Feeling Things Out: Bidirectional Signaling of the Cell–ECM Interface, Implications in the Mechanobiology of Cell Spreading, Migration, Proliferation, and Differentiation

Abstract

Biophysical cues stemming from the extracellular environment are rapidly transduced into discernible chemical messages (mechanotransduction) that direct cellular activities-placing the extracellular matrix (ECM) as a potent regulator of cell behavior. Dynamic reciprocity between the cell and its associated matrix is essential to the maintenance of tissue homeostasis and dysregulation of both ECM mechanical signaling, via pathological ECM turnover, and internal mechanotransduction pathways contribute to disease progression. This review covers the current understandings of the key modes of signaling used by both the cell and ECM to coregulate one another. By taking an outside-in approach, the inherent complexities and regulatory processes at each level of signaling (ECM, plasma membrane, focal adhesion, and cytoplasm) are captured to give a comprehensive picture of the internal and external mechanoregulatory environment. Specific emphasis is placed on the focal adhesion complex which acts as a central hub of mechanical signaling, regulating cell spreading, migration, proliferation, and differentiation. In addition, a wealth of available knowledge on mechanotransduction is curated to generate an integrated signaling network encompassing the central components of the focal adhesion, cytoplasm and nucleus that act in concert to promote durotaxis, proliferation, and differentiation in a stiffness-dependent manner.

Cell-Laden Agarose-Collagen Composite Hydrogels for Mechanotransduction Studies

“…As many degenerative and regenerative processes are related to mechanical loading, the field of mechanobiology is widely expanding. The interest in understanding how mechanical signals influence cell behavior is in fact shared across disciplines as diverse as cancer and developmental biology, regenerative medicine, tissue engineering, and clinical disciplines such as pulmonology and orthopedics (Jaalouk and Lammerding, 2009;Martino et al, 2018;Miller et al, 2020). As an example, mechanical loading is a known contributor to intervertebral disc (IVD) degeneration, which when associated with pain and inflammation, is defined as degenerative disc disease (Adams and Roughley, 2006).…”

Osteogenic and Adipogenic Differentiation of Mesenchymal Stem Cells in Gelatin Solutions of Different Viscosities

“…Cell functions are regulated by various biological and physicochemical cues DOI: 10.1002/adhm.202000617 from ECM. [1][2][3][4][5][6] Although influence of biological and chemical cues on cell functions, such as stem cell differentiation, has been intensively studied so far, accumulating evidences indicate that physical cues, such as elasticity and viscoelasticity, also play an important role in regulating cell functions. [7,8] Many approaches have been developed to explore the effect of such a physical cue, stiffness, on stem cell differentiation.…”

Win, Lose, or Tie: Mathematical Modeling of Ligand Competition at the Cell–Extracellular Matrix Interface

“…The translation of biophysical cues provided by the ECM into biochemical signals by the cells is a process called mechanotransduction. For cells, mechanotransduction is central to maintaining homeostasis in many biological processes like proliferation, migration, differentiation, and apoptosis ( Miller et al, 2020 ). It is known, for example, that the composition and mechanical properties of the extracellular environment in which mesenchymal stem cells are grown influences whether they differentiate into adipocytes, osteoblasts, or chondrocytes ( Assis-Ribas et al, 2018 ).…”

“…The initial presence and the changes in the amounts of ECM proteins are sensed first by the integrins, the direct interaction partners of these proteins. Therefore, a detailed analysis and understanding of the effects of abnormal ligand deposition and ligand competition on integrin–ligand dynamics can help us understand the decision-making processes of the cells in response to the changes in ECM conditions ( Garreta et al, 2019 ; Miller et al, 2020 ; Geuens et al, 2020b ).…”