Embryonal Stem (ES) Cell-Derived Macrophages: A Cellular System that Facilitates the Genetic Dissection of Macrophage Function

The monocyte/macrophage (M�) contributes to atherosclerotic lesion initiation and progression through a variety of interactions with cells of the artery wall that depend on the elucidation of a host of cytokines and growth factors by cells residing in the intima. The number and complexity of these interactions make it difficult to determine which cellular functions are contributing to the progression of atherosclerosis and which might be exploited to interrupt that progression. Studies of macrophage functions in atherosclerosis have been hindered by the limitations of available macrophage cell lines and primary cultures, including poor transfectability and the transformed state of imM ortal cell lines. Recent studies have demonstrated that pluripotential mouse embryonic stem cells can be differentiated down specific hematopoietic lineages in vitro, including lines that give rise to macrophages (1 ). This technique provides a genetically tractable cellular system for studying myeloid cell function. Macrophages arising from this differentiation system demonstrate cell surface presentation of classic macrophage markers and macrophage functions including phagocytosis and responses to inflammatory stimuli. There are several important advantages inherent in using embryonic stem (ES) cell derived macrophages as a cell culture system for studying M� function. As the cells are not transformed, and the progenitor cells arising from ES cells are capable of reconstituting the entire hematopoietic compartment of a mouse, they represent a cell culture system that appears to retain the physiologic regulation on growth and differentiation that is absent from transformed myelomonocytic cell lines.