ECM in health and disease

Intro

Fibrosis and wound healing are central themes in more than 300 chronic diseases. This session will examine how these processes are interlinked and whether they can be modulated to block fibrosis progression.

Leveraging mechanobiology to drug the fibrotic matrix

Thomas H. Barker, Professor of Biomedical Engineering at University of Virginia. He is co-Founder, President and Chief Scientific Officer, Vasarya Therapeutics, Inc. and co-Founder and BOD at SelSym Biotechnology, Inc.

Abstract: The extracellular matrix (ECM) is a dynamic structural scaffold that presents numerous signals to cells, from biophysical to biochemical.  Critical signals generated by the ECM include integrin receptor signaling, cell-surface proteoglycan signaling, and receptor tyrosine kinase signaling through ECM-bound growth factors and cytokines.  The ECM both presents these signals as a solid (non-diffusible) substrate enhancing their signaling persistence as well as spatially organizing these combined queues leading to synergistic signaling responses.  In short, the ECM is a mechanochemical information orchestrator.  For this reason, the ECM is central to all tissue function from development and homeostasis to disease and thus represents perhaps the single most attractive target in disease treatment.  Yet there are few, if any, demonstrative examples of ECM targeting for disease treatment.  This is in large part due to the ubiquitous nature of ECM proteins.  Despite mass spec-based quantified differences in diseased versus healthy tissue ECM, the overlap in protein species and their presence in healthy tissues throughout the body has made therapeutically targeting the ECM an extremely risky business, driving most groups to focus on integrin inhibition to disrupt ECM-cell signaling.  In this seminar, I will present an alternative strategy that leverages ECM mechanobiology.  For the past decade, we have identified force-mediated conformational changes, i.e mechanoswitches, within the ECM protein fibronectin and have additionally explored environmentally triggered post-translational modifications that further promote the activation of fibronectin’s mechanoswitch within its integrin-binding domain.  I will present data on an antibody drug that recognizes a mechanically exposed cryptic epitope on fibronectin, that demonstrates promising disease tissue specificity and exhibits efficacy in multiple models of fibrosis and in a human in vitro disease model of active fibrosis.

Metabolic and epigenetic control of fibroblast memory in systemic sclerosis

John Varga, Professor of Medicine and Dermatology, Chief, Division of Rheumatology at University of Michigan

Abstract: Systemic sclerosis (SSc) is a paradigm for multiple organ fibrosis that is driven by resident myofibroblasts in affected tissues (skin, lungs, heart and kidneys).  SSc patients display many hallmarks of biological aging, including dysregulated nutrient metabolism, cellular senescence, telomere shortening, low-grade inflammation and mesenchymal drift. Recent insights from single cell-level tissue analysis and animal models suggest an important role for the NAD metabolic enzymes CD38 and NNMT in pathogenesis. These enzymes link cellular metabolism and epigenetic reprogramming that underlies the cell-autonomous memory of SSc myofibroblasts. Targeting these enzymes may restore organismal NAD homeostasis, and are currently being tested as therapy in fibrotic and age-related conditions including SSc.