Researchers at Hokkaido University have discovered that the formation of adhesion-induced patterns between cells in keratinocytes can be explained simply by starvation and strong adhesion.
Fingerprints are one of the best-known examples of pattern formation by epithelial cells. The primary cells of the epithelium are keratinocytes, and they are known to form patterns at both microscopic and macroscopic levels. While the factors affecting this pattern formation have been described, the exact mechanisms underlying the process are not yet fully understood.
A team of researchers led by Associate Professor Ken Natsuga of Hokkaido University Graduate School of Medicine has revealed that cell-cell adhesion regulates pattern formation in keratinocytes. Their findings were published in the journal Life Sciences Alliance.
“In this study, we used an immortalized keratinocyte cell line, called HaCaT, which retains all the properties of normal keratinocytes,” Natsuga explained. “To ensure that our findings were accurate, we established single cell cultures of this cell line.”
The team observed pattern formation in both the original heterogeneous cell line and in cultures derived from single cells. During culture, keratinocytes moved randomly and spontaneously formed regions of high and low density, leading to pattern formation.
Pattern formation was markedly influenced by starvation. When the culture medium was renewed, the patterns darkened, but reappeared as nutrients from the culture medium were consumed by the keratinocytes.
The team then examined gene expression in keratinocytes, which revealed that cell adhesion proteins and keratinocyte differentiation proteins were upregulated in high-density regions. “As cell adhesion is necessary for the development of high cell density regions, we specifically investigated the expression of adherens junction (AJ) molecules, such as E-cadherin and actin,” Natsuga explained. “We found that these molecules were localized at the intercellular junctions in high-density regions.”
The authors used a mathematical model to confirm that under spatially uniform density and stress conditions, strong cell adhesion leads to the formation of density patterns. They were also able to show that keratinocyte patterns influenced cell proliferation and differentiation, and that serum deprivation influences epidermal stratification (a type of differentiation) in mouse skin cells.
“Our study presents a new and robust model of cell-cell adhesion-induced pattern formation (CAIP),” concludes Natsuga. “We have deepened our mechanistic understanding of cellular organization and its consequences for cell fate decisions and epithelial stratification.” The team demonstrated that epithelial cell-cell adhesion is essential and sufficient for pattern formation. Future work will focus on adding more variables to the model to understand other processes that occur simultaneously during development.