In the March 23, 2009 issue of the Journal of Cell Biology, Nguan Soon Tan et al. show that skin fibroblasts use the PPARβ/δ protein to control the proliferation of epithelial cells. Their results highlight how communications between different cell types are critical to maintaining the skin barrier.
Signals exchanged between the dermis and epidermis coordinate their function, but dissecting these signals is complex. For instance, PPARβ/δ is a nuclear hormone receptor found to regulate gene expression; in mice lacking PPARβ/δ, epidermal cells proliferate excessively after wounding. However, cultured keratinocytes from these mice did not proliferate faster than normal cells and were, in fact, more susceptible to apoptosis. According to the report, this discrepancy was the first indication that PPARβ/δ might regulate crosstalk between layers of the skin—i.e., the epidermal hyperproliferation seen in the knockout mice could be due to faulty signals from the dermal cells.
Researchers looked at a situation where the different types of cells were not in isolation but could communicate with each other, and organotypic skin cultures provided a good technique for this.The authors discovered that PPARβ/δ stimulates the production of sIL-1ra, a protein that inhibits IL-1 signaling by competing for the IL-1 receptor. Normally, this would decrease the IL-1 signal received by fibroblasts and therefore reduce the growth factor signals sent back to the keratinocytes but in the absence of PPARβ/δ, fibroblasts keep stimulating keratinocyte division. Similarly, PPARβ/δ knockout mice expressed less sIL-1ra after wounding and produced more growth factors that stimulate the epidermis.
"Proliferation is important in early stages of wound healing," explained Tan in a Eureka report decribing this research, but excessive proliferation can cause hypertrophic scarring." Contradictory reports exist on whether PPARβ/δ promotes or inhibits epithelial cancers but Tan's group found that fibroblasts lacking the protein can increase the proliferation of squamous carcinoma cells. The researchers now plan to investigate PPARβ/δ's expression in tumor-associated fibroblasts.