Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23020
標題: 小鼠胚幹細胞衍生之神經先驅細胞的分化與去分化
Differentiation and dedifferentiation of embryonic stem cell-derived neural progenitor cells
作者: 陳靜雯
Chen, Ching-Wen
關鍵字: embryonic stem cell;胚幹細胞;neural differentation;dedifferentiation;神經分化;去分化
出版社: 生命科學系所
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摘要: 
神經發育是一個複雜的過程,在神經分化的機制與神經幹細胞自我更新維持的機制目前仍然不是非常的清楚。對於未決定分化方向的外胚層細胞(uncommitted ectoderm)走向神經的分化來說,纖維母細胞生長因子(Fibroblast growth factor, FGF)是一個必須存在的生長因子。藉由使用無血清的神經分化方式我們證實隨著FGF1濃度的增加可以促進並且誘導小鼠胚幹細胞分化同時具有Sox1/N-cadherin/nestin表現的細胞,證實這一群細胞為原始的神經母細胞(primitive neuroblasts)。而FGF促進神經分化的能力並不是透過增加Sox1+細胞的增生或是減少細胞的凋亡所引起的。另外也發現,抑制MAP kinase中的JNK1(c-Jun N-terminal kinase-1)或是ERK (extracellular signal-related kinases)而非p38路徑會抑制神經的分化,其抑制神經分化的機制是透過抑制胚幹細胞的分化,而不是讓胚幹細胞分化為中內胚層的細胞。此外,我們的實驗中也證實了FGF無法回復BMP或是Wnt抑制神經分化的作用,但是可以干擾在含有BMP和Wnt的情況下分化細胞中內生性IdⅠ以及Tcf的訊息。由這些證據顯示FGF所調節ES cells分化為神經主要是透過調控MPAK路徑的活化和部分抑制BMP和Wnt的訊息。在維持神經幹細胞的自我更新的部分,我們藉由加入puromycin篩選及在培養基中添加入EGF和FGF的方式之下,可以得到長期具有Sox1-GFP表現的細胞(LS cells),這些細胞具有神經幹細胞的標誌且可以分化為其他種類的神經細胞,但是這些細胞打入裸鼠體內時會形成畸胎瘤。而LS cells可以再程式化回復至全能性(pluripotent)的狀態,而這些細胞會表現全能性幹細胞的標誌之外也同時表現分化細胞的標誌。在Oct4和Nanog啟動子區域甲基化的狀態則是呈現低甲基化,這個情況與46C ES cells相似。以上的結果顯示,LS和LSP cells與EpiSCs是較為相似的細胞。因此若是未來想要使用胚幹細胞衍生的細胞於臨床治療上,應當更加注意、監測並且避免腫瘤的形成。

Neurogenesis is a complex process. The mechanism of neural differentiation and
the way to maintain the self-renewal of neural stem cells (NSCs) are still not very
clear. Fibroblast growth factor (FGF) is essential for uncommitted ectoderm to acquire
a neural fate and the self-renewal of NSCs. By using serum-free neural induction
method, we demonstrated that FGF1 dose-dependently promoted the induction of
Sox1/N-cadherin/nestin triple positive cells, which represent primitive neuroblasts,
from mouse embryonic stem (ES) cells. FGF-enhanced neurogenesis is not mediated
through the rescue of the apoptosis or the enhancement of the proliferation of Sox1+
cells. We further showed that the inactivation of c-Jun N-terminal kinases (JNKs) and
extracellular signal-related kinases (ERKs), but not p38 mitogen-activated protein
kinase (MAPK), inhibited the neural formation through the inhibition of ES
differentiation, but not through the formation of endomesodermal cells. We also
demonstrated that FGF cannot rescue the inhibition effect of BMP and Wnt in neural
induction, but can interfere with the endogenous BMP/IdⅠ or Wnt/Tcf signaling in
differentiating cells. The evidence indicated that FGF-mediated neural induction of
ES cells was through MAPK activation and partially through BMP and Wnt signaling
inhibition. The part of maintenance for NSCs self-renewal, by using puromycin
selection and supplement FGF and EGF in the culture medium, we obtained the
long-term Sox1-GFP+ expression cells (LS cells). These cells expressed neural stem
cell markers and had the capacity to differentiate into neural lineages, but they formed
teratoma in nude mice. LS cells could reprogram to pluripotent state (LSP cells) and
expressed pluripotent and differentiation makers. The Oct4 and Nanog promoter DNA
methylation in LS and LSP cells exhibited hypomethylation, which was similar to that
of 46C ES cells. All of these data showed that LS and LSP cells may be EpiSC-like
cells. Therefore, if we want to use the ES-derivatives for clinical purposes in the
future, we should heed, monitor and try to avoid the possible formation of tumors.
URI: http://hdl.handle.net/11455/23020
其他識別: U0005-0602201116505800
Appears in Collections:生命科學系所

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