Time (and PPAR-beta/delta) heals ...( Mammalian skin requires constant mai...)

Mammalian skin requires constant maintenance, but how do skin cells know when to proliferate and at what rate? In the March 23, 2009 issue of the Journal of Cell Biology, Nguan Soon Tan and colleagues reveal that skin fibroblasts use a protein called PPARβ/δ to make sure overlying 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 fibroblasts 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, PPARβ/δ is an important protein for maintaining healthy skin, but its precise function remains controversial.

PPARβ/δ is a nuclear hormone receptor that regulates gene expression. In mice lacking PPARβ/δ, 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 Nguan Soon Tan, this discrepancy was the first indication that PPARβ/δ might regulate crosstalk between layers of the skinthe epidermal 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), organotypic skin cultures (OTCs) are made by embedding dermal fibroblasts in a gel of extracellular matrix proteins. Keratinocytes are se
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