Keratinocyte Cytonemes Mediate Notch Signaling and Regulate Epidermal Homeostasis

Core Concepts

Cytoneme-mediated intercellular signaling between differentiated and undifferentiated keratinocytes is critical for maintaining epidermal homeostasis, and its dysregulation can contribute to the development of human skin diseases.

Abstract

The skin is a multilayered structure composed of the epidermis, dermis, and hypodermis. The epidermis, the outermost layer, plays a crucial role in providing a protective barrier against environmental threats. It consists of various layers, including the basal layer with stem cells, the intermediate layer with undifferentiated keratinocytes, and the outermost periderm layer with fully differentiated keratinocytes.
The maintenance of epidermal homeostasis requires a delicate balance between keratinocyte differentiation and proliferation, which is regulated by complex intercellular signaling pathways. One such critical pathway is the Notch signaling, which exhibits spatially restricted expression patterns in the epidermal layers.
This study reveals that fully differentiated keratinocytes in the periderm extend actin-based cellular protrusions called cytonemes, which establish physical contact with the underlying undifferentiated keratinocytes in the intermediate layer. These cytonemes mediate Notch signaling activation in the undifferentiated keratinocytes, thereby controlling their differentiation and proliferation.
Inhibition of cytoneme extension or Notch signaling in undifferentiated keratinocytes leads to abnormal keratinocyte differentiation and hyperproliferation, resembling the hallmarks of various human skin diseases, such as psoriasis and atopic dermatitis.
The study further demonstrates that the pro-inflammatory cytokine interleukin-17 (IL-17), a key player in the pathogenesis of skin diseases, negatively regulates keratinocyte cytonemes by modulating the actin cytoskeleton. Additionally, the gene clint1, associated with skin diseases, also appears to function as a regulator of cytoneme-mediated signaling.
In conclusion, the findings suggest that the dysregulation of cytoneme-mediated intercellular communication between keratinocytes can contribute to the development of human skin diseases, providing a novel perspective on the underlying mechanisms.

Stats

Keratinocytes extend cytonemes with an average speed of 2.98 μm/min during extension and 1.9 μm/min during retraction, with an average length of 18.21 μm.
Inhibition of cytoneme extension leads to a significant increase in the expression of the undifferentiated keratinocyte marker krtt1c19e and the number of keratinocytes in the periderm layer.
Overexpression of IL-17 receptors (il17rd or il17ra1a) in differentiated keratinocytes results in a significant reduction in cytoneme extension and Notch signaling in undifferentiated keratinocytes.
Clint1 mutants exhibit a decrease in cytoneme extension and Notch signaling, accompanied by abnormal keratinocyte differentiation and hyperproliferation.

Quotes

"Cytoneme-mediated intercellular signaling between peridermal and underlying undifferentiated keratinocytes is essential for epidermal remodeling and maintenance."
"The overproduction of IL-17 ligands by immune cells in conditions such as psoriatic or other skin diseases leads to epidermal imbalance through altered cytoneme signaling in keratinocytes."
"Dysregulated cytoneme-mediated intercellular communication between keratinocytes can contribute to the development of human skin diseases."

Key Insights Distilled From

Cytoneme-mediated intercellular signaling in keratinocytes essential for epidermal remodeling

by Wang,Y., He,... at www.biorxiv.org 11-12-2023

https://www.biorxiv.org/content/10.1101/2023.11.08.566303v3

Deeper Inquiries

How do basal stem cells detect the need for increased keratinocyte production to maintain the intermediate layer, and is this process also mediated by cytoneme-based signaling?

Basal stem cells detect the need for increased keratinocyte production through signaling mechanisms that involve cytonemes. While the exact process is not fully understood, it is hypothesized that cytoneme-mediated intercellular signaling between fully differentiated keratinocytes in the periderm and undifferentiated keratinocytes in the intermediate layer plays a crucial role in this detection. The cytonemes from fully differentiated keratinocytes transmit signals to the underlying undifferentiated keratinocytes, potentially triggering a response that leads to increased keratinocyte production to maintain the intermediate layer. This signaling cascade likely involves the activation of key pathways such as Notch signaling, which is known to regulate keratinocyte differentiation and proliferation. The communication between these different layers of the epidermis through cytonemes is essential for the proper maintenance and remodeling of the skin.

How do IL-17 and clint1 regulate the actin cytoskeleton and, consequently, the formation and function of keratinocyte cytonemes?

IL-17 and clint1 regulate the actin cytoskeleton, impacting the formation and function of keratinocyte cytonemes. IL-17 signaling negatively regulates cytoneme extension by down-regulating Cdc42 GTPases, which are essential for controlling actin polymerization. IL-17 overexpression leads to a reduction in Cdc42 expression in keratinocytes, resulting in disorganization of microridges and a decrease in cytoneme extension. On the other hand, clint1, a gene associated with psoriasis and atopic dermatitis, influences cytoneme-mediated intercellular signaling in keratinocytes. Mutants lacking clint1 exhibit compromised cytoneme signaling, leading to abnormal keratinocyte differentiation and hyperproliferation. These findings suggest that both IL-17 and clint1 play crucial roles in regulating the actin cytoskeleton, ultimately affecting the formation and function of keratinocyte cytonemes.

Could targeting the regulation of keratinocyte cytonemes be a potential therapeutic approach for treating human skin diseases, and what are the challenges and opportunities in this area?

Targeting the regulation of keratinocyte cytonemes could indeed be a promising therapeutic approach for treating human skin diseases, particularly those characterized by aberrant keratinocyte differentiation and proliferation such as psoriasis and atopic dermatitis. By modulating cytoneme-mediated intercellular signaling between keratinocytes, it may be possible to restore the balance in epidermal maintenance and remodeling, thereby alleviating the symptoms of these skin conditions. However, there are challenges and opportunities in this area.
Challenges:

Specificity: Ensuring that the targeting of keratinocyte cytonemes is specific to the affected cells without causing off-target effects.
Delivery: Developing effective delivery methods to target and modulate cytoneme signaling in the skin.
Long-term Efficacy: Ensuring that the therapeutic approach has long-term efficacy and does not lead to resistance or recurrence of skin diseases.

Opportunities:

Personalized Medicine: Tailoring treatments based on individual variations in cytoneme signaling and skin disease pathology.
Combination Therapies: Exploring the potential of combining cytoneme-targeted therapies with existing treatments for synergistic effects.
Research Advancements: Continued research into the mechanisms of cytoneme signaling and its role in skin diseases can lead to novel therapeutic targets and approaches.

In conclusion, while targeting keratinocyte cytonemes holds promise as a therapeutic approach for skin diseases, further research and development are needed to overcome challenges and fully realize the potential benefits of this strategy.