Wen-Yen Huang

Post-translational modification of delta antigen of hepatitis D virus.

The hepatitis delta virus (HDV) genome has only one open reading frame, which encodes the viral small delta antigen. After RNA editing, the same open reading frame is extended 19 amino acids at the carboxyl terminus and encodes the large delta antigen. These two viral proteins escort the HDV genome through different cellular compartments for the complicated phases of replication, transcription and, eventually, the formation of progeny virions. To orchestrate these events, the delta antigens have to take distinct cues to traffic to the right compartments and make correct molecular contacts. In eukaryotes, post-translational modification (PTM) is a major mechanism of dictating the multiple functions of a single protein. Multiple PTMs, including phosphorylation, isoprenylation, acetylation, and methylation, have been identified on hepatitis delta antigens. In this chapter we review these PTMs and discuss their functions in regulating and coordinating the life cycle of HDV.

Stress-induced premature senescence of dermal papilla cells compromises hair follicle epithelial-mesenchymal interaction

BACKGROUND Hair follicle is miniorgan constituted by keratinocytes and its distinctive mesenchyme of dermal papilla. Its aging is characterized by organ atrophy and impaired stem cell activation and differentiation. The contribution of dermal papilla to hair follicle aging change is not well understood. OBJECTIVE This work was aimed at exploring the possible role of premature dermal papilla senescence in the pathogenesis of hair follicle aging. METHODS Dermal papilla cells were challenged with H2O2 to induce premature senescence and the proliferation, apoptosis, gene expression and protein secretion were characterized. Its effect on epithelial-mesenchymal interaction was analyzed by co-culture in vitro and implantation of protein-coated beads in vivo. RESULT Dermal papilla cells were more resistant to oxidative stress-induced apoptosis than dermal fibroblasts. The surviving dermal papilla cells showed signs of senescence but still preserved key dermal papilla signature gene expression. In addition to the failure to respond to mitogenic stimulation from keratinocytes, they lost the ability to induce hair follicle neogenesis, promoted interfollicular epidermal differentiation, inhibited follicular differentiation and, importantly, suppressed clonal growth of hair follicle stem cells. They produced higher levels of multiple inflammatory cytokines, including IL-6. Functionally, IL-6 inhibited clonal keratinocyte growth in vitro and blocked the transition from telogen to anagen in vivo. CONCLUSION Stress-induced premature dermal papilla senescence can contribute to hair follicle aging change due to compromised epithelial-mesenchymal interaction.

Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy

Genotoxicity-induced hair loss from chemotherapy and radiotherapy is often encountered in cancer treatment, and there is a lack of effective treatment. In growing hair follicles (HF), quiescent stem cells (SC) are maintained in the bulge region, and hair bulbs at the base contain rapidly dividing, yet genotoxicity-sensitive transit-amplifying cells (TAC) that maintain hair growth. How genotoxicity-induced HF injury is repaired remains unclear. We report here that HFs mobilize ectopic progenitors from distinct TAC compartments for regeneration in adaptation to the severity of dystrophy induced by ionizing radiation (IR). Specifically, after low-dose IR, keratin 5+ basal hair bulb progenitors, rather than bulge SCs, were quickly activated to replenish matrix cells and regenerated all concentric layers of HFs, demonstrating their plasticity. After high-dose IR, when both matrix and hair bulb cells were depleted, the surviving outer root sheath cells rapidly acquired an SC-like state and fueled HF regeneration. Their progeny then homed back to SC niche and supported new cycles of HF growth. We also revealed that IR induced HF dystrophy and hair loss and suppressed WNT signaling in a p53- and dose-dependent manner. Augmenting WNT signaling attenuated the suppressive effect of p53 and enhanced ectopic progenitor proliferation after genotoxic injury, thereby preventing both IR- and cyclophosphamide-induced alopecia. Hence, targeted activation of TAC-derived progenitor cells, rather than quiescent bulge SCs, for anagen HF repair can be a potential approach to prevent hair loss from chemotherapy and radiotherapy. Cancer Res; 77(22); 6083-96. ©2017 AACR.

Activation of mTORC1 Signaling is Required for Timely Hair Follicle Regeneration from Radiation Injury

Transit amplifying cells (TACs) are highly proliferative in nature and tend to be sensitive to ionizing radiation. Due to the abundance of TACs that support the elongation of hair shafts, growing hair follicles are highly sensitive to radiation injury. How hair follicles repair themselves after radiation injury is unclear. In this study, we observed that in 4 Gy irradiated mice, hair follicle dystrophy was induced with apoptosis-driven loss of hair matrix cells, which are the TACs that fuel hair growth. The dystrophy was repaired within 96 h without significant hair loss, indicating that a regenerative attempt successfully restored the TAC population to resume anagen growth. Soon after irradiation, mTORC1 signaling was activated in the TAC compartment and its activation was maintained until the regeneration process was completed. Inhibition of mTORC1 by rapamycin treatment increased radiation-induced cell apoptosis, reduced cell proliferation and delayed restoration of Wnt signaling in the hair matrix after radiation injury, leading to prolonged dystrophy and hair loss. These results demonstrate that mTORC1 signaling is activated after irradiation and is required for timely regeneration of the TAC pool of hair follicles, so that hair growth can resume after radiation injury.

