رؤى - Computational Biology - # Regulation of Sebaceous Gland Homeostasis by Notch Signaling

The Jag2/Notch1 Signaling Axis Regulates Sebaceous Gland Differentiation and Progenitor Proliferation in Adult Skin

Q: How does Notch signaling mechanistically regulate the balance between sebocyte differentiation and progenitor proliferation in the sebaceous gland?

Notch signaling plays a crucial role in regulating the balance between sebocyte differentiation and progenitor proliferation in the sebaceous gland. Mechanistically, Notch signaling functions as a key regulator of cell fate decisions by inducing or inhibiting differentiation. In the context of the sebaceous gland, Notch activity promotes correct sebocyte differentiation while also restricting progenitor proliferation. When Notch signaling is active, it leads to the expression of downstream effectors that drive sebocyte differentiation. This activation of Notch signaling in the basal stem cells of the sebaceous gland promotes the transition of these cells into mature sebocytes. On the other hand, when Notch signaling is inhibited, either by blocking the Jag2 ligand or the Notch1 receptor, sebocyte differentiation is halted, and the basal stem cells remain in a proliferative state. This results in the accumulation of basal-like cells in the sebaceous gland, forming epithelial remnants. Therefore, the mechanistic regulation by Notch signaling involves the activation of pathways that drive sebocyte differentiation while simultaneously inhibiting uncontrolled proliferation of progenitor cells. This delicate balance ensures the proper maintenance and function of the sebaceous gland in homeostatic skin.

Q: What other signaling pathways or transcriptional regulators might interact with the Jag2/Notch1 axis to fine-tune sebaceous gland homeostasis?

In addition to the Jag2/Notch1 axis, several other signaling pathways and transcriptional regulators may interact to fine-tune sebaceous gland homeostasis. One such pathway is the Wnt/β-catenin signaling pathway, which has been implicated in regulating sebaceous gland development and function. Wnt signaling is known to crosstalk with Notch signaling in various tissues, and it is possible that these pathways interact in the sebaceous gland to coordinate sebocyte differentiation and proliferation. Moreover, the Hedgehog signaling pathway is another key regulator of skin development and homeostasis. Hedgehog signaling has been shown to influence sebaceous gland morphogenesis and maintenance. Interactions between the Hedgehog pathway and Notch signaling may contribute to the precise control of sebocyte differentiation and progenitor proliferation in the sebaceous gland. Transcriptional regulators such as PPARγ, AR, and various co-factors involved in lipid metabolism and sebocyte function may also interact with the Jag2/Notch1 axis to fine-tune sebaceous gland homeostasis. These regulators play essential roles in the differentiation and lipid production of sebocytes, and their cross-talk with Notch signaling could further modulate the balance between differentiation and proliferation in the sebaceous gland.

Q: Could modulation of the Notch pathway be a potential therapeutic strategy for skin disorders associated with sebum dysregulation, such as acne or dry skin?

Modulation of the Notch pathway holds promise as a potential therapeutic strategy for skin disorders associated with sebum dysregulation, including acne and dry skin. Given the critical role of Notch signaling in sebocyte differentiation and progenitor proliferation, targeting this pathway could help restore the balance in the sebaceous gland and improve skin conditions. For conditions like acne, where there is an overproduction of sebum leading to clogged pores and inflammation, modulating Notch signaling could help regulate sebocyte differentiation and reduce sebum production. By promoting proper differentiation of sebocytes, Notch pathway modulation may prevent the formation of comedones and acne lesions. In cases of dry skin, where there is insufficient sebum production leading to skin barrier impairment, enhancing Notch signaling could stimulate sebocyte differentiation and lipid production, improving skin hydration and barrier function. By promoting the maturation of sebocytes, the Notch pathway modulation may help restore the natural moisturizing factors in the skin. Overall, targeting the Notch pathway for therapeutic intervention in skin disorders associated with sebum dysregulation offers a promising approach to rebalance sebaceous gland function and address the underlying causes of these conditions. Further research and clinical studies are needed to explore the full potential of Notch pathway modulation as a treatment strategy for acne, dry skin, and other sebum-related skin disorders.

المفاهيم الأساسية

The Jag2/Notch1 signaling axis is essential for proper sebocyte differentiation in adult skin, and its inhibition retains sebaceous gland stem/progenitor cells in a proliferative state, blocking further differentiation.

الملخص

The study investigates the role of Notch signaling in regulating sebaceous gland (SG) homeostasis in adult skin. Using monoclonal antibodies to selectively inhibit different Notch receptors and ligands, the authors demonstrate that the Jag2/Notch1 signaling axis is the primary regulator of sebocyte differentiation.

Key highlights:

Inhibition of Jag2 or Notch1 results in the loss of mature sebocytes, with the SG being filled with proliferative basal-like cells.
Notch activity is normally observed in the basal stem/progenitor cells of the SG, but is lost upon Jag2 inhibition.
The basal-like cells that accumulate in the SG upon Notch inhibition express stem/progenitor markers, indicating a block in differentiation.
The loss of sebocyte differentiation is reversible - mature sebocytes recover as Notch activity returns after antibody clearance.

