Journal of dermatological science最新文献

英文中文

Downregulation of carnitine acetyltransferase by promoter hypermethylation regulates ultraviolet-induced matrix metalloproteinase-1 expression in human dermal fibroblasts. 启动子超甲基化对肉碱乙酰转移酶的下调调节了紫外线诱导的人真皮成纤维细胞中基质金属蛋白酶-1的表达。

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-27 DOI: 10.1016/j.jdermsci.2024.09.005

Min Ji Song, Min-Kyoung Kim, Chi-Hyun Park, Haesoo Kim, Si Hyung Lee, Dong Hun Lee, Jin Ho Chung

Background: Overexposure to ultraviolet (UV) radiation accelerates skin aging, resulting in wrinkle formation, reduced skin elasticity, and hyperpigmentation. UV irradiation induces increased matrix metalloproteinases (MMPs) that degrade collagen in the extracellular matrix. Skin aging is also accompanied by epigenetic alterations such as promoter methylation by DNA methyltransferases, leading to the activation or suppression of gene expression. Although carnitine acetyltransferase (CRAT) is implicated in aging, the effect of UV on the expression of CRAT and regulatory mechanisms of UV-induced MMP-1 expression remain unknown.

Objective: We investigated changes in CRAT expression upon UV irradiation and its effect on MMP-1 expression.

Methods: Primary human dermal fibroblasts were UV irradiated with either control or 5-AZA-dC. CRAT knockdown or overexpression was performed to investigate its effect on MMP-1 expression. The mRNA level was analyzed by quantitative real-time PCR, and protein level by western blotting.

Results: The expression of CRAT was decreased in UV-irradiated human skin in vivo and in human dermal fibroblasts in vitro. CRAT was downregulated upon UV irradiation by hypermethylation, and treatment with 5-Aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, reversed UV-induced downregulation of CRAT. CRAT knockdown activated the JNK, ERK, and p38 MAPK signaling pathways, which increased MMP-1 expression. Stable overexpression of CRAT alleviated UV-induced MMP-1 induction.

Conclusion: CRAT downregulation caused by promoter hypermethylation may play an important role in UV-induced skin aging via upregulation of MMP-1 expression.

背景：过度暴露于紫外线（UV）辐射会加速皮肤老化，导致皱纹形成、皮肤弹性降低和色素沉着。紫外线照射会诱导基质金属蛋白酶（MMPs）增加，从而降解细胞外基质中的胶原蛋白。皮肤老化还伴随着表观遗传学的改变，如 DNA 甲基转移酶导致启动子甲基化，从而激活或抑制基因表达。虽然肉碱乙酰转移酶（CRAT）与衰老有关，但紫外线对 CRAT 表达的影响以及紫外线诱导 MMP-1 表达的调控机制仍不清楚：我们研究了紫外线照射时 CRAT 表达的变化及其对 MMP-1 表达的影响：方法：用对照组或 5-AZA-dC 对原代人真皮成纤维细胞进行紫外线照射。方法：用对照组或 5-AZA-dC 对原代人真皮成纤维细胞进行紫外线照射，敲除或过表达 CRAT，以研究其对 MMP-1 表达的影响。mRNA水平通过实时定量PCR分析，蛋白水平通过Western印迹分析：结果：CRAT在体内紫外线照射的人类皮肤和体外人类真皮成纤维细胞中的表达均下降。用 DNA 甲基转移酶抑制剂 5-Aza-2'-deoxycytidine 处理可逆转紫外线诱导的 CRAT 下调。CRAT 下调激活了 JNK、ERK 和 p38 MAPK 信号通路，从而增加了 MMP-1 的表达。稳定过表达 CRAT 可减轻紫外线诱导的 MMP-1 诱导：结论：启动子高甲基化导致的CRAT下调可能通过上调MMP-1的表达在紫外线诱导的皮肤老化中扮演重要角色。

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引用次数: 0

The decrease in peripheral blood basophils in a mouse model of IgE-induced inflammation involves their migration to lymph nodes. 在 IgE 诱导的炎症小鼠模型中，外周血嗜碱性粒细胞的减少涉及它们向淋巴结的迁移。

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-21 DOI: 10.1016/j.jdermsci.2024.09.004

Ni Ma, Izumi Kishimoto, Aki Tajima, Noriko Kume, Naotomo Kambe, Hideaki Tanizaki

Background: During the active phase of urticaria, a decrease in peripheral blood basophils, known as basopenia, is observed. We previously reported that basopenia occurs as a result of basophils migrating to the skin in a contact dermatitis model where a Th2 response is induced with oxazolone.

