Epithelial mechanosensation   Leave a comment

“How do cells sense and respond to their environment?” is a question that underlies much biomedical research. Historically, research has focused on chemical sensing: cells possess specialized receptors which bind to specific molecules leading to some resultant action (e.g. gene transcription). More recently, it has become appreciated that cells can respond to mechanical forces and stresses (“mechanosensation”) in addition to chemicals. This body of research is more preliminary in nature, and much less is understood. The current model for mechanosensation is the “ciliary hypothesis”, which states that cells possessing a specialized organelle (the primary cilium) can sense and respond to mechanical stimuli.

Cilia are microtubule-based projections from the cell body (general references http://www.ifcbiol.org/Primaryciliumweb/index.html). Cilia grow from the mature mother centriole of the mother-daughter pair of centrioles in the cell’s centrosome. Most cell types have solitary cilia while only cells on specific mucus membranes (e.g., respiratory tract, oviduct, and epididymis) have motile cilia. The motile cilia are present in large numbers per cell and are arranged as array on the apical membrane so that they can affect directional transport of material present in the surface mucus layer, e.g., trapped particles in the respiratory tract or eggs in the female uterine tube. In contrast, solitary or sensory cilia are present in most cells of the body and their functions are only now beginning to be defined. Their existence has been known from morphological studies since the sixties; however, because very little has been known about their functions, not much attention has been paid to this particular organelle until recently.

Several observations have illustrated the importance of the solitary cilium: 1) Smell, taste, and vision occurs via modified cilia, i.e., olfactory or gustatory sensory cilia and outer segments of rod cell, respectively. 2) Some receptors are specifically located on neurocilia. 3) mutations that occur in proteins that result in mislocation of normal ciliary proteins or malfunction of solitary cilia in the renal epithelium produce polycystic kidney disease, which is characterized by the transformation of an absorptive epithelium into a secretory one with formation of cysts. 5) Defects in solitary cilia present during development result in inversion of the normal left-right axis of internal organ, e.g., the heart forms on the right side. In addition, osteocyte cilia have been proposed to be important mechanosensors that determine in part bone formation.

Ciliopathies are clinical disease states involving the primary cilium, and number over 120. Many ciliopathies share common features including renal cystic disease, retinitis pigmentosa, situs inversus, and polydactyly. It is important to realize that ciliopathies form a class of genetic disease whose etiology lies not with dysfunction in single genes and their products, but with dysfunction in an integrated aspect of cellular physiology. Historically, there has been a distinction between motile ciliary dysfunction (e.g. primary ciliary dyskenisias) and the so-called primary ciliopathies, but this distinction has been blurred by a large number of recent results using molecular techniques.

In spite of the growing body of mechanosensation work, the cellular basis for mechanotransduction of the mechanical input to a biological response remains unclear. There is good evidence that the primary cilium acts to transduce flow energy into bending energy, which can then be used by proteins located at the base of the cilium. There is also good evidence that the cytoskeleton, brush border, or glycocalyx can transduce flow-mediated mechanical stresses to altered proteins. The reason for the ambiguity results from experimental flow protocols. Often, the applied flow is of high magnitude (ml/min) and applied acutely; this is not the case in vivo, where the renal volumetric flow rate is approximately 10 nl/min and is chronic. Thus, in many experimental studies, the shear stress applied to the epithelium is non-physiological. Another ambiguity is that fluid flow experiments, by their nature, apply a mechanical disturbance over the entire surface of the cell, making a precise determination of the site of mechanosensation impossible.

In the related field of endothelial mechanosensation, the science has progressed substantially further, but still suffers from the same deficits. As a specific example, the flow protocols for in vitro experiments overwhelmingly steady-state (constant) flow, while the actual state of hemodynamics involves time-dependent complex flows. While this fact is becoming more appreciated, the relevant experiments have yet to be performed, and so my research is targeted towards these experiments.


Posted March 18, 2011 by resnicklab

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