前列腺素對毛囊輻射損傷的保護作用： 維持短暫擴張細胞以促進毛囊即時再生

Abstract

放射治療為現今廣泛應用的癌症治療項目，雖然隨著時代演進與科技的進步，放射治療技術已有了長足的進展，但仍無法避免放射線對正常組織的損傷。由於毛囊在體內具有快速分裂增生的特性，生長期的毛囊是對放射線損傷最敏感的器官之一，而掉髮是放射線治療常見的副作用，目前還沒有有效的方法來治療由放射線引起的掉髮。組織幹細胞通常負擔組織受傷後再生的重責。毛囊幹細胞位於毛囊凸部，具有靜止休眠的特性，刺激其活化通常需要複雜且長時間的訊息傳遞過程。若幹細胞無法即時被活化，會導致細胞修復及功能恢復的遲滯。因此，有效地促進受損器官的再生過程將有助於縮短功能恢復的時間。 在我們的研究中發現，在放射線照射前，局部給予前列腺素E2（prostaglandin E2, PGE2）可防止小鼠毛囊進入衰退期與休止期，進而減少放射傷害所造成的掉髮。位於毛囊凸部處於靜止的毛囊幹細胞並沒有被活化來參與修復過程，毛囊短暫擴張細胞所在位置-毛囊球的萎縮情況在前列腺素處理後顯著減少，毛囊生長期的同心圓層結構被快速再生。我們發現在前列腺素的作用下，能將短暫擴張細胞的細胞週期暫時停滯在細胞週期的G1期，因此降低了短暫擴張細胞的輻射敏感度，從而降低短暫擴張細胞的細胞凋亡並減少了毛囊的萎縮狀況。透過保存毛囊短暫擴張細胞，加速了毛囊的自我修復，並因而能跳過輻射傷害造成的生長期提早終止與活化毛囊凸部幹細胞時所需經過衰退期與休止期造成的滯留時間。我們同時利用細胞週期素激酶抑制劑4和6（cyclin-dependent kinases 4/6 inhibitor, CDK4/6 inhibitor：palbociclib isethionate （PD0332991））以全身給藥的方式造成小鼠細胞週期G1期的暫時停滯，發現也能在毛囊細胞面對輻射傷害下，提供類似的保護效果。 我們的研究結果顯示，局部使用前列腺素E2可以通過調節細胞週期來保護毛囊短暫擴張細胞對抗輻射傷害，並且能保留毛囊短暫擴張細胞作為「儲備幹細胞」來進行即時的組織再生而恢復生長期的生長，因而能跳過活化毛囊凸部幹細胞時所需經過衰退期與休止期造成的滯留時間。透過短暫調整細胞週期達到毛囊對於輻射敏感度的調控，將能保存更多毛囊短暫擴張細胞以面對輻射傷害，這可能可以作為一個新的策略，來改善臨床上因放射線造成的落髮與其他正常組織對於輻射傷害的預防。

Radiotherapy is commonly used in cancer treatment. Despite the advances in technology and the considerable progress in radiotherapy, injury to normal tissues is still inevitable. Due to the highly proliferative nature, the anagen hair follicles are one of the organs that are most sensitive to radiation injury and hair loss is a common side effect that still lacks an effective treatment. Tissue stem cells are often responsible for regeneration after injury. Due to the quiescent nature of bulge stem cells in hair follicles, their activation requires considerable time and signaling relays to reset hair cycles. Treatment that can fasten the regenerative process will help to shorten the downtime before functional recovery. In our study, we found that local prostaglandin E2 (PGE2) pretreatment could reduce hair loss from radiation injury by preventing entry into catagen (regression phase) and telogen (resting phase). The quiescent hair follicle bulge stem cells were not activated. Instead, the dystrophy of hair bulbs where hair follicle transit amplifying cells (TACs) reside was reduced and concentric layers of anagen hair follicle structures were quickly regenerated. We found that pretreatment of PGE2 reduced the radiosensitivity of TACs by transiently arresting them in the G1 phase, and thus reducing hair follicle TACs' apoptosis and mitigating hair follicle dystrophy. The preservation of more hair follicle TACs accelerated hair follicle self-repair and bypassed radiation-induced premature termination of anagen and thus shortened the residence time caused by the catagen and telogen phases required that to activate the hair follicle bulge stem cells. We also used the CDK4/6 inhibitor: palbociclib isethionate (PD0332991) to temporarily arrest the G1 phase of the mouse cell cycle by systemic administration, and we found that it can also provide the similar protection to hair follicle cells in the face of radiation damage. Our results show that locally treatment with PGE2 protects hair follicle TACs from radiation injury by transiently modulating the hair follicle cell cycle. The preserved hair follicle TACs can be reserved as the reserved stem cells for the timely tissue regeneration and the following anagen regrowth and thus bypass the long downtime needed to rest hair cycles through telogen for bulge stem cell activation. More hair follicle TACs can be reserved confronting radiation injury by transiently regulating the radiosensitivity of TACs through cell cycle modulation. This can be a new preventive treatment strategy for improving radiation induced hair loss and other radiation associated normal tissue injury.