Objective: Although there is currently no established model for urticaria, given that urticaria is an IgE-mediated immediate-type allergic reaction, we aimed to determine whether an IgE-mediated model could reproduce the decrease in basophils in peripheral blood observed during the active phase of urticaria.

Methods: Mice were pretreated with 2,4,6-trinitrophenylhaptene (TNP)-specific IgE and basophil dynamics were examined following stimulation with TNP-ovalbumin. Mast cell-deficient WBB6F1-Kit^W/Kit^W-v mice were used to investigate the role of mast cells in this IgE-mediated model.

Results: Following stimulation, we observed immediate ear swelling and basopenia after 0.5 hours. However, the number of basophils observed in the skin lesions was low, while a higher number of basophils were observed in the antigen-draining lymph nodes (LN). In mast cell-deficient mice, no increase in basophils in the LN was observed, reflecting reduced antigen influx into the LN, but basophils remained in the skin.

Conclusions: In the IgE-mediated mouse model, basopenia was observed, which coincided with the induction of inflammation in the skin. The migration of basophils to the LN in this model suggests that the systemic immune system, including the LN, should be considered when exploring the pathogenesis of urticaria in humans.

背景：在荨麻疹的活动期，可观察到外周血嗜碱性粒细胞减少，即嗜碱性粒细胞减少症。我们以前曾报道过，在接触性皮炎模型中，嗜碱性粒细胞迁移到皮肤会导致嗜碱性粒细胞减少：尽管目前还没有荨麻疹的成熟模型，但鉴于荨麻疹是一种 IgE 介导的即时型过敏反应，我们旨在确定 IgE 介导的模型是否能重现荨麻疹活动期观察到的外周血嗜碱性粒细胞减少的现象：方法：用 2,4,6-三硝基苯基硫醇（TNP）特异性 IgE 对小鼠进行预处理，并在 TNP-ovalbumin 刺激后检测嗜碱性粒细胞的动态变化。使用肥大细胞缺陷的 WBB6F1-KitW/KitW-v 小鼠来研究肥大细胞在这种 IgE 介导的模型中的作用：结果：刺激后，我们观察到耳朵立即肿胀，并在 0.5 小时后出现嗜碱性粒细胞减少。然而，在皮肤病变中观察到的嗜碱性粒细胞数量较少，而在抗原引流淋巴结（LN）中观察到的嗜碱性粒细胞数量较多。在肥大细胞缺陷的小鼠中，淋巴结中的嗜碱性粒细胞没有增加，这反映了流入淋巴结的抗原减少，但皮肤中仍有嗜碱性粒细胞：结论：在 IgE 介导的小鼠模型中，观察到嗜碱性粒细胞减少，这与皮肤炎症的诱导相吻合。该模型中嗜碱性粒细胞向LN的迁移表明，在探索人类荨麻疹的发病机制时，应考虑包括LN在内的全身免疫系统。

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引用次数: 0

Corrigendum to “Decreased TET2/5-hmC reduces the integrity of the epidermal barrier via epigenetic dysregulation of filaggrin in psoriatic lesions” [J. Dermatol. Sci. 113 (2024) 103–112] 对 "银屑病皮损中 TET2/5-hmC 的减少通过丝胶蛋白的表观遗传失调降低了表皮屏障的完整性 "的更正 [J. Dermatol. Sci.

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-01 DOI: 10.1016/j.jdermsci.2024.07.003

引用次数: 0

Revealing the UV response of melanocytes in xeroderma pigmentosum group A using patient-derived induced pluripotent stem cells 利用源自患者的诱导多能干细胞揭示 A 组色素性角化症黑色素细胞的紫外线反应。

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-01 DOI: 10.1016/j.jdermsci.2024.06.004

Background

Xeroderma pigmentosum (XP) is characterized by photosensitivity that causes pigmentary disorder and predisposition to skin cancers on sunlight-exposed areas due to DNA repair deficiency. Patients with XP group A (XP-A) develop freckle-like pigmented maculae and depigmented maculae within a year unless strict sun-protection is enforced. Although it is crucial to study pigment cells (melanocytes: MCs) as disease target cells, establishing MCs in primary cultures is challenging.

Objective

Elucidation of the disease pathogenesis by comparison between MCs differentiated from XP-A induced pluripotent stem cells (iPSCs) and healthy control iPSCs on the response to UV irradiation.

