Growth Factors and the Extracellular Matrix

ONE of the objectives pursued actively for the past 80 years by cell biologists has been to reconstruct from single cells maintained in vitro the corresponding functional tissue. This not only requires that cells obtained from a given tissue and maintained singly in vitro proliferate actively but also that upon reaching confluence they reconstruct the tissue to which they belong in vivo in such a way that both the morphological characteristics of the tissue and its functions are preserved. In recent years, the discovery of mitogenic factors that maintained cells in an active stage of proliferation, thereby preventing their precocious senescence in vitro, has made it possible, in the case of a few tissues, to achieve these objectives. The discovery of growth factors is in a sense not a recent occurrence. The first growth factor to be identified was erythropoietin. This factor, first identified by Carnot and Deflandre in 1906, controls the proliferation of erythroblasts, the progenitors of red blood cells (1). It was not until the 1950's, however, that new growth factors specific to other tissues were to be discovered. Among them was the nerve growth factor (NGF), discovered by Levi-Montalcini and colleagues (2), and the epidermal growth factor (EGF), discovered by Cohen (3). NGF, which was shown to be essential for the survival of sympathetic neurons in tissue culture, was soon used to enable neurons maintained in vitro to survive and to differentiate (4). EGF was discovered primarily through its mitogenic effect on the basal cell layer of the epidermis. This was indirectly reflected in vivo by precocious eyelid opening and tooth eruption in neonatal rats injected with EGF. With organ culture of skin or cornea, EGF induces a spectacular hyperplasia of the epithelial cell layers. It was not until 20 years later, however, that the impact of EGF on cell culture technology was to be felt. This factor is now used in many laboratories as a probe to explore the basic mechanisms through which cells such as fibroblasts divide (5, 6). It is also used in keratinocyte cultures, where it delays the terminal differentiation of the cells, thereby rendering long-term culturing of that cell type possible (7).