2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/654977摘要：幹細胞行為之調控對於組織工程與再生醫學具有關鍵的角色。成體幹細胞廣泛分佈人體各個器官，於維持組織器官恆定及修復扮演著重要的角色。這些幹細胞往往分佈於組織器官的某個特定環境或部位(niche)，可以接受外來環境所給予的訊號並做出反應。毛囊幹細胞分佈於毛囊的突部(bulge)，受到鄰近環境所給予的抑制及活化性訊號所調控。當活化性訊號增強，而抑制性訊號減弱時，可以活化毛囊幹細胞而引請毛囊週期性再生。反之則會使毛囊停滯於休止期。目前已知可以調控毛囊幹細胞的環境因子包括全身性賀爾蒙及鄰近毛囊幹細胞的皮膚脂肪細胞、皮膚神經及毛囊乳突細胞。刺激性的接觸性皮膚炎是常見的皮膚發炎，主因刺激性物質破壞了表皮屏障，進而引起以先天性免疫細胞浸潤為主的皮膚發炎。我們的初步研究結果顯示，利用刺激性接觸性皮膚炎所引發的適度發炎，可以誘發毛囊提早進入生長期，新生毛髮。因此，我們假說免疫系統是可以活化毛囊幹細胞的一種環境因子，促使毛囊進入生長期。在此計畫中，我們設計實驗以了解毛囊幹細胞如何與周遭的發炎環境對話以測試及驗證此假說。我們的目標包括 1.利用動物實驗，建立以刺激性接觸性皮膚炎促進毛囊生長的研究動物模型，並特化其所引起毛囊生長週期及毛囊幹細胞動態的變化。2.利用藥物及基因剔除鼠研究此模型中活化毛囊幹細胞及促進毛囊再生的免疫細胞機制 3. 利用藥物及基因操控在活體動物及體外培養環境，釐清此模型中活化毛囊幹細胞以加速毛囊進入生長期的分子機轉。此計劃的發現可以與其他組織工程技術及治療方法合併以發展促進毛囊再生的新策略，也有潛力發展成小分子藥物以治療禿髮。利用控制性發炎活化組織幹細胞的策略，也有機會應用在其他器官與組織的再生。<br> Abstract: The ability to control the behavior of stem cells is key to both tissue engineering and regenerative medicine. Various organs have distinct adult tissue stem cells that help to maintain tissue homeostasis and contribute to tissue repair. They are located in distinct niches and regulated by the surrounding environment. Hair follicle stem cells are located in the “bulge” of follicular epithelium and their activation fuels the cyclic regrowth of hair follicles throughout life. They are regulated by both the activating and inhibiting signals from the environment. Higher activating signals with lower inhibiting signals tend to activate hair follicle stem cells, while lower activating signals with higher inhibiting signals inhibit them. Currently, the known environmental factors regulating hair follicle stem cells include systemic hormones, local adipose tissue, nerves innervating hair follicles and hair follicle dermal papilla cells. The role of immune response in activating hair follicle stem cells is not yet characterized. Irritant contact dermatitis, characterized by infiltration of mainly innate immune cells in skin, is a common skin inflammation that is elicited by contact with an irritant that disrupts epidermal barriers and damages epidermal keratinocytes. Our preliminary data showed that controlled irritant contact dermatitis can robustly induce hair regeneration. We hence hypothesize that immune system can be an environmental activator for hair follicle stem cells. In this proposal, we design experiments to study how hair follicle stem cells communicate with an inflammatory environment of irritant contact dermatitis. We test our hypothesis by 1.setting up stable animal models to characterize how hair cycles and hair follicle stem cell activity are changed by irritant contact dermatitis 2. clarifying the cellular mechanisms of how immune cells promote hair regeneration in vivo by depleting different types of immune cells with specific drugs and gene knock-out mice 3. exploring the molecular mechanisms hair follicle stem cell activation with pharmacological and genetic perturbation in vivo and in vitro. The learned knowledge here can be combined into tissue engineering or other treatment schemes to develop new strategies for hair regeneration. It also holds the potential to develop topical small molecules to enhance hair regrowth. The concept of activating organ stem cells with controlled inflammation may also be applied to the regeneration of other organs.毛囊再生幹細胞免疫接觸性皮膚炎禿髮治療hair follicle regenerationstem cellimmunityirritant contact dermatitisalopeciatreatment