Methods

iPSCs were established from a XP-A fibroblasts and differentiated into MCs. Differences in gene expression profiles between XP-A-iPSC-derived melanocytes (XP-A-iMCs) and Healthy control iPSC-derived MCs (HC-iMCs) were analyzed 4 and 12 h after irradiation with 30 or 150 J/m² of UV-B using microarray analysis.

Results

XP-A-iMCs expressed SOX10, MITF, and TYR, and showed melanin synthesis. Further, XP-A-iMCs showed reduced DNA repair ability. Gene expression profile between XP-A-iMCs and HC-iMCs revealed that, numerous gene probes that were specifically upregulated or downregulated in XP-A-iMCs after 150-J/m² of UV-B irradiation did not return to basal levels. Of note that apoptotic pathways were highly upregulated at 150 J/m² UV exposure in XP-A-iMCs, and cytokine-related pathways were upregulated even at 30 J/m² UV exposure.

Conclusion

We revealed for the first time that cytokine-related pathways were upregulated even at low-dose UV exposure in XP-A-iMCs. Disease-specific iPSCs are useful to elucidate the disease pathogenesis and develop treatment strategies of XP.

背景：色素性皮肤病（XP）的特点是对光敏感，会导致色素失调，并且由于 DNA 修复缺陷，暴露在阳光下的部位容易患皮肤癌。XP A 组（XP-A）患者除非严格执行防晒措施，否则会在一年内出现雀斑样色素斑和色素沉着斑。虽然研究作为疾病靶细胞的色素细胞（黑素细胞：MCs）至关重要，但在原代培养物中建立 MCs 却具有挑战性：方法：从 XP-A 成纤维细胞建立 iPSCs 并分化成 MCs。结果：XP-A-iPSC衍生的黑色素细胞（XP-A-iMCs）和健康对照iPSC衍生的MCs（HC-iMCs）在接受30或150 J/m2的UV-B照射4和12小时后，基因表达谱的差异通过微阵列分析进行了分析：结果：XP-A-iMCs表达SOX10、MITF和TYR，并显示黑色素合成。此外，XP-A-iMCs 的 DNA 修复能力下降。XP-A-iMCs与HC-iMCs的基因表达谱显示，在150-J/m2的UV-B照射后，XP-A-iMCs中特异性上调或下调的许多基因探针并没有恢复到基础水平。值得注意的是，在 150 J/m2 紫外线照射下，XP-A-iMCs 中的凋亡通路被高度上调，而细胞因子相关通路即使在 30 J/m2 紫外线照射下也被上调：我们首次发现，即使在低剂量紫外线照射下，细胞因子相关通路也会在 XP-A-iMCs 中上调。疾病特异性iPSCs有助于阐明XP的疾病发病机制和制定治疗策略。

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引用次数: 0

Cold shock therapy promotes hair growth in association with upregulation of cold-inducible RNA-binding protein and vascular endothelial growth factor 冷休克疗法促进毛发生长与冷诱导 RNA 结合蛋白和血管内皮生长因子的上调有关。

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-01 DOI: 10.1016/j.jdermsci.2024.08.001

引用次数: 0

Semaxanib, a VEGF inhibitor, suppresses melanogenesis by modulating CRTC3 independently of VEGF signaling 塞马沙尼（一种血管内皮生长因子抑制剂）通过调节 CRTC3（独立于血管内皮生长因子信号）抑制黑色素生成

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-01 DOI: 10.1016/j.jdermsci.2024.07.004

Background

Dysregulation of melanogenesis contributes to the development of skin hyperpigmentation diseases, which poses a treatment challenge. Following the establishment of CRTC3 screening methods to explore small molecules inhibiting melanogenesis for the topical treatment of hyperpigmentation diseases, we identified a candidate molecule, semaxanib.

Objective

To explore the antimelanogenic effects of semaxanib, a vascular endothelial growth factor receptor (VEGFR) 2 inhibitor, for potential applications in hyperpigmentation management and to unravel the role of VEGF signaling in melanocyte biology by investigating mechanism of action of semaxanib.

Methods

Mouse-derived spontaneously immortalized melanocytes, B16F10, and normal human primary epidermal melanocytes cells were treated with semaxanib, and cellular responses were assessed using cell viability assays and melanin content measurements. Molecular mechanisms were investigated using transcriptional activity assays, reverse-transcription polymerase chain reaction, and immunoblotting analysis. In vivo studies were conducted using an epidermis-humanized transgenic mouse model and ex vivo human skin tissues.

