Multiscale Biophysical Signaling Regulates Tissue Morphogenesis and Degeneration

Abstract

Mechanical forces are tightly coupled to key cellular processes during organogenesis and tissue degeneration. Many biological responses to mechanical stimulation are controlled by the cell nucleus, which is physically connected to the cytoplasm, cell membrane, and surrounding tissue matrix. Through their integration, these components are assembled into mechanically driven molecular networks and dynamically organized systems, resulting in multiscale regulation of collective cell behavior in tissues. Treatment of injuries or disease where mechanical function is crucial requires an improved understanding of the interplay between tissue composition, mechanics, and cellular activity.

Consequently, my hypothesis is that dynamic reciprocity between the cell nucleus and the extracellular matrix (ECM) govern tissue development and degeneration. In this thesis, I investigate the relationship between the composition of the ECM and its emergent material properties, how the nucleus reacts to mechanical cues from the ECM, and then I connect these investigations with a multiscale approach to study how macroscale mechanical cues affect tissue development through altering gene expression. Chapter 1 motivates this work by providing an overview of techniques ex vivo and how regenerative therapies can be informed by ontogeny. In Chapter 2, we devise a method to directly probe the stiffness of the nucleus using atomic force microscopy (AFM) to study the effects of disease-related enzymatic degradation on nuclear mechanics. In Chapter 3, we validate the use of hyperelastic models to describe soft material indentation with AFM and elucidate how ECM protein networks affect nonlinear mechanical properties. In Chapter 4, we identify the changes in the developing enthesis ECM with mechanical properties, composition, and organization through embryogenesis and adolescence, and further, resulting from macroscale muscle contractions in a mouse model. In Chapter 5, we describe how coordinated movement is incorporated into the genetic code of chondrocytes during embryogenesis to control cartilage morphology in the developing joint. Overall, my research findings demonstrate the vital function of dynamic reciprocity between the ECM and cell nucleus in development and disease, and broaden the scope of AFM methodology and analysis.