Using three-dimensional (3D) skin models, Spiro Getsios, PhD, assistant professor in dermatology and cell and molecular biology, is exploring a communications network, the complexities of which are just beginning to be understood.
Grown on collagen lattices over the course of two weeks, the 3D skin “raft cultures” – named for the way they float to create an air-liquid interface – are providing new understanding into the way epithelial cells converse with one another.
“The model we use is a tremendous example of the bedside giving insight to the bench,” Getsios said of the way clinical skin-grafting techniques for burn patients were the inspiration for cell biologists to create better cell culture models in the lab. “Many people who work in skin biology use submerged two-dimensional cultures to understand how normal epithelial cells work. But the architecture and the relationship of cell-to-cell contacts in this multi-layered epithelium can’t be recapitulated in these submerged 2D cultures. The solution is that we build 3D models of human skin where an artificial substrate is used as a platform for keratinocytes – skin cells – to grow on an air-liquid interface.”
Getsios learned how to build these human skin equivalents with the help of Laimonis Laimins, PhD, chair of microbiology-immunology, and now trains investigators in the Northwestern University Skin Disease Research Center Keratinocyte Core that he directs. He is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Several years ago, the Getsios lab discovered a new skin cell-to-cell signaling pathway called the Eph/ephrin axis that allows skin epithelial cells to exchange information with one another. Published as the March cover story in the Journal of Investigative Dermatology, Getsios used the 3D human skin equivalent to model inflammation and was able to show the benefits of a potential treatment for psoriasis, a common condition that causes skin thickening and irritation.
In normal conditions, sufficient levels of the protein ephrin keep a specific receptor – EphA2 – in check to maintain skin tissue differentiation. In psoriasis, ephrin levels are reduced and EphA2 receptors are dramatically increased. Getsios’ lab was able to show that a therapeutic treatment providing more ephrin can eliminate the increase in EphA2 and restore normal differentiation. If designed to penetrate the skin in a topically applied solution, the ephrin therapy could someday be used to treat inflammatory skin conditions or tumors where EphA2 levels are up-regulated.
“The raft cultures give us a unique tool to regenerate what we think is close to the in vivo state of skin, and then we spend most of our time trying to destroy that normalcy,” Getsios said. “We think that by understanding the skin’s normal biology we will also be able to provide insight into diseases like inflammation and cancer, where cells start to misbehave and divide in the wrong place.”