Results

Semaxanib ameliorated melanin content in cultured melanocytes by downregulating the expression of melanogenesis-associated genes by suppressing the CRTC3/microphthalmia-associated transcription factors. Topical application of semaxanib reduced melanin accumulation in the ultraviolet B–stimulated ex vivo human epidermis and tail of K14-stem cell factor transgenic mice. Mechanistically, the antimelanogenic effect induced by semaxanib was associated with SIK2-CRTC3-MITF rather than VEGF signaling in melanocytes.

Conclusion

Semaxanib emerges as a promising candidate for the development of therapeutics for hyperpigmentation, potentially working independently of VEGF signaling in human melanocytes.

背景黑色素生成失调导致了皮肤色素沉着疾病的发生，这给治疗带来了挑战。目的探索血管内皮生长因子受体（VEGFR）2抑制剂semaxanib的抗黑色素生成作用，以发现其在色素沉着治疗中的潜在应用，并通过研究semaxanib的作用机制揭示VEGF信号在黑色素细胞生物学中的作用。方法用 semaxanib 处理小鼠自发永生的黑色素细胞 B16F10 和正常人原发性表皮黑色素细胞，并用细胞活力测定和黑色素含量测量评估细胞反应。利用转录活性测定、反转录聚合酶链反应和免疫印迹分析研究了分子机制。结果 semaxanib通过抑制CRTC3/微眼病相关转录因子，下调黑色素生成相关基因的表达，从而改善了培养黑色素细胞中黑色素的含量。局部应用semaxanib可减少紫外线B刺激的体外人体表皮和K14干细胞因子转基因小鼠尾部的黑色素积累。从机理上讲，semaxanib诱导的抗黑色素生成作用与黑素细胞中的SIK2-CRTC3-MITF而非血管内皮生长因子信号转导有关。

{"title":"Semaxanib, a VEGF inhibitor, suppresses melanogenesis by modulating CRTC3 independently of VEGF signaling","authors":"","doi":"10.1016/j.jdermsci.2024.07.004","DOIUrl":"10.1016/j.jdermsci.2024.07.004","url":null,"abstract":"<div><h3>Background</h3><p>Dysregulation of melanogenesis contributes to the development of skin hyperpigmentation diseases, which poses a treatment challenge. Following the establishment of CRTC3 screening methods to explore small molecules inhibiting melanogenesis for the topical treatment of hyperpigmentation diseases, we identified a candidate molecule, semaxanib.</p></div><div><h3>Objective</h3><p>To explore the antimelanogenic effects of semaxanib, a vascular endothelial growth factor receptor (VEGFR) 2 inhibitor, for potential applications in hyperpigmentation management and to unravel the role of VEGF signaling in melanocyte biology by investigating mechanism of action of semaxanib.</p></div><div><h3>Methods</h3><p>Mouse-derived spontaneously immortalized melanocytes, B16F10, and normal human primary epidermal melanocytes cells were treated with semaxanib, and cellular responses were assessed using cell viability assays and melanin content measurements. Molecular mechanisms were investigated using transcriptional activity assays, reverse-transcription polymerase chain reaction, and immunoblotting analysis. <em>In vivo</em> studies were conducted using an epidermis-humanized transgenic mouse model and <em>ex vivo</em> human skin tissues.</p></div><div><h3>Results</h3><p>Semaxanib ameliorated melanin content in cultured melanocytes by downregulating the expression of melanogenesis-associated genes by suppressing the CRTC3/microphthalmia-associated transcription factors. Topical application of semaxanib reduced melanin accumulation in the ultraviolet B–stimulated <em>ex vivo</em> human epidermis and tail of K14-stem cell factor transgenic mice. Mechanistically, the antimelanogenic effect induced by semaxanib was associated with SIK2-CRTC3-MITF rather than VEGF signaling in melanocytes.</p></div><div><h3>Conclusion</h3><p>Semaxanib emerges as a promising candidate for the development of therapeutics for hyperpigmentation, potentially working independently of VEGF signaling in human melanocytes.</p></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141845138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to “Dual effect of tacrolimus on mast cell-mediated allergy and inflammation through MAS-related G protein-coupled receptor-X2” [J. Dermatol. Sci. 112 (2023) 128–137] 他克莫司通过 MAS 相关 G 蛋白偶联受体-X2 对肥大细胞介导的过敏和炎症的双重作用》[J. Dermatol. Sci. 112 (2023) 128-137] 更正。

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-01 DOI: 10.1016/j.jdermsci.2024.06.005