External light activates hair follicle stem cells through eyes via an ipRGC–SCN–sympathetic neural pathway

Significance Intrinsically photosensitive retinal ganglion cells (ipRGCs) exhibit several important functions including the circadian photo entrainment, pupillary light reflex, alertness, and phototaxis. Whether ipRGCs regulate other physiological activities is unknown. We show that external light stimulation can activate hair follicle stem cells through the eyes via an ipRGC–suprachiasmatic nucleus–sympathetic nervous circuit. Immediately after ipRGCs are stimulated by light, the systemic sympathetic activities are activated. In skin, the local release of norepinephrine activates hair follicle stem cells. This neural circuit enables prompt communication between peripheral tissues and the external environment. Due to the systemic activation of sympathetic activities, this circuit can also allow for timely responses to external light in other organs. It also highlights a function of ipRGCs in regulating autonomic nervous activity. Changes in external light patterns can alter cell activities in peripheral tissues through slow entrainment of the central clock in suprachiasmatic nucleus (SCN). It remains unclear whether cells in otherwise photo-insensitive tissues can achieve rapid responses to changes in external light. Here we show that light stimulation of animals’ eyes results in rapid activation of hair follicle stem cells with prominent hair regeneration. Mechanistically, light signals are interpreted by M1-type intrinsically photosensitive retinal ganglion cells (ipRGCs), which signal to the SCN via melanopsin. Subsequently, efferent sympathetic nerves are immediately activated. Increased norepinephrine release in skin promotes hedgehog signaling to activate hair follicle stem cells. Thus, external light can directly regulate tissue stem cells via an ipRGC–SCN autonomic nervous system circuit. Since activation of sympathetic nerves is not limited to skin, this circuit can also facilitate rapid adaptive responses to external light in other homeostatic tissues.

Increased risk of chronic kidney disease in patients with rosacea: A nationwide population-based matched cohort study

Background Rosacea is a chronic inflammatory skin disorder. Inflammation and oxidative stress are involved in the etiopathogenesis of rosacea and chronic kidney disease (CKD). This study aimed to investigate the association between rosacea and CKD. Methods This population-based cohort study identified 277 patients with rosacea in the Taiwan National Health Insurance Research Database during 2001–2005. These patients were matched for age, sex, and comorbidities with 2216 patients without rosacea. All subjects were individually followed-up for 8–12 years to identify those who subsequently developed CKD Results The incidence rates of CKD per 1000 person-years were 16.02 in patients with rosacea and 10.63 in the non-rosacea reference population. After adjusting for other covariates and considering the competing risk of mortality, patients with rosacea remained at increased risk of CKD (adjusted sub-distribution hazard ratio (aSD-HR) 2.00; 95% confidence interval (CI) 1.05–3.82). The aSD-HRs (95% CI) for CKD were 1.82 (0.83–4.00) and 2.53 (1.11–5.75) for patients with mild and moderate-to-severe rosacea, respectively. Conclusions Rosacea is an independent risk factor for CKD. High rosacea severity and old age further increased CKD risk in patients with rosacea. Careful monitoring for CKD development should be included as part of integrated care for patients with rosacea.

ABCG2 deficiency in skin impairs re-epithelialization in cutaneous wound healing.

The ATP‐binding cassette transporter ABCG2 is expressed in the interfollicular epidermis and mediates the side‐population phenotype in skin cells. However, the role of ABCG2 in skin is unclear. Increased expression levels of ABCG2 were found at the basal layer of transitional epidermis adjacent to cutaneous wounds in human patients, indicating that ABCG2 may be involved in regulating the wound healing process. To investigate the role of ABCG2 in cutaneous wound healing, full‐thickness skin wounds were created in ABCG2 knockout (ABCG2‐KO) and wild‐type mice. The healing process was analysed and revealed that ABCG2 deficiency in skin results in delays in wound closure and impairments in re‐epithelialization, as evidenced by reductions in both suprabasal differentiation and in p63‐expressing keratinocytes migrating from transitional epidermis to epithelial tongues. The reduction in p63‐expressing cells may be due to elevated levels of reactive oxygen species in ABCG2‐KO epidermis, which can cause DNA damage and lead to proliferation arrest. To determine whether ABCG2 deficiency affects the potency of epidermal stem/progenitor cells (EPCs), transplantation studies were carried out, which demonstrated that ABCG2‐KO EPCs display higher levels of γH2AX and lose the capacity to differentiate into suprabasal keratinocytes. A competitive repopulation assay confirmed that ABCG2 expression is critical for the proper expansion and differentiation of EPCs in cutaneous wounds. As EPCs are known to contribute to the healing of larger wounds, the current findings imply a functional role for ABCG2 in the expansion and differentiation of p63‐expressing EPCs. Thus, ABCG2 deficiency in skin impairs re‐epithelialization in cutaneous wound healing.