Cell-Cell Interactions

CHAPTER

11.2

Cell-Cell Interactions
SHARAD KUKRETI, KONSTANTINOS KONSTANTOPOULOS, L A R R Y V. M C I N T I R E

Cox Laboratory for Biomedical Engineering, Institute of Biosciences and Bioengineering, Rice University, Houston, TX 77005-1892, USA

1 Introduction

Cell adhesion is instrumental in diverse biological phenomena, including tissue morphogenesis, inflammation, and thrombosis.Cell-cell interactions play a vital role in assembling cells together and in determining the overall tissue architecture during tissue generation. A relevant example is neovascularization or formation of new blood vessels. The endothelium which forms the inner layer of the vessel wall is a biologically active monolayer presenting a dynamic interface between flowing blood and tissues of the body.Adhesive junctions between endothelial cells not only help in maintaing the integrity of the vessel structure experiencing hemodynamic forces due to blood flow, but also actively regulate the permeability of bioactive molecules and transmigration of various leukocyte populations across the endothelial monolayer during inflammation. In the vascular system, cell attachment during inflammatory orthrombotic processes occurs under flow conditions and depends on the balance between the dispersive hydrodynamic forces and the adhesive forces generated by the interaction of membrane-bound receptors and their ligands. Cellular interactions are required to be highly specific in nature for proper regulation of events to result in homeostatic inflammation and coagulation. Inflammatory processesnormally protect the body from infections by foreign pathogens. However, when dysregulated, leukocyte migration to healthy tissues can lead to unwanted disorders and pathologic conditions. Similarly, defective modulation of the hemostatic mechanism can lead to the formation of platelet rich thrombus which can compromise the patency of the blood

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vessel. Understandingthe complex interplay among blood flow, cell adhesion, and vascular biology at the molecular level is crucial for developing tissue engineering based approaches for therapeutic interventions. This chapter reviews families of adhesion receptors involved in inflammatory or thrombotic responses and endothelial-endothelial cell adhesive junctions. We also discuss the signaling mechanisms associatedwith the adhesion processes, particularly those mediated by integrins and cadherins. Finally we discuss cell-cell adhesion in graft rejection and platelet-biomaterial interactions as relevant examples in current tissue engineering research.

2 Families of adhesion receptors

2.1 Selectins

All three known members of this family share a similar cassette structure of three ordered domains. (i)(ii) (iii) N-terminal Ca 2+ dependent lectin or carbohydrate binding motif. Epidermal Growth Factor (EGF)-like motif. Complement regulatory (CR) motif.

Selectin binding is completely dependent on the conformational changes associated with filling of two Ca 2+ binding sites and is also sensitive to pH, with decreased binding below physiological pH. 2.1.1 P-selectin Monoclonal antibodiesrecognizing activated but not resting platelets led to the discovery of P-selectin molecule. This 140 kDa integral membrane protein resides in the a-granules of unactivated platelets. Subsequently, it was also identified in the Wiebel-Palade bodies of endothelial cells [1]. Sorting of P-selectin into these granules is determined by sequences in its cytoplasmic tail which interact with the sorting machineryin cells. Upon stimulation with agonists like histamine or thrombin, P-selectin gets rapidly distributed to the cell plasma membrane [2]. On endothelial cells, P-selectin expression declines to basal levels after 30 minutes of stimulation. Internalized P-selectin molecules are degraded in the lysosomes, a process that is also regulated by specific amino acid sequences in its cytoplasmic domain....