ABSTRACT
Tissue cells are subjected to a variety of biochemical and biophysical stimuli from their local microenvironment. The ability of cells to sense these stimuli and orchestrate appropriate responses is essential for the integration of form and function underlying tissue homeostasis. Conversely, failure of any of these processes and the consequent loss of form and function integration are hallmarks of a large family of mechanobiology diseases including fibrosis and cancer. In this chapter, we discuss our previous studies aiming to understand how cells integrate form, mechanics, and function in the context of mammary and lung tissues. Special attention is given to our findings highlighting the prominent role of integrin receptors and their signaling factors, matrix metalloproteinases and transforming growth factor beta in the mechanical homeostasis of soft tissues. In addition, we describe studies linking cell shape, epigenetics, and chromatin organization. Based on the
latter and related findings, we argue that normal mechanical and morphological cues are protective against mechanobiology diseases. 8.1 Introduction: Biochemical Cues Cannot Do
It AloneIn normal conditions, many organs in our body are very soft compared to the rigid structures of the musculo-skeletal system. Examples of such very soft organs include the liver, kidney, lung, brain, breast, and pancreas [1]. A common important property of these soft organs is their compartmentalization. Thus, the part of the organ that performs the tissue-specific function (i.e., the parenchyma) is generally separated from the parts of the organ (i.e., the stroma) that provide structural and “logistic” support to the parenchyma by a specialized extracellular matrix (ECM) known as basement membrane (BM). For example, the parenchyma in the mammary tissue includes the epithelial-rich alveolar/acinar structures responsible for secreting milk during lactation, whereas the stroma includes the fibroblast-rich connective tissue, blood capillaries and nerves [2]. In addition, tissues in each compartment exhibit an exquisite integration of form and function. Thus, mammary acini are organized in a three-dimensional (3D) thin layer of polarized epithelial cells that enclose a central lumen to facilitate the vectorial secretion of milk proteins, whereas the surrounding stroma is rich in fibrillar collagens and other ECM filaments that provide mechanical support to the whole organ. Intriguingly, a hallmark of many prevalent diseases affecting soft organs is a chronic loss of normal tissue elasticity in which tissues become too stiff-as in fibrosis, cancer, or sclerosis-with a concomitant loss of tissue compartmentalization and function.