引用次数: 0

JSID flier with late breaking announce 联合材料与发展倡议传单，内含最新消息

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-01 DOI: 10.1016/S0923-1811(24)00186-5

引用次数: 0

Exposure to volatile ferroptosis inhibitor, TEMPO, reduced cutaneous ischemia-reperfusion injury progression to pressure ulcer formation in a mouse model 在小鼠模型中暴露于挥发性铁素体抑制剂 TEMPO，可减少皮肤缺血再灌注损伤进展为压疮的形成

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-01 DOI: 10.1016/j.jdermsci.2024.07.005

Background

Ischemia– reperfusion (I/R) injury-induced oxidative stress is a key factor in the pathogenesis of pressure ulcer formation. Ferroptosis is an iron-dependent programmed cell death that connects oxidative stress and inflammation in various diseases. Recent studies revealed the protective effect of inhibition of ferroptosis in I/R injury. However, the role of ferroptosis in cutaneous I/R injury remains elusive.

Objective

To assess the role of ferroptosis in the progression of cutaneous I/R injury.

Methods

Cutaneous I/R injury experiments and histopathological studies were performed in wild-type mice with or without exposure to volatile ferroptosis inhibitor, TEMPO (2,2,6,6-Tetramethylpiperidine-1-oxyl). The suppressive effects of TEMPO on ferroptosis inducing cell death and oxidative stress were examined in vitro.

Results

Inhibition of ferroptosis with TEMPO significantly reduced ulcer formation after cutaneous I/R injury. Fluctuated ferroptosis markers, such as GPX4, ACSL4, and 4-HNE expression in the I/R skin site, were reversed by TEMPO treatment. Inhibition of ferroptosis reduced apoptosis, CD3⁺ infiltrating lymphocytes, and improved vascularity in the I/R skin site. Inhibition of ferroptosis also suppressed the enhancement of Nrf2 activation. In vitro, ferroptosis and the activation of ferroptosis-related gene expression by RSL3 stimulation were markedly ameliorated by TEMPO treatment in mouse fibroblasts. Inhibiting ferroptosis also suppressed the elevation of the mRNA levels of NOX2 and HO-1 caused by ferroptosis.

Conclusion

Cutaneous I/R injury-induced ferroptosis likely promotes cell death, vascular loss, infiltration of inflammatory cells, and oxidative stress. The inhibition of ferroptosis with TEMPO might have potential clinical application as novel therapeutic agent for cutaneous I/R injury.

背景缺血再灌注（I/R）损伤诱导的氧化应激是压疮形成的关键发病因素。铁变态反应是一种铁依赖性程序性细胞死亡，它将各种疾病中的氧化应激和炎症联系在一起。最近的研究表明，抑制铁变态反应对 I/R 损伤有保护作用。方法在野生型小鼠中进行了皮肤 I/R 损伤实验和组织病理学研究，无论是否暴露于挥发性铁氧化酶抑制剂 TEMPO（2,2,6,6-四甲基哌啶-1-氧）。结果用 TEMPO 抑制铁变态反应可显著减少皮肤 I/R 损伤后溃疡的形成。TEMPO治疗逆转了I/R皮肤部位波动的铁变态反应标志物，如GPX4、ACSL4和4-HNE的表达。抑制铁变态反应可减少细胞凋亡和CD3+浸润淋巴细胞，并改善I/R皮肤部位的血管。抑制铁氧化还能抑制 Nrf2 激活的增强。在体外，TEMPO 可明显改善小鼠成纤维细胞的铁蛋白沉着和 RSL3 刺激铁蛋白沉着相关基因表达的激活。结论皮肤 I/R 损伤诱导的铁变态反应可能会促进细胞死亡、血管损伤、炎症细胞浸润和氧化应激。用 TEMPO 抑制铁蛋白沉积可能作为皮肤 I/R 损伤的新型治疗药物，具有潜在的临床应用价值。

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引用次数: 0

Optimization of an adeno-associated viral vector for epidermal keratinocytes in vitro and in vivo 体外和体内表皮角质细胞腺相关病毒载体的优化。

IF 4.6

Journal of dermatological science

Pub Date : 2024-09-01 DOI: 10.1016/j.jdermsci.2024.07.006

Background

Local gene therapies, including in vivo genome editing, are highly anticipated for the treatment of genetic diseases in skin, especially the epidermis. While the adeno-associated virus (AAV) is a potent vector for in vivo gene delivery, the lack of efficient gene delivery methods has limited its clinical applications.

