胚胎干细胞分化潜能研究进展

胚胎干细胞(ESC)是来源于哺乳动物早期胚胎的一种具有多向分化潜能的细胞。目前已经从胚胎干细胞分化培育出了心肌细胞,神经细胞,血管内皮细胞和壁细胞,胰岛细胞等。胚胎干细胞的诱导分化可以从形成拟胚体途径,也可以直接分化。对胚胎干细胞的研究具有广阔的应用前景,但也存在很多问题尚待解决。     

胚胎干细胞

第一次卵裂什么是胚胎干细胞?当受精卵分裂发育成囊胚时(受精后5～6天),内层细胞团的细胞即为胚胎干细胞。胚胎干细胞具有全能性,可以自我更新并具有分化为体内所有组织的能力。早在1970年科学家已从小鼠中分离出胚胎干细胞并在体外进行培养。而人的胚胎干细胞的体外培养直到最近才获得成功。进一步说,胚胎干细胞是一种高度未分化细胞,能分化出所有组织和器官,包括生殖细胞。研究和利用胚胎干细胞是当前生命科学领域的核心问题之一。     

干细胞概述

干细胞是存在于胚胎和成体中的一类特殊细胞,它能长期地自我更新,在特定的条件下具有分化形成多种终末细胞的能力,不同来源的干细胞分化潜能各异。从早期胚胎内细胞团分离的胚胎干细胞能分化形成个体所有的细胞类型,并具有在体外无限增殖的能力,是最具有临床应用前景和研究价值的干细胞之一。在成体各种组织和器官中也存在成体干细胞,用于维持机体结构和功能的稳态。近期有关成体干细胞可塑性的研究和成体组织中多能干细胞存在的证据扩大了人们对成体干细胞分化潜能的认识。干细胞具有的多向分化潜能和自我更新能力使其成为未来再生医学的重要种子细胞,并成为研究人类早期胚层特化和器官形成、药物筛选以及基因治疗的最佳工具。     

胚胎干细胞中微小RNA功能与机制研究进展

胚胎干细胞自问世之初便承载了人们对于治疗各种疾病的期望。其来源于早期胚胎发育囊胚的内细胞团,这些细胞具有快速增殖和分化为所有其他体细胞的特性。由于这些特性,胚胎干细胞必须被小心加以控制才不至于在治疗过程中产生不受限制的生长(即致瘤性)和不必要的细胞污染。控制胚胎干细胞的增殖和分化的前提是人们尽可能多地掌握其内在调控的关键分子机制。对胚胎干细胞的增殖和分化的调控发生在多个层面,包括细胞信号通路、染色质高级结构、转录因子、微小RNA和长非编码RNA。简要综述胚胎干细胞中微小RNA的调控功能和机制研究进展,并展望这一领域未来的发展方向。     

胚胎干细胞的体外诱导分化模型

胚胎干细胞是具有全能性及无限制的自我更新与分化能力的一类特殊的细胞群体 ,它能通过祖细胞为中介 ,分化为各种类型的体细胞 ,可重演体内干细胞的分化过程。自 80年代从小鼠囊胚的内细胞团分离到胚胎干细胞并建系到现在已建立了神经细胞、肌肉细胞、上皮细胞、造血细胞等体外分化体系。将胚胎干细胞体外分化成为可利用的分化模型 ,无论从组织结构、细胞及分子水平都体现了体内分化过程的体外重演 ,再加上胚胎干细胞系具有体系简单 ,影响因子少 ,可控制 ,便于研究等特点 ,因此可用于研究早期胚胎发育和细胞分化调控 ;可成为器官移植和修复…     

诱导小鼠胚胎干细胞在体外分化为骨骼肌细胞的实验研究

小鼠胚胎干细胞是从胚泡未分化的内部细胞团中得到的干细胞,它在体外培养的环境中具有无限增殖、自我更新以及多向分化的特性。将小鼠胚胎干细胞在体外诱导分化为肌肉细胞,并且利用这些分化得来的肌肉细胞治疗肌肉退行性疾病,是干细胞研究领域的热点。该实验的目的在于筛选小鼠胚胎干细胞向骨骼肌细胞定向分化的实验条件,有效地将体外单层贴壁培养的小鼠胚胎干细胞诱导分化成骨骼肌细胞。最终发现,10-8mol/L维甲酸(retinoid acid,RA)+0.5%二甲基亚砜(dimethyl sulfoxide,DMSO)组诱导小鼠胚胎干细胞在体外分化成骨骼肌前体细胞的效率最高,分化得到的骨骼肌前体细胞经进一步纯化,能分化为多核的肌管。该实验为治疗肌肉退行性疾病提供了细胞来源,也为研究小鼠胚胎干细胞分化为骨骼肌细胞的机制提供了有利的条件。     

Zfx基因与干细胞自我更新

干细胞具有自我更新保持不分化状态的特性,不同的干细胞具有不同的自我更新机制. Zfx基因(zinc fin ger-X gene)在部分胚胎干细胞和造血干细胞中高表达,该基因高表达有利于胚胎干细胞和造血干细胞自我更新; Zfx基因表达不足或缺乏的胚胎干细胞和造血干细胞自我更新的能力下降,细胞凋亡明显增加.在胚胎干细胞和造血干细胞中发现一些Zfx基因直接调控的靶基因,Zfx 基因可能是控制各种干细胞自我更新的共同的分子机制. Zfx基因表达不足不影响胚胎干细胞和造血干细胞的分化,缺乏 Zfx基因的胚胎干细胞和造血干细胞能够正常分化为各自的功能细胞.     

