Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease.

Cellular switching from an epithelial-to-mesenchymal phenotype, and conversely from a mesenchymal-toepithelial phenotype, are important biological programs that are operative from conception to death in mammalian organisms. Indeed, the capacity of cells to switch between these states has been fundamental to the generation of complex body patterns throughout evolution. Phenotypic switching from an epithelial to mesenchymal cell, termed epithelial-tomesenchymal transition (EMT), was a paradigm that evolved from numerous observations on early embryonic development, the foundations of which date back to the 1920s and the pioneering work of Johannes Holtfreter on embryo formation and differentiation.1,2 By the late 1960s, seminal chick embryo studies by Elizabeth Hay3 led to the first formal description that epithelial cells can undergo a dramatic phenotypic transformation and give rise to embryonic mesoderm.4 Subsequent studies have revealed that this process is reversible (mesenchymal-to-epithelial transition [MET]), and gradually the term “transition” has come to replace “transformation.” Given that EMT/MET was initially identified and described by developmental biologists, it is perhaps not surprising that these processes are best understood during embryonic implantation and development. As explored in this review, it is now known that successive waves of cellular transition, from an epithelial to mesenchymal and then back to an epithelial state, are required for normal embryonic patterning and organ formation. In addition, numerous studies that span a broad spectrum of physiological and pathological conditions have expanded our knowledge of EMT/MET and now provide evidence for the important role played by these processes in various adult conditions including fibrosis, wound repair, inflammation, and malignancy. Indeed, our conceptual framework now also encompasses several variations and subcategories of cellular phenotypic switching, including endothelial-to-mesenchymal transition (EndMT). In this review, epithelial, endothelial, and mesenchymal phenotypic cellular switching will be explored in the cardiovascular system, spanning cardiovascular development through to adult end organ disease. Key areas of recent scientific progress will be examined, including recent developmental and pathological insights, which potentially may lead to novel therapeutic opportunities.