胚幹細胞維持自我更新之訊息調控徑路

Signaling Pathways of Self-renewal in Embryonic Stem Cells

10.6730/JAAT.200806_9(3).0003

歐耀文(Yao-Wen Ou)；唐品琦(Pin-Chi Tang)；朱志成(Jyh-Cherng Ju)

胚幹細胞 ； 自我更新 ； 白血病抑制因子 ； 訊息傳導徑路 ； Embryonic stem cells ； Self-renewal ； Leukemia inhibitory factor ； Signaling pathways

台灣農學會報

9卷3期（2008 / 06 / 01）

226 - 242

繁體中文

胚幹細胞(embryonic stem cells, ES cells)為分離自早期胚胎之細胞株，具有分化之多能性(pluripotency)，可無限增殖，並有分化形成個體內各種組織細胞之能力。此分化多能性是透過ES cells之自我更新來維持，而自我更新乃由細胞間與細胞內複雜之訊息傳遞機制所調控。白血病抑制因子(leukemia inhibitory factor, LIF)與其下游STAT-3(signal transducers andactivators of transcription-3)之訊息傳遞徑路，可維持小鼠ES cells於不分化狀態，使小鼠EScells穩定表現多能性轉錄因子Oct-4與Nanog，但此LIF/STAT-3徑路卻無法維持人類ES cells不分化。由此可知，人類ES cells之自我更新必需藉由其他訊息傳遞徑路來維持。其它與維持ES cells自我更新有關之分子還包含了BMP(bone morphogenetic protein)與Wnt之訊息傳遞徑路。LIF活化STAT-3同時也活化了促進神經細胞分化之ERK(extracellular-signal-regulated kinase)徑路，而BMP可抑制ERK之活性，並阻止ES cells往神經細胞方向分化，但無法阻止其分化為非神經細胞。這些訊息傳遞機制同時致活了ES cells自我更新與分化之徑路，其間如何保持良好的平衡關係仍需要進一步研究。本文主要探討小鼠與人類ES cells自我更新有關之訊息傳遞徑路，期望透過了解這些訊息分子調控之特性，應用於其他動物模式、人類臨床醫療與再生醫學之研究。

Embryonic stem (ES) cells are derived from an embryo in the early stages of development. These cells retain their pluripotency and capacity of unlimited proliferation. They can develop into all kinds of tissues/cells and maintain self-renewal in the body. Their ability to self-renew is modulated by complicated extrinsic and intrinsic signaling mechanisms. The cytokine leukemia inhibitory factor (LIF) and its downstream effector STAT-3 (signal transducers and activators of transcription 3) are signaling molecules that support self-renewal by expressing transcription factors Oct-4 and Nanog in mouse ES cells. However, LIF alone can not maintain human ES cells in undifferentiation, suggesting the existence of other pathways in this process. Other related signaling pathways are the bone morphogenetic protein (BMP) and Wnt. LIF activates STAT-3 and extracellular-signal-regulated kinase (ERK) simultaneously, and promotes neural differentiation. BMP has been reported to suppress ERK activity and inhibit neural differentiation of ES cells, but it can not prevent ES cell differentiation toward non-neural cell types. Self-renewal of ES cells has to synchronize with their differentiation pathways, and the delicate homeostasis among these signaling cascades is still unclear. In this paper, we discuss the signal transduction in ES cell self-renewal through which a better understanding of how these signaling molecules being modulated is extensively reviewed. However, the crosstalk and integration of these pathways remain to be elucidated.