cells act as the functional stem cells of the lung, when one becomes senescent, adjacent non-senescent alveolar type II cells must compensate, which leads to increased frequency of replication, accelerated telomere attrition, and a predisposition to senescence. A second feed-forward loop is triggered by matrix deposition, which stiffens lung tissue, 80 and can lead to the conversion of fibroblasts to myofibroblasts 79 and increased epithelial-cell activation, collagen and matrix deposition, and lung remodelling.…”

Plasma membrane and cytoskeleton dynamics during single-cell wound healing

“…force linked to plasmalemma to cortex attachments) [3],contacts with the extra-cellular matrix (ECM), cell-cell contacts, shear stresses, stretch stresses, or even hydrostatic pressure, may also be involved in cellular tensegrity (reviewed in [6,9]). The same forces may also modify the "tensegral" stability of the cell, resulting in mechanotransduction [9,10], which in turn control many biological processes.…”