山羊胚胎大脑皮层神经干细胞分离、培养与鉴定

目的 :从山羊胚胎大脑皮层中分离培养并鉴定神经干细胞。方法 :利用NBS培养和单细胞克隆技术在山羊胚胎大脑皮层中分离出具有单细胞克隆能力的细胞 ,并进行培养、传代、分化观察 ,采用免疫组化检测克隆细胞的神经巢蛋白 (Nestin)抗原和分化后特异性成熟神经细胞抗原的表达。结果 :从胚龄 2 4～ 30d的新鲜山羊胚胎大脑皮层中成功分离出神经干细胞 ,该细胞具有连续克隆能力 ,可传代培养 ,表达神经巢蛋白抗原。分化后的细胞表达神经元细胞、胶质细胞和少突胶质细胞的特异性抗原。结论 :山羊胚胎大脑皮层中存在具有自我更新能力和多分化潜能的神经干细胞。     

胚胎干细胞生物学特性及其应用前景

胚胎干细胞是来源于着床前的囊胚内细胞团或早期胎儿的原始生殖细胞的一类未分化的全能性多能性干细胞,具有无限增殖和全能分化的潜力。胚胎干细胞在发育生物学基础研究、动物胚胎工程研究生产和临床医学上具有诱人的应用前景。     

胚胎干细胞体外诱导分化

胚胎干细胞能在体外长期不断自我更新,具有高度分化潜能,可分化成胎儿和成体的几乎所有类型的细胞,如心肌细胞、神经细胞、上皮细胞、肝细胞、血细胞、胰岛细胞、脂肪细胞及生殖细胞等。在细胞治疗和组织器官替代治疗、发育生物学等的研究中将具有广阔的应用前景。目前已有多种胚胎干细胞体外定向诱导的报道。本文从体外诱导分化影响因素和几种主要诱导细胞类型进行分析和总结,为胚胎干细胞的诱导分化研究提供参考资料。     

肿瘤干细胞与表观遗传学调控

关于恶性肿瘤发生、复发与转移机制的研究由来已久,但目前的临床治疗方法依然不能克服肿瘤复发与转移的难题,肿瘤患者的生存率并未得到显著改善。近年来的研究提示肿瘤的起源、复发与转移的真正原因可能是存在于肿瘤内的极少数具有干细胞特性的细胞,即肿瘤干细胞（cancer stem cells,CSC）。与此同时,越来越多的研究表明,对于肿瘤干细胞的发生与功能维持,表观遗传学的调控机制可能发挥着极其重要的作用。该文简要综述目前肿瘤干细胞和表观遗传学相关领域的研究进展,并对肿瘤干细胞形成及发展过程中表观遗传学的调控作用及机制进行重点介绍。     

STORM: a general model to determine the number and adaptive changes of epithelial stem cells in teleost, murine and human intestinal tracts

Intestinal stem cells play a pivotal role in the epithelial tissue renewal, homeostasis and cancer development. The lack of a general marker for intestinal stem cells across species has hampered analysis of stem cell number in different species and their adaptive changes upon intestinal lesions or during development of cancer. Here a two-dimensional model, named STORM, has been developed to address this issue. By optimizing epithelium renewal dynamics, the model examines the epithelial stem cell number by taking experimental input information regarding epithelium proliferation and differentiation. As the results suggest, there are 2.0-4.1 epithelial stem cells on each pocket section of zebrafish intestine, 2.0-4.1 stem cells on each crypt section of murine small intestine and 1.8-3.5 stem cells on each crypt section of human duodenum. The model is able to provide quick results for stem cell number and its adaptive changes, which is not easy to measure through experiments. Its general applicability to different species makes it a valuable tool for analysis of intestinal stem cells under various pathological conditions.     

Micro-RNA mediated regulation of proliferation,self-renewal and differentiation of mammalian stem cells

Metazoan growth and development is maintained by populations of undifferentiated cells, commonly known as stem cells. Stem cells possess several characteristic properties, including dividing through self-renewing divisions and generating progeny that differentiate to have specialized cell fates. Multiple signaling pathways have been identified which coordinate stem cell proliferation with maintenance and differentiation. Relatively recently, the small, non-protein coding microRNAs (miRNAs) have been identified to function as important regulators in stem cell development. Individual miRNAs are capable of directing the translational repression of many mRNAs targets, generating widespread changes in gene expression. In addition, dysfunction of miRNA expression is commonly associated with cancer development. Cancer stem cells, which are likely responsible for initiating and maintaining tumorigenesis, share many similarities with stem cells and some mechanisms of miRNA function may be in common between these two cell types.     

