幹細胞之訊息途徑及表基因調控-子計畫四：人類間質幹細胞的神經分化之分子機制研究(1/3)

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題名:	幹細胞之訊息途徑及表基因調控-子計畫四：人類間質幹細胞的神經分化之分子機制研究(1/3)
作者:	余永倫(Yung-Luen Yu)
貢獻者:	醫學院癌症生物學研究所;中國附醫分子醫學中心分子癌症學
關鍵詞:	人類間質幹細胞;神經分化;訊號傳遞;EZH2;human mesenchymal stem cells (hMSCs), neuron differentiation, signal pathways,EZH2
日期:	2008-11-30
上傳時間:	2009-09-01 15:55:47 (UTC+8)
摘要:	由成人骨髓分離出的間質幹細胞具有自我更新、多功能分化的能力。而這多功能的分化能力取決於人類間質幹細胞如何決定其分化方向。本子計劃旨在研究人類間質幹細胞在神經分化過程中的關鍵性訊號傳遞路徑和EZH2 交互作用的分子機制。我們將找出神經分化中重要的receptor tyrosine kinases (RTKs) 和 mitogen-activated protein kinases (MAPKs) 分子，並研究其於神經分化中所扮演的角色。由於我們初步篩選出的這些激酶，其中還有許多在神經分化中的角色仍然不清楚。因此，我們將進一步研究這些分子於神經分化中的分子機制。此外，甲基化修飾是在幹細胞分化過程中基因外遺傳調控方式重要的一種。而EZH2 具有甲基轉換酶的活性，我們也將找出在間質幹細胞神經分化的過程中EZH2 的標的基因，並研究其於神經分化中所扮演的角色。我們觀察到神經分化後和EZH2 結合的基因啟動子數目明顯較分化前少。這意味著，在這些基因中大部分於分化過程中是需要被活化的而來進一步維持其神經分化的特性。我們進一步將這些 EZH2 的標的基因分類，並研究其中與神經分化相關基因的分子機制。此子計畫藉由上述方式研究完成後，將更瞭解人類間質幹細胞神經分化的分子機制。我們預期能找出一些能調控間質幹細胞分化方向的關鍵性分子，希冀這些知識在未來能有重要的臨床應用。 Human mesenchymal stem cells (hMSCs) from bone marrow of adults are self-renewed, multipotent cells that can differentiate into neurons, adipocyte, and osteoblast etc. Such multipotency depends on how hMSCs decide their cell fates. In this sub-project, our main goal is to investigate the critical signal pathways and molecular mechanisms of the interactions of EZH2, that drive hMSCs specifically differentiate to neural cell type. We will identify the critical receptor tyrosine kinases (RTKs) and mitogen-activated protein kinases (MAPKs) and elucidate their roles in neuron differentiation. Our preliminary results revealed that the phosphorylation of 19% of RTKs (8/42) and MAPKs (4/21) were down-regulated after neuron differentiation. In contrast, 23.8% of p-MAPKs (5/21) were up-regulated. The roles of many kinases identified in our initial screening in neuron differentiation of hMSCs are still unclear. We will further investigate their molecular mechanisms in neuron differentiation. In addition to kinase cascades, methylation is an important epigenetic regulation of stem cell differentiation. EZH2 possesses methyltransferase activity, which regulates gene expression through methylation on histone and DNA. We will also identify the target genes of EZH2 and explore their roles in neuron differentiation of hMSCs. Our preliminary data showed that among 28869 promoters in human genome, 4506 (15.6%) and 1743 (6%) promoters were bound by EZH2 in control and neuron differentiated hMSCs, respectively. Within these identified promoters, only 6.8% (424 out of 6249) was overlapped. After neuron differentiation, less numbers of promoters bound by EZH2 were observed, indicating that the majority of genes need to be reactivated and to maintain the neural phenotype during differentiation. We will further classify these genes and also look for the associated proteins of EZH2 to investigate their roles in neuron differentiation of hMSCs. Once the objectives could be achieved by these approaches, it will provide new insights into the molecular mechanisms of neuron differentiation of hMSCs. We may identify subset of signature genes that distinguish differential type of differentiation lineages, and the knowledge may have important clinical implications in the future.
顯示於類別:	[癌症生物學研究所] 研究計畫

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