Deconstructing the extracellular matrix: imaging 3D-bioprinted models to understand the effect of abnormal mechano-environment on collagen remodeling

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Biological tissues are not uniquely composed of cells. A substantial part of their volume is extracellular space, which is largely filled by an intricate network of macromolecules constituting the extracellular matrix (ECM). The ECM serves as the scaffolding for tissues and organs throughout the body, playing an essential role in their structural and functional integrity. This proposal combines tissue engineering (by 3D bioprinting tissue models) with high resolution imaging to provide a new window on healthy ECM, and on abnormal processes that replace healthy with fibrotic tissue following tissue injury. At the heart of the proposal, we will design and engineer tissues to model injury and repair. Upon injury, recovery requires the coordinated activation of a variety of different reparative pathways, including ECM alterations. Fibroblasts are cells thereby stimulated mechanically (via ECM changes) and chemically to undergo differentiation into myofibroblasts. (Myo)fibroblasts are essential to tissue repair; they secrete collagen to grow new ECM, regulated by the constantly changing physico-chemical environment. Dysregulation is common, however. Excessive scar tissue in turn affects the (myo)fibroblasts' micro-environment, leading to repair defects referred to as remodelling. This excessive deposition of distorted collagens ultimately causes fibrosis; the overgrowth, hardening, and/or scarring of various tissues. Key questions remain unanswered: How do the ECM and tissue-resident cells interact? What are the mechanisms that drive ECM remodeling? Addressing these fundamental questions would have far-reaching consequences; fibrosis can occur in many tissues including lungs, liver, heart, and brain, and is a hallmark of several diseases including certain cancers, atherosclerosis and asthma. The goal of this research proposal is to reveal how abnormal physico-chemical environments affect cellular communication responses. In so doing, we will contribution significantly to synthetic ECM model development and image analysis tools; we expect that application of customized image processing, machine learning, and 3D visualization tools to our multimodal images will reveal the biological structures and responses responsible for ECM defective repair. This unique, interdisciplinary research program spans cellular biology, machine learning, tissue engineering, optical imaging and spectroscopy themes. We will develop and validate next generation 3D lung tissue models; parallel development of image processing strategies to characterize engineered fibrotic networks will provide a variety of unique HQP training opportunities. Success will position us strategically to enhance the Canadian presence in the burgeoning field of tissue engineering and imaging. In the long term, this research will guide the identification of new therapeutic targets for this widespread, deadly, and otherwise incurable condition affecting the lives of many Canadians.