Time (and PPARβ/δ) heals all wounds

Time (and PPAR␤ր␦) heals all wounds M ammalian skin requires constant maintenance, but how do skin cells know when to proliferate and at what rate? Nguan Soon Tan and colleagues reveal that skin fi broblasts use a protein called PPAR␤/␦ to make sure over-lying epithelial cells don't proliferate too quickly. Their results highlight how communications between different cell types are critical to maintain the skin as a barrier against the outside world. Skin has two main layers: the underlying dermis, made up of fi broblasts and other cells, and the outer epidermis, containing epithelial keratinocytes. Signals are exchanged between these layers to coordinate their function, but dissecting these signals is tricky. For example, PPAR␤/␦ is an important protein for maintaining healthy skin, but its precise function remains controversial. PPAR␤/␦ is a nuclear hormone receptor that regulates gene expression. In mice lacking PPAR␤/␦, epidermal cells proliferate excessively after wounding (1). But cultured keratinocytes from these mice don't proliferate any faster than normal cells and, in fact, are more susceptible to apoptosis (2). According to Tan, this discrepancy was the fi rst indication that PPAR␤/␦ might regulate crosstalk between layers of the skin—the epi-dermal hyperproliferation seen in the knockout mice could be due to faulty signals from the dermal cells. But this couldn't be studied further in mice, as it is not yet possible to delete a gene exclusively from the dermis. " We had to look at a situation where the different types of cells were not in isolation but could communicate with each other, " says Tan. " Organotypic skin cultures are a really good technique for this. " First developed in the 1980s (3), or-ganotypic skin cultures (OTCs) are made by embedding dermal fi broblasts in a gel of extracellular matrix proteins. Keratino-cytes are seeded on top and the two cell types develop into an in vitro version of skin that looks remarkably like the real thing. The fi broblasts and keratinocytes can therefore be manipulated separately— knocking down or overexpressing pro-teins—before the skin is reconstructed. Chong et al. found that PPAR␤/␦-defi cient fi broblasts made wild-type kera-tinocytes hyperproliferative in OTCs by secreting extra doses of several growth factors. The fi-broblasts were stimulated to produce these growth factors by keratinocyte-released cy-tokine IL-1—underscoring the reciprocity between the two cell types. Blocking either the IL-1 signal or any of the growth factors released by the fi broblasts returned the OTCs to …