Objective

To optimize the AAV gene delivery system with higher gene delivery efficiency and specificity for epidermis and keratinocytes (KCs), using AAV capsid and promoter engineering technologies.

Methods

AAV variants with mutations in residues reported to be critical to determine the tropism of AAV2 for KCs were generated by site-directed mutagenesis of AAVDJ. The infection efficiency and specificity for KCs of these variants were compared with those of previously reported AAVs considered to be suitable for gene delivery to KCs in vitro and in vivo. Additionally, we generated an epidermis-specific promoter using the most recent short-core promoter and compared its specificity with existing promoters.

Results

A novel AAVDJ variant capsid termed AAVDJK2 was superior to the existing AAVs in terms of gene transduction efficiency and specificity for epidermis and KCs in vitro and in vivo. A novel tissue-specific promoter, termed the K14 SCP3 promoter, was superior to the existing promoters in terms of gene transduction efficiency and specificity for KCs.

Conclusion

The combination of the AAVDJK2 capsid and K14 SCP3 promoter improves gene delivery to epidermis in vivo and KCs in vitro. The novel AAV system may benefit experimental research and development of new epidermis-targeted gene therapies.

背景：包括体内基因组编辑在内的局部基因疗法在治疗皮肤（尤其是表皮）遗传疾病方面备受期待。虽然腺相关病毒（AAV）是体内基因递送的有效载体，但缺乏高效的基因递送方法限制了其临床应用：目的：利用 AAV 的囊膜和启动子工程技术，优化 AAV 基因递送系统，提高表皮和角质形成细胞（KCs）的基因递送效率和特异性：方法：通过定点突变AAVDJ产生了AAV变体，这些变体的残基据报道是决定AAV2对KCs滋养性的关键。我们将这些变体对KC的感染效率和特异性与之前报道的被认为适合在体外和体内向KC传递基因的AAV进行了比较。此外，我们使用最新的短核启动子生成了表皮特异性启动子，并将其特异性与现有启动子进行了比较：结果：一种名为 AAVDJK2 的新型 AAVDJ 变体包囊在体外和体内的基因转导效率以及对表皮和 KC 的特异性方面优于现有的 AAV。被称为 K14 SCP3 启动子的新型组织特异性启动子在基因转导效率和对 KCs 的特异性方面优于现有的启动子：结论：AAVDJK2包囊与K14 SCP3启动子的结合提高了体内表皮和体外KCs的基因转导效率。这种新型的 AAV 系统可能有利于表皮靶向基因疗法的实验研究和开发。

{"title":"Optimization of an adeno-associated viral vector for epidermal keratinocytes in vitro and in vivo","authors":"","doi":"10.1016/j.jdermsci.2024.07.006","DOIUrl":"10.1016/j.jdermsci.2024.07.006","url":null,"abstract":"<div><h3>Background</h3><p>Local gene therapies, including <em>in vivo</em> genome editing, are highly anticipated for the treatment of genetic diseases in skin, especially the epidermis. While the adeno-associated virus (AAV) is a potent vector for <em>in vivo</em> gene delivery, the lack of efficient gene delivery methods has limited its clinical applications.</p></div><div><h3>Objective</h3><p>To optimize the AAV gene delivery system with higher gene delivery efficiency and specificity for epidermis and keratinocytes (KCs), using AAV capsid and promoter engineering technologies.</p></div><div><h3>Methods</h3><p>AAV variants with mutations in residues reported to be critical to determine the tropism of AAV2 for KCs were generated by site-directed mutagenesis of AAVDJ. The infection efficiency and specificity for KCs of these variants were compared with those of previously reported AAVs considered to be suitable for gene delivery to KCs <em>in vitro</em> and <em>in vivo</em>. Additionally, we generated an epidermis-specific promoter using the most recent short-core promoter and compared its specificity with existing promoters.</p></div><div><h3>Results</h3><p>A novel AAVDJ variant capsid termed AAVDJK2 was superior to the existing AAVs in terms of gene transduction efficiency and specificity for epidermis and KCs <em>in vitro</em> and <em>in vivo</em>. A novel tissue-specific promoter, termed the K14 SCP3 promoter, was superior to the existing promoters in terms of gene transduction efficiency and specificity for KCs.</p></div><div><h3>Conclusion</h3><p>The combination of the AAVDJK2 capsid and K14 SCP3 promoter improves gene delivery to epidermis <em>in vivo</em> and KCs <em>in vitro</em>. The novel AAV system may benefit experimental research and development of new epidermis-targeted gene therapies.</p></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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