藉由輻射刺激探討真皮層中的巨環境影響毛囊再生

Abstract

根據WHO在2018年統計指出，癌症是全球第二大死因，約占整體死因的六分之一。每種類型的癌症有不同的治療方式，包括：外科手術、化學治療、放射治療。然而，藉由放射治療對於局部的癌細胞進行毒殺，其所造成的副作用較嚴重，例如：皮膚會出現潮紅、乾燥、發癢，或是疲倦、食慾減低，甚至是局部照射範圍有掉髮的現象。 皮膚是哺乳動物最大的器官系統，而毛囊是動態微小器官並且深入生長於皮膚真皮層中，作為微小器官的毛囊，有著規律的生長週期，包含：生長期、凋亡期、休止期。各時期的毛囊均會有不同的結構或是細胞組成；而圍繞著毛囊的巨環境，例如有：神經、血管、脂肪組織等。除此之外，在毛囊內亦有幹細胞的分佈以維持毛髮週期不斷的循環再生。然而，生長期的毛囊若接受放射治療、輻射傷害後，會使毛囊進入萎縮性生長期或是萎縮性衰退期。 本實驗室先前的研究已發現毛囊在不同輻射劑量刺激下，會促使毛囊進入不同程度的衰退期。本研究的目的為探討輻射刺激後真皮層的巨環境與毛囊再生的關係，以期能瞭解輻射刺激後之毛囊再生機轉。實驗以輻射劑量2 Gy與5.5 Gy誘導毛囊進入適應性衰退期。毛囊在5.5 Gy輻射刺激後會有萎縮的現象，而在稍後恢復形態；而肌肉纖維與膠原纖維也因5.5 Gy輻射刺激後發生皺縮的現象，且此現象的改變與毛囊衰退期時間相吻合。我們以質譜定序且定量輻射後真皮層細胞的蛋白質，以期能從中獲得毛囊再生的相關資訊。從定序結果中發現，脂肪代謝相關蛋白在總蛋白質中有顯著的差異。最後，我們以5.5 Gy輻射處理小鼠後，餵食脂肪溶解抑制劑，以驗證脂肪溶解在毛囊再生中扮演的角色。實驗結果顯示，餵食脂肪溶解抑制劑的小鼠，其毛囊會延遲再次進入生長期約10天。 總結以上的實驗結果，本研究驗證了真皮層巨環境中之脂肪代謝在輻射刺激後之毛囊再生扮演重要的角色，脂肪代謝對於輻射刺激後之毛囊再生不可或缺。

According to WHO organization report, cancer is the second highest cause of death, accounting for approximately one sixth of death incidence in the world. There are several types of cancer treatments depending on the type of cancer and how advanced it is. Examples of current methods include chemotherapy, radiotherapy and surgery. A localized radiotherapy treatment, utilizing low doses or high doses of radiation to kill cancer cells, often causes a variety of side effects such as itchy skin, tiredness and temporary localized hair loss. Skin is the largest organ in mammals. The hair follicle(HF) is one of the characteristic features of mammals serves as a unique mini-organ, anchoring into the skin. The hair follicle keeps regular hair growth cycle in three different stages: anagen, catagen and telogen stages. Each stage has different hair structures,cell populations, and macroenvironment in dermis. In addition, there are stem cells distributed in hair follicle in order to sustain hair cycle regeneration. Hair follicles would enter either dystrophy anagen or dystrophy catagen if the hair follicles are exposed to long term radiation during a radiotherapy. Our lab's previous studies indicated 2 Gray (Gy) and 5.5 Gy ionizing radiation may induce hair dystrophy in different manners. The aim of this study is to figure out the relationship between dermal macroenvironment and hair regeneration in adaptation to irradiation dystrophy, and to understand the mechanism of hair follicle regeneration upon radiation damage. In this study, HFs in 5.5Gy ionizing radiation will degenerate and recover afterwards. Afterwards, dermal macro-environment will be dramatically changed as seen in immunostaining of oil red O(ORO) and Masson trichome staining after radiation treatment. Thus, we utilized mass spectrometry to identify and quantify protein expression in dermal macroenvironment after ionizing radiation. Based on protein sequencing data, it indicates that proteins associated with fatty acid metabolism would be changed significantly after radiation. Finally, we used Acipimox (lipolysis inhibitor) as our functional assay for animal model to confirm that lipolysis plays the important role in hair regeneration after ionizing radiation. The results indicated that HFs would delay re-entering of anagen stage almost 10 days, comparing with no-drug intake control group. In summary, our findings revealed that fatty acid metabolism of dermal macroenvironment would be a vital factor of hair regeneration after ionizing radiation. Thus, we believe that fatty acid is essential for hair follicle regeneration stimulated by ionizing radiation.