The epidermis, the outer layer of the skin, has two sets of protective barri-44ers: the stratum corneum (SC) and the tight junctions (TJs). These two barriers prevent the easy penetration of external antigens into the body. The SC is unique, as it can maintain its homeostasis, even if it consists of dead ke-ratinocytes (corneocytes). In addition, the SC is known as a habitat for skin microbiota, and alterations in skin microbiota composition, termed dysbiosis, have been associated with chronic inflammatory conditions, such as atopic der-matitis (AD).Our group is currently trying to clarify (1) how SC homeostasis is main-tained under normal conditions and how it is impaired and affects microenvi-ronments of the skin under inflammation and (2) how skin microbiota interacts with the host epidermis and worsens the inflammatory state. Our comprehen-sive experimental approaches combine molecular biology, live imaging, micro-biology, and data-driven clinical research. We recently demonstrated via intravital imaging of mouse skin that a unique type of cell death, termed corneoptosis, of the uppermost stratum granulosum keratinocytes (SG1 cells) requires controlled intercellular acidification to con-vert SG1 cells into corneocytes. In addition, we found that corneocytes undergo differentiation and develop three-tiered zonation in the SC. Intriguingly, the upper SC-pH zone possesses acclimation capacity, changing its pH according to the external environment. Furthermore, we have succeeded in long-term con-tinuous measurement of skin electrical resistance using nanomesh electrodes with excellent elasticity, durability, and air permeability. This enables us to mea-sure dynamic patterns of change in SC barrier functions of mouse and human skin. Combining these tools and techniques and going back and forth between our essential science findings in mice and those in clinical science in humans, we aimed to develop more targeted therapeutic approaches with fewer side ef-fects for patients suffering from inflammatory skin diseases, such as AD.Figure: Comprehensive analysis of skin barrier homeostasisOur team is trying to clarify the mechanisms of skin bar-rier homeostasis by focusing on the stratum corneum (SC), tight junction (TJ), and SG1 cells. We established a live imaging system, mainly focusing on a unique type of SG1 cell death termed ‘corneoptosis’ and pH changes in the SC. We found that the corneoptosis is composed of two phases (phase I and II) using an optimized plasmid injection method to study the cornification process in mice. We also found that the SC has three stepwise pH zones, and we are currently studying the host-microbe interactions on the skin and intracellular pH in inflam-matory skin conditions.Recent Major PublicationsFukuda K, Ito Y, Furuichi Y, Matsui T, Horikawa H, Miyano T, Okada T, Logtestijn M, Tanaka RJ, Miyawaki A, Amagai M. Three stepwise pH progressions in stratum corneum for homeostatic maintenance of the skin. Nat Commun 15, 4062 (2024)Tahara U, Matsui T, Atsugi T, Fukuda K, Terooatea TW, Minoda A, Kubo A, Amagai M. Keratinocytes of the Upper Epidermis and Isthmus of Hair Follicles Express Hemoglobin mRNA and Protein. J Invest Dermatol 143, 2346-55.e10 (2023)Sekita A, Kawasaki H, Fukushima-Nomura A, Yashiro K, Tanese K, Toshima S, Ashizaki K, Miyai T, Yazaki J, Kobayashi A, Namba S, Naito T, Wang QS, Kawakami E, Seita J, Ohara O, Sakurada K, Okada Y, Amagai M, Koseki H. Multifaceted analysis of cross-tissue transcriptomes reveals phenotype-endotype associations in atopic der-matitis. Nat Commun 14, 6133 (2023)Invited presentationsAmagai M. “Skin microbiome as a new bacteriotherapy for inflammatory skin diseases” the 25th World Congress of Dermatology (Singapore, Singapore) July 2023Amagai M. “Homeostatic mechanisms of skin barri-ers; tight junctions, stratum corneum, and epidermal nerves” Duke University seminar (Durham, USA) May 2023Laboratory for Skin HomeostasisTeam Leader: Masayuki Amagai
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