Innovative Treatments Based on Emerging Mechano-Biology of Inflammatory and Senescent Fibroblasts
Science
Mechano-Biology: Tissue Stiffness as a Driving Force of Human Diseases
Mechano-biology studies the relationship between cells and their physical microenvironment, and how cells can detect and respond to changes in the rigidity of their surrounding extracellular matrix (ECM). Changes in the biophysical cues of the ECM (i.e. tissue stiffness, viscoelasticity) directly control cellular behavior during tissue repair and regeneration, inflammation and fibrosis. Tissue stiffness activates mechanical signaling pathways and change gene expression programs in cells via specific ECM receptors known as via “Mechano-Sensors”.
Tissue Stiffness-Cell Interactions are Regulated by Mechano-Sensors and Drive Cellular Responses Including Cell Plasticity, Migration and Division
The Extracellular Matrix Supplies the 3D Physical Structure in Which Cells Live
Stiffness Drives Fibroblast Mechano-Biology and Functions
Fibroblasts are highly mechanosensitive cells. As matrix stiffness increases, their phenotype and function shift — from homeostatic in low-stiffness environments, to pro-inflammatory at intermediate stiffness, and to a profibrotic state under high stiffness. Prolonged exposure to elevated stiffness ultimately drives fibroblasts into senescence.
Mechano-Biology of Fibro-Inflammatory Diseases
Extracellular matrix (ECM) stiffening and remodeling is a hallmark of inflammatory and fibrotic diseases in which excessive ECM deposition and crosslinking distort tissue architecture and impair organ function. Progressive and irreversible tissue damage is a primary or contributing factor in human diseases including Idiopathic Pulmonary Fibrosis (IPF), Scleroderma (SSc), Inflammatory Bowel Disease (IBD)/Crohn's disease and Rheumatoid Arthritis (RA)
IPF
Current IPF therapies only slow fibrosis but do not reverse it. Stiffness-driven fibroblasts fuel disease progression.
IBD/Crohn’s
Up to 40% of Crohn’s patients develop fibrosis or strictures, which current anti-inflammatory therapies fail to treat.
RA-ILD/Scleroderma
TNF inhibitors fail in 30% RA patients as stiffness-driven fibroblasts sustain inflammation and fibrosis.
Mechano-Sensors as Targets in Human Disease and the Development of Zenon’s Innovative Mechano-Therapeutics
In the era of “-omics” sciences, genetic abnormalities and pathologic cellular communication through soluble biochemical signaling dominate the way we think about the development and treatment of human diseases. However, recent discoveries demonstrated that cellular behavior is largely controlled by biophysical cues such as tissue stiffness. Research in the Lagares Lab has identified mechanisms in which increased tissue stiffness alters cell behavior and drives disease progression. Zenon is targeting “mechano-sensors” selectivety upregulated in pathologic cells in inflammation, aging, cancer and fibrosis, which drive unique cellular disease mechanisms currently untreatable by existing treatments.
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