Serum Starvation Induces Self-Organizing Patterns in Keratinocytes through Cell-Cell Adhesion

Core Concepts

Serum starvation induces keratinocytes to spontaneously form patterns with areas of high and low cell density, which is mediated by adherens junctions and regulates cell differentiation and proliferation through the YAP pathway.

Abstract

The study investigates the mechanism underlying the spontaneous patterning of keratinocytes, a type of epithelial cell in the skin. When cultured keratinocytes are subjected to serum starvation, they develop a self-organized pattern characterized by areas of high and low cell density.
Key highlights:

The patterning is an intrinsic property of keratinocytes and is not dependent on cell heterogeneity.
Adherens junctions (AJs) are essential for the pattern formation, as disrupting AJs through pharmacological or genetic approaches abolishes the patterning.
Mathematical modeling indicates that cell-cell adhesion alone is sufficient to drive the emergence of high/low density regions.
The patterning spatially regulates keratinocyte differentiation and proliferation through the YAP pathway, which senses cell density.
Serum starvation, which induces the patterning, also enhances the stratification of the epidermis in 3D culture and ex vivo skin models.
These findings demonstrate that the intrinsic self-organizing property of epithelial cells, mediated by cell-cell adhesion, can dictate their spatial organization and fate determination. The modulation of this "cell-cell adhesion-induced patterning" (CAIP) may have implications for wound healing and regenerative medicine.

Stats

Keratinocytes in areas of high cell density were cuboidal, compact, and stratified, whereas those in areas of low cell density were flat.
The pattern was disrupted by medium changes, but reappeared after 2 days.
Serum starvation was crucial for the pattern formation, as the pattern disappeared upon serum replenishment.
Adherens junction disruption, either pharmacologically or genetically, abolished the patterning.
CTNNA1-knockout keratinocytes failed to form a stratified epidermis in 3D culture.
Serum starvation enhanced the stratification of the epidermis in 3D culture and ex vivo skin models.

Quotes

"Serum starvation induces keratinocytes to spontaneously form patterns with areas of high and low cell density, which is mediated by adherens junctions and regulates cell differentiation and proliferation through the YAP pathway."
"Cell-cell adhesion alone is sufficient to drive the emergence of high/low density regions in keratinocytes."
"The modulation of this 'cell-cell adhesion-induced patterning' (CAIP) may have implications for wound healing and regenerative medicine."

Key Insights Distilled From

Cell–cell adhesion drives patterning in stratified epithelia

by Mai,Y., Koba... at www.biorxiv.org 11-26-2023

https://www.biorxiv.org/content/10.1101/2023.11.24.567740v1

Deeper Inquiries

How might the CAIP mechanism be leveraged to promote wound healing in clinical settings?

The CAIP mechanism, which involves cell-cell adhesion-induced patterning, could be utilized to enhance wound healing in clinical settings by promoting epithelial stratification. By inducing serum starvation, which triggers the formation of keratinocyte patterns characterized by areas of high and low cell density, the process can be harnessed to facilitate the final stages of wound closure. The spatial organization of cells in the epidermis, influenced by CAIP, can lead to thicker epidermal sheets, aiding in the efficient and effective healing of wounds. This self-organizing property of epithelial cells, driven by cell-cell adhesion, can be manipulated to optimize the regenerative process and promote faster and more robust wound healing outcomes.

What other epithelial tissues or developmental processes could the CAIP phenomenon be involved in, beyond the skin epidermis?

The CAIP phenomenon, driven by cell-cell adhesion, could potentially play a role in the patterning and organization of various epithelial tissues beyond the skin epidermis. Epithelial tissues in organs such as the gastrointestinal tract, respiratory system, and reproductive system exhibit complex spatial arrangements of cells with different functions. The intrinsic self-organizing property of epithelial cells, as demonstrated by CAIP, could contribute to the patterning of these tissues during development and homeostasis. For example, in the gastrointestinal tract, the formation of villi and crypts could involve similar mechanisms of cell-cell adhesion-induced patterning. Additionally, in the respiratory system, the branching patterns of the airway epithelium and the alveolar structures could be influenced by CAIP. Understanding the role of cell-cell adhesion in these tissues could provide insights into their morphogenesis and function.

Could the insights from this study on the role of cell-cell adhesion in self-organizing patterns have broader implications for understanding tissue morphogenesis and homeostasis?

The insights gained from the study on the role of cell-cell adhesion in self-organizing patterns, as demonstrated by CAIP, have significant implications for understanding tissue morphogenesis and homeostasis in various biological contexts. By elucidating how cell-cell adhesion drives multicellular patterning in epithelial tissues, the study sheds light on the fundamental mechanisms underlying tissue organization and spatial arrangement of cells with different fates. This knowledge can be applied to diverse fields, including developmental biology, regenerative medicine, and tissue engineering.
The findings suggest that the intrinsic self-organizing property of epithelial cells, mediated by cell-cell adhesion, plays a crucial role in tissue patterning and differentiation. By manipulating cell-cell adhesion, researchers and clinicians may be able to modulate tissue morphogenesis, promote wound healing, and potentially even engineer complex tissue structures in the future. Overall, the study provides a valuable framework for investigating the role of cell-cell adhesion in tissue development, maintenance, and repair, with broad implications for advancing our understanding of tissue biology and regenerative processes.