The authors conclude that Notch signaling is required to promote sebocyte differentiation and restrict progenitor proliferation in the adult SG. Inhibition of this signaling axis retains the stem/progenitor cells in an immature, proliferative state, without permanently altering their differentiation potential.

تخصيص الملخص

إعادة الكتابة بالذكاء الاصطناعي

إنشاء الاستشهادات

ترجمة المصدر

إلى لغة أخرى

إنشاء خريطة ذهنية

من محتوى المصدر

زيارة المصدر

biorxiv.org

الإحصائيات

Percentage of N1ICD positive basal stem cells in SGs:

Control: 50%
Jag1 inhibition: 50%
Jag2 inhibition: 1%
Number of cells expressing adipophilin (mature sebocyte marker):

Day 7, Control: Normal
Day 7, Jag2 inhibition: Significantly lower
Day 14, Jag2 inhibition: Increased from day 7, but still lower than control
Number of proliferating (Ki67+) cells in SGs:

Day 7, Control: Normal
Day 7, Jag2 inhibition: Significantly higher

اقتباسات

"Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation."
"Notch inhibition does not result in a permanent cell fate switch, but maintains the stem/progenitor state, allowing the recovery of the differentiation process with the restoration of Notch activity."

الرؤى الأساسية المستخلصة من

The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation

by Abidi,S. N. ... في www.biorxiv.org 05-07-2024

https://www.biorxiv.org/content/10.1101/2024.05.05.592588v2

استفسارات أعمق

How does Notch signaling mechanistically regulate the balance between sebocyte differentiation and progenitor proliferation in the sebaceous gland?

Notch signaling plays a crucial role in regulating the balance between sebocyte differentiation and progenitor proliferation in the sebaceous gland. Mechanistically, Notch signaling functions as a key regulator of cell fate decisions by inducing or inhibiting differentiation. In the context of the sebaceous gland, Notch activity promotes correct sebocyte differentiation while also restricting progenitor proliferation.
When Notch signaling is active, it leads to the expression of downstream effectors that drive sebocyte differentiation. This activation of Notch signaling in the basal stem cells of the sebaceous gland promotes the transition of these cells into mature sebocytes. On the other hand, when Notch signaling is inhibited, either by blocking the Jag2 ligand or the Notch1 receptor, sebocyte differentiation is halted, and the basal stem cells remain in a proliferative state. This results in the accumulation of basal-like cells in the sebaceous gland, forming epithelial remnants.
Therefore, the mechanistic regulation by Notch signaling involves the activation of pathways that drive sebocyte differentiation while simultaneously inhibiting uncontrolled proliferation of progenitor cells. This delicate balance ensures the proper maintenance and function of the sebaceous gland in homeostatic skin.

What other signaling pathways or transcriptional regulators might interact with the Jag2/Notch1 axis to fine-tune sebaceous gland homeostasis?

In addition to the Jag2/Notch1 axis, several other signaling pathways and transcriptional regulators may interact to fine-tune sebaceous gland homeostasis. One such pathway is the Wnt/β-catenin signaling pathway, which has been implicated in regulating sebaceous gland development and function. Wnt signaling is known to crosstalk with Notch signaling in various tissues, and it is possible that these pathways interact in the sebaceous gland to coordinate sebocyte differentiation and proliferation.
Moreover, the Hedgehog signaling pathway is another key regulator of skin development and homeostasis. Hedgehog signaling has been shown to influence sebaceous gland morphogenesis and maintenance. Interactions between the Hedgehog pathway and Notch signaling may contribute to the precise control of sebocyte differentiation and progenitor proliferation in the sebaceous gland.
Transcriptional regulators such as PPARγ, AR, and various co-factors involved in lipid metabolism and sebocyte function may also interact with the Jag2/Notch1 axis to fine-tune sebaceous gland homeostasis. These regulators play essential roles in the differentiation and lipid production of sebocytes, and their cross-talk with Notch signaling could further modulate the balance between differentiation and proliferation in the sebaceous gland.

Could modulation of the Notch pathway be a potential therapeutic strategy for skin disorders associated with sebum dysregulation, such as acne or dry skin?

Modulation of the Notch pathway holds promise as a potential therapeutic strategy for skin disorders associated with sebum dysregulation, including acne and dry skin. Given the critical role of Notch signaling in sebocyte differentiation and progenitor proliferation, targeting this pathway could help restore the balance in the sebaceous gland and improve skin conditions.
For conditions like acne, where there is an overproduction of sebum leading to clogged pores and inflammation, modulating Notch signaling could help regulate sebocyte differentiation and reduce sebum production. By promoting proper differentiation of sebocytes, Notch pathway modulation may prevent the formation of comedones and acne lesions.
In cases of dry skin, where there is insufficient sebum production leading to skin barrier impairment, enhancing Notch signaling could stimulate sebocyte differentiation and lipid production, improving skin hydration and barrier function. By promoting the maturation of sebocytes, the Notch pathway modulation may help restore the natural moisturizing factors in the skin.
Overall, targeting the Notch pathway for therapeutic intervention in skin disorders associated with sebum dysregulation offers a promising approach to rebalance sebaceous gland function and address the underlying causes of these conditions. Further research and clinical studies are needed to explore the full potential of Notch pathway modulation as a treatment strategy for acne, dry skin, and other sebum-related skin disorders.