Grant: Canada Postdoctoral Research Award (CPRA) program

Lung fibrosis affects 5 million people worldwide, with an average survival time of 2-3 years after diagnosis. In fibrosis, excessive, stiff scars reduce lung compliance and impair gas exchange, ultimately making it impossible for patients to breathe. The only effective treatment for patients with end-stage fibrosis is a lung transplant. Fibrosis can be understood as a persistent repair response in which inflammatory cells called macrophages continue instructing fibroblasts to repair micro-injuries to the delicate lung tissues with collagen scar tissue. In normal repair, the macrophage-fibroblast interaction is temporary and beneficial, but in fibrosis, both cell types persist beyond healing, leading to the buildup of harmful scar tissue. The Hinz Lab found that fibroblasts that spend too much time in a stiff scar tissue environment maintain their scar-making activities, even after being placed in a soft, healthy-like environment. They suggest that such "mechanical memory" is a key factor that shifts the balance from temporary repair to ongoing fibrosis. We still do not know if macrophages also retain mechanical memory, and how this memory influences how they guide -or, misguide- fibroblasts. To explore this, I will use engineered gel systems that replicate the structure and stiffness of lung tissue-soft gels to mimic healthy lungs, and stiff gels to mimic fibrotic lungs. These gels are made from decellularized lung extracellular matrix, a biological material closely resembling the natural lung environment. By studying how fibroblasts and macrophages interact within these gels, we aim to uncover how mechanical memory and intercellular communication contribute to persistent lung scarring. Understanding these mechanisms could lead to new therapies to break the cycle of fibrosis and promote healing without scarring.