The voyage of stem cell toward terminal differentiation: a brief overview

Presently, worldwide attempts are being made to apply stem cells and stem cell-derived products to a wide range of clinical applications and for the development of cell-based therapies. In order to harness stem cells and manipulate them for therapeutic application, it is very important to understand the basic biology of stem cells and identify the factors that govern the dynamics of these cells in the body. Several signaling pathways have emerged as key regulators of stem cells. Some of these signaling pathways regulate the stem cell's proliferative capacity and therefore act as direct regulators of the stem cell, whereas others are involved in shaping and maintaining the stem cell niche and therefore act as indirect regulators of the stem cell. It is difficult to identify which signaling pathways critically affect the stem cell's behavior and which are important for maintaining the quiescent population. A stem cell receives different extrinsic signals compared with the bulk population and responds to them differently. In order to manipulate these adult cells for therapeutic approaches it is crucial to identify how signaling pathways regulate stem cells either directly by regulating proliferative status or indirectly by influencing the niche. The main challenge is to identify whether different factors provide diverse extrinsic signals to the stem cell and its daughter cell population, or whether there are intrinsic differences in stem cell and daughter cell populations that is reflected in their behavior. In this study, we will focus on the various aspects of stem cell biology and differentiation, as well as exploring the potential strategies to intervene the differentiation process in order to obtain the desired yield of cells applicable in regenerative medicine.     

Micro-RNA mediated regulation of proliferation,self-renewal and differentiation of mammalian stem cells

Metazoan growth and development is maintained by populations of undifferentiated cells, commonly known as stem cells. Stem cells possess several characteristic properties, including dividing through self-renewing divisions and generating progeny that differentiate to have specialized cell fates. Multiple signaling pathways have been identified which coordinate stem cell proliferation with maintenance and differentiation. Relatively recently, the small, non-protein coding microRNAs (miRNAs) have been identified to function as important regulators in stem cell development. Individual miRNAs are capable of directing the translational repression of many mRNAs targets, generating widespread changes in gene expression. In addition, dysfunction of miRNA expression is commonly associated with cancer development. Cancer stem cells, which are likely responsible for initiating and maintaining tumorigenesis, share many similarities with stem cells and some mechanisms of miRNA function may be in common between these two cell types.Key words: stem cell, miRNA, mammalian, neuroblast, pluripotency, cancer, ESC, self-renewal     

Stem cell exhaustion and leukemogenesis

Cancer is the result of a combination of genetic alterations, which aid transformation of cells. However, oncogenic alterations also simultaneously induce some detrimental effects on the cells such as apoptosis, senescence, and differentiation. Such negative effects caused by certain oncogenic events are overcome by other cooperating genetic hits. We propose stem cell exhaustion as a novel detrimental effect that is caused by a wide variety of oncogenic alterations. Interestingly, in most cases, the stem cell exhaustion due to oncogenic alterations is preceded by an abnormal expansion of stem/progenitor cells. This preceding stem/progenitor cell expansion may be a key feature that still promotes cancer development, along with cooperating hits that rescue stem cell exhaustion. This review summarizes current knowledge about hematopoietic stem cell exhaustion and the mechanisms to overcome stem cell exhaustion in cancer development. J. Cell. Biochem. 107: 393–399, 2009. © 2009 Wiley‐Liss, Inc.     

成体干细胞的研究及潜在应用

成体干细胞(adultstemcells)存在于人和哺乳动物的多种成体中,具有自我更新和一定的分化潜能.现已从骨髓、软骨、血液、神经、肌肉、脂肪、皮肤、角膜缘、肝脏、胰腺等许多组织中获得干细胞,并在部分成体干细胞的体外分离培养、扩增及诱导分化等研究中取得突破性进展,发现部分成体干细胞具有预想不到的分化潜能.成体干细胞不仅是发育生物学研究的理想模型,而且是细胞移植治疗、人工组织或器官构建的种子细胞和基因治疗的理想载体细胞,因此,在揭示生命的本质和规律及再生医学中有十分广阔的应用前景.     

Democracy derived? New trajectories in pluripotent stem cell research

How has the development of human induced pluripotent stem cells (hiPSCs) modified the trajectory of stem cell research? Here, coauthorship networks of stem cell research articles and analysis of cell lines used in stem cell research indicate that hiPSCs are not replacing human embryonic stem cells, but instead, the two cell types are complementary, interdependent research tools. Thus, we conclude that a ban on funding for embryonic stem cell research could have unexpected negative ramifications on the nascent field of hiPSCs.     

多细胞生物干细胞不对称分裂的内在调节机制研究进展

多细胞生物的发育是从一个受精卵分化成多种类型细胞的过程。细胞多样性形成的基础是不等分裂,不等分裂是干细胞自我更新和自我维持的关键。干细胞不等分裂有细胞内和细胞外两种调节机制。果蝇神经干细胞增殖和分化、植物胚胎发育、表皮气孔形成及根内皮层的分化,是研究不等细胞分裂调节机制最多的发育背景。本综述介绍了果蝇神经干细胞和植物胚胎发育早期、表皮气孔发生及根皮层内皮层中细胞不等分裂内在调节机制的研究进展。