Dynamic Mechanical Environments Alter Chromatin Architecture Stability

Abstract

Cellular adaptations in response to changes in the tissue mechanical environment are critical for maintaining organ function and homeostasis. Cells in mechanically regulated tissues, such as cardiomyocytes in the heart or chondrocytes in cartilage tissue, demonstrate a high degree of plasticity and uniquely respond to mechanical cues leading to overall tissue remodeling to accommodate the mechanical loads. However, chronic exposure to abnormal mechanical environments can lead to maladaptive states with decreased cellular plasticity even after a return to normal physiological loading. In other words, cells remember previous mechanical environments, which can decrease the potential to return to a native healthy state. Recent literature suggests remodeling of chromatin architecture in response to mechanical loading can persist over time after the stimulus is removed, providing a potential mechanism to store mechanical memory. Understanding the mechanisms and impacts of mechanical memory could elucidate cell therapy strategies for diverse disciplines in medicine.

The central aim of this thesis is to understand how dynamic mechanical environments influence chromatin architecture stability and in turn induce a mechanical memory that decreases phenotypic plasticity of cells. To explore this aim, Chapter 1 first introduces cellular plasticity and mechanical memory in chondrocytes and cardiac cells. Chapter 2 focuses on understanding the impact of mechanical memory in vitro in a tissue regeneration model to repair cartilage defects. Our results demonstrate that expanding chondrocytes in vitro, a critical step to cartilage defect repair procedures, induces epigenetic changes associated with the loss of chondrocyte identity. We show that these epigenetic changes are retained when the cells are transferred to 3D environments, limiting the chondrogenic potential of expanded cells. Work presented in Chapter 3 demonstrates that inhibiting or suppressing epigenetic modifiers can prevent or reverse the mal-adaptive effects of mechanical memory in the context of cartilage tissue regeneration. Finally, work presented in Chapter 4 determines the extent that mechanical memory develops in vivo since previous studies have only focused on the effect of in vitro environments. Using an in vivo hypertension model, our results demonstrate that cardiac tissue retains a multiscale mechanical memory in vivo from an induced temporary hypertensive response.