Dongwon Kim

dsRNA Released by Tissue Damage Activates TLR3 to Drive Skin Regeneration

Regeneration of skin and hair follicles after wounding--a process known as wound-induced hair neogenesis (WIHN)--is a rare example of adult organogenesis in mammals. As such, WIHN provides a unique model system for deciphering mechanisms underlying mammalian regeneration. Here, we show that dsRNA, which is released from damaged skin, activates Toll-Like Receptor 3 (TLR3) and its downstream effectors IL-6 and STAT3 to promote hair follicle regeneration. Conversely, TLR3-deficient animals fail to initiate WIHN. TLR3 activation promotes expression of hair follicle stem cell markers and induces elements of the core hair morphogenetic program, including ectodysplasin A receptor (EDAR) and the Wnt and Shh pathways. Our results therefore show that dsRNA and TLR3 link the earliest events of mammalian skin wounding to regeneration and suggest potential therapeutic approaches for promoting hair neogenesis.

To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease

Despite similar components, the heterogeneity of skin characteristics across the human body is enormous. It is classically believed that site-specific fibroblasts in the dermis control postnatal skin identity by modulating the behavior of the surface-overlying keratinocytes in the epidermis. To begin testing this hypothesis, we characterized the gene expression differences between volar (ventral; palmoplantar) and nonvolar (dorsal) human skin. We show that KERATIN 9 (KRT9) is the most uniquely enriched transcript in volar skin, consistent with its etiology in genetic diseases of the palms and soles. In addition, ectopic KRT9 expression is selectively activated by volar fibroblasts. However, KRT9 expression occurs in the absence of all fibroblasts, although not to the maximal levels induced by fibroblasts. Through gain-of-function and loss-of-function experiments, we demonstrate that the mechanism is through overlapping paracrine or autocrine canonical WNT-β-catenin signaling in each respective context. Finally, as an inxa0vivo example of ectopic expression of KRT9 independent of volar fibroblasts, we demonstrate that in the human skin disease lichen simplex chronicus, WNT5a and KRT9 are robustly activated outside of volar sites. These results highlight the complexities of site-specific gene expression and its disruption in skin disease.

A new target for squamous cell skin cancer

Prostaglandins (PGs) derived from arachidonic acid of cell membrane are synthesized by PG G/H synthase (cyclooxygenase; COX-1/-2) and signal as autocrine/paracrine lipids (1, 2). Similar to other tissues, COX-1 is constitutively expressed in keratinocytes of normal epidermis, whereas COX-2 expression is more variable and regulated (3, 4). COX-2 is induced for example by cytokines and growth factors; accumulated prostaglandins from COX-2 regulate pain, inflammation, and cancers (2, 3). In the case of cancer, increased levels of PGs disrupt differentiation and thus contribute to the sensitization of cells to carcinogens and ensuing hyperplasia (5, 6). Therefore, the inhibition of COX-2 activity with aspirin like compounds has been suggested as a potent chemo-preventive therapy to suppress tumor development, not just in skin but particularly for gastrointestinal cancers (2, 7).

The Negative Regulator CXXC5: Making WNT Look a Little Less Dishevelled.

Wingless-related integration site (WNT)/β-catenin signaling regulates diverse physiological functions including tissue regeneration. Activation of WNT signaling can be inhibited by various agents. Lee etxa0al. investigate the interaction of CXXC-type zinc finger protein 5 (CXXC5) with Dishevelled as one such negative regulator of WNT in hair follicle regeneration.

Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release

Background Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis, and skin injury caused by scratching. In particular, the barrier‐defective epidermis in patients with AD with loss‐of‐function filaggrin mutations has increased IL‐1&agr; and IL‐1&bgr; levels, but the mechanisms by which IL‐1&agr;, IL‐1&bgr;, or both are induced and whether they contribute to the aberrant skin inflammation in patients with AD is unknown. Objective We sought to determine the mechanisms through which skin injury, dysbiosis, and increased epidermal IL‐1&agr; and IL‐1&bgr; levels contribute to development of skin inflammation in a mouse model of injury‐induced skin inflammation in filaggrin‐deficient mice without the matted mutation (ft/ft mice). Methods Skin injury of wild‐type, ft/ft, and myeloid differentiation primary response gene–88–deficient ft/ft mice was performed, and ensuing skin inflammation was evaluated by using digital photography, histologic analysis, and flow cytometry. IL‐1&agr; and IL‐1&bgr; protein expression was measured by means of ELISA and visualized by using immunofluorescence and immunoelectron microscopy. Composition of the skin microbiome was determined by using 16S rDNA sequencing. Results Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis‐driven intracellular IL‐1&agr; release from keratinocytes. IL‐1&agr; was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or cohousing of ft/ft mice with unaffected wild‐type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL‐1&agr; localization. Conclusions Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL‐1&agr; release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets. Graphical abstract Figure. No Caption available.

dsRNA sensing induces loss of cell identity

How cell and tissue identity persist despite constant cell turnover is an important biologic question with cell therapy implications. Although many mechanisms exist, we investigated the controls for site-specific gene expression in skin, given its diverse structures and functions. For example, the transcriptome of inxa0vivo palmoplantar (i.e., volar) epidermis is globally unique, including Keratin 9 (KRT9). Although volar fibroblasts have the capacity to induce KRT9 in nonvolar keratinocytes, we show here that volar keratinocytes continue to express KRT9 in inxa0vitro solo cultures. Despite this, KRT9 expression is lost with volar keratinocyte passaging, despite stable hypomethylation of its promoter. Coincident with KRT9 loss is a gain of the primitive keratin 7 and a signature of dsRNA sensing, including the double-stranded RNA (dsRNA) receptor DExD/H-Box Helicase 58 (DDX58/RIG-I). Exogenous dsRNA inhibits KRT9 expression in early passage volar keratinocytes or inxa0vivo footpads of wild-type mice. Loss of DDX58 in passaged volar keratinocytes rescues KRT9 and inhibits KRT7 expression. Additionally, DDX58-null mice are resistant to the ability of dsRNA to inhibit KRT9 expression. These results show that the sensing of dsRNA is critical for loss of cell-specific gene expression; our results have important implications for how dsRNA sensing is important outside of immune pathways.

Science Fiction in South and North Korea: Reading Science and Technology as Fantasized in Cultures

Science fiction like Star Trek is not only good fun but it also serves a serious purpose, that of expanding the human imagination. . . . There is a two-way trade between science fiction and science. Science fiction suggests ideas that scientists incorporate into their theories, but sometimes science turns up notions that are stranger than any science fiction. . . . Nevertheless, today’s science fiction is often tomorrow’s science fact. The physics that underlies Star Trek is surely worth investigating. To confine our attention to terrestrial matters would be to limit the human spirit (Krauss 2007: xi–xiii).1