Epidermis : Hemoglobin's Antioxidant and Barrier Roles

1. Epidermal Evolution: Research published in the Journal of Investigative Dermatology provides important insights into skin's defense mechanism against aging and cancer

2. Unexpected Hemoglobin Role: Uncover a groundbreaking study's findings that highlight the unexpected high expression of hemoglobin genes, particularly HBA1/2 and HBB, in the upper epidermis.

3. Protective Functions: Understand the significance of epidermal hemoglobin as an endogenous antioxidant, demonstrating its role in shielding keratinocytes against oxidative stress.

4. Hair Follicle Insights: Discover the prominent expression of HBA in the isthmus portion of hair follicles, suggesting a potential link to immune regulation and protection of keratinocyte stem cells.

5. Implications for Skin Health: Grasp the broader implications of these findings for skin health, offering insights into potential connections between hemoglobin, oxidative stress, and skin-related diseases such as aging and cancers.

The epidermis, the outermost tissue of the body, serves as a fascinating model to explore how organisms navigate and overcome environmental challenges. In particular, the transition from aquatic to terrestrial life in vertebrates marked a pivotal moment, introducing significant environmental changes such as heightened atmospheric oxygen levels, desiccation, and increased exposure to ultraviolet radiation. These challenges triggered selective pressures, propelling the evolution of vertebrate anatomy. One remarkable adaptation is the development of a distinct epidermal structure known as the keratinized stratified squamous epithelium, primarily composed of keratinocytes (KCs)

Decoding the Epidermal Layers

Epidermal KCs originate from the proliferative stratum basale, undergo differentiation, and ascend to form layers, culminating in the unique stratum corneum. As these cells differentiate, they express various genes with protective barrier functions, crucial for shielding against external insults The importance of these genes is evident in skin barrier disorders, emphasizing the critical role of the upper epidermal layers in defense Unraveling the Transcriptome: A Comparative Analysis

In a groundbreaking study, a comparative transcriptome analysis was conducted on the whole and upper epidermis, shedding light on the intricacies of gene expression. Unexpectedly, the study unveiled high expression of hemoglobin genes in the upper epidermis of both human and mouse samples. Hemoglobin, traditionally associated with oxygen transport in erythrocytes, was found to play a surprising role in epidermal KCs, acting as an endogenous antioxidant.

Results: Identifying Hemoglobin Genes in Epidermal KCs

To identify the hemoglobin genes involved, the study analyzed highly expressed genes in the upper epidermis of humans. The comprehensive microarray analysis distinguished clear differences between the whole and upper epidermis, with hemoglobin genes, specifically HBA1/2 and HBB, exhibiting elevated expression in the upper epidermis. Further single-cell RNA-sequencing analyses provided insights into the localization of hemoglobin gene expression in differentiated epidermal KCs.

Beyond Oxygen Transport: Hemoglobin's Unexpected Role

Traditionally recognized for its role in oxygen transport, hemoglobin's expression in nonerythroid cells, including the epidermis, adds a new layer to its functionality. The study, utilizing an enzymatically isolated epidermis, confirmed not only the mRNA expression but also the protein expression of hemoglobin in human and mouse epidermal KCs.

HBA Expression in Hair Follicles: A Key to Immune Regulation

The study revealed prominent HBA expression in the isthmus portion of hair follicles (HF), suggesting a potential role in the immune regulation and protection of KC stem cells. This finding aligns with the known antimicrobial properties of HBA-derived peptides, adding another dimension to the understanding of epidermal function.

Regulation of HBA Expression: A Balancing Act

The research demonstrated that HBA expression in the mouse epithelium had a clear boundary between cutaneous and noncutaneous keratinized epithelia. This regulation, distinct from other terminal differentiation markers, highlights the specificity of hemoglobin gene expression in the cutaneous keratinized epithelium.

Implications for Skin Health: HBA as an Endogenous Antioxidant

The study's core finding suggests that epidermal hemoglobin, particularly HBA, acts as an endogenous antioxidant in response to oxidative stress. This insight opens new avenues for understanding skin diseases related to reactive oxygen species (ROS), such as aging and cancers.

Future Directions and Implications

While this study provides a groundbreaking exploration into the unexpected role of hemoglobin in epidermal KCs, further research is warranted. Future investigations should delve into the protein-level interactions and the physiological implications of epidermal hemoglobin. Understanding the regulatory mechanisms of HBA expression in nonerythroid cells could offer valuable insights into skin health and disease.

Conclusion

In summary, the study's revelations on the expression and function of hemoglobin in the epidermis contribute significantly to our understanding of vertebrate adaptation to terrestrial life. The unexpected role of hemoglobin as an endogenous antioxidant in epidermal KCs unveils a new chapter in the intricate story of skin evolution.

Reference Article

https://www.jidonline.org/article/S0022-202X(23)02560-5/fulltext

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