Novel approaches to target fibroblast mechanotransduction in fibroproliferative diseases

Elucidating the interaction between stretch and stiffness using an agent-based spring network model of progressive pulmonary fibrosis

“…Within the processes of self-healing and fibrosis are myriad interactions between cell types and systems that result in the behaviors and structures observable in tissue ( Ezzo and Hinz, 2003 ; Moore and Herzog, 2013 ; Pally and Naba, 2024 ). Many of these interactions are not fully understood, therefore in this paper we did not endeavor to include each of these, but instead created a lumped-parameter model ( Brown et al, 2011 ) that focuses on broad behaviors such as the deposition and digestion of tissue in response to stiffness and stretch.…”

“…Similarly, the strain, , of the spring that an agent traverses also makes a contribution to the level of agent activation, representing activation via the release of ECM-bound latent TGF-beta, ( Hinz, 2009 ; Ezzo and Hinz, 2023 ), stretch-sensitive channels ( Murata et al, 2014 ), and signaling pathways such as YAP and MRTF-A ( Cui et al, 2015 ). This contribution is proportional to where is the target (homeostatic) strain at steady-state and we arbitrarily set .…”

“…When , the change in approaches zero exponentially for the homeostatic state. If is at its maximum value, the change in will also approach zero for the fully fibrotic state, representing how activated myofibroblasts resist apoptosis ( Ezzo and Hinz, 2023 ). The upper limit on represents the finite carrying capacity of tissue for fibroproliferative cells.…”

“…In a mechanically dynamic organ such as the lung, the mechanical stimulus provided by cyclical stretch also affects fibroblast behavior by, for example, activating stretch-regulated channels in the cell membrane ( Murata et al, 2014 ). Stretch also contributes to the release of latent TGF-β ( Klingberg, F. et al, 2014 ; Ezzo and Hinz, 2023 ; Hinz, 2009 ), a cytokine essential for wound healing that is involved in the transformation from fibroblasts to myofibroblasts ( Hinz, 2009 ). Signaling pathways such as YAP and MRTF-A have also been linked to fibroblast proliferation in response to cyclical stretch ( Cui et al, 2015 ).…”

Mechanisms of Fibroblast Activation during Fibrotic Tissue Remodeling

“…Fibroblasts are adherent cells and thus interact with the ECM. Increased tissue stiffness due to accumulating collagen fibers and loss of the normal ECM structure leads to increased mechanical force and stress for the fibroblasts [62]. The mechanisms behind this mechanotranduction in fibroblasts are extensively reviewed elsewhere [61][62][63].…”