Results and Problems in Cell Differentiation-猫眼课题宝

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2018

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其他

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Parvez Alam

从发育中和成人大脑中分离出的神经干细胞是用于细胞替代疗法等临床应用的理想细胞来源。与更常用的胚胎干细胞和多能干细胞相比，这些细胞的明显优势是它们已经具有神经定向。特别重要的是，这些细胞不需要同样水平的体外培养，而体外培养可能是成本和劳动力密集型的。胎儿神经干细胞可以很容易地从胎儿大脑中获得，并随着时间的推移在培养物中扩增。同样，成体干细胞在体外和体内动物模型中的潜力也得到了探索。在本章中，我们将介绍开发这些细胞所取得的进展以及将它们用于临床应用的优势。神经干细胞可能有多种来源，近年来关注的焦点是胚胎干（ES）细胞和诱导多能干（iPS）细胞。这些细胞可以很容易地分化为神经谱系，从那里它们可以进一步定向为神经系统的不同细胞类型。这些细胞已被广泛探索的一种治疗方法是细胞替代疗法（CRT）。 CRT 旨在替代因疾病过程而损失的细胞。神经退行性疾病，如帕金森病 (PD) 和亨廷顿病 (HD)，存在局灶性细胞损失，是此类方法的理想候选者。研究表明，移植到患病大脑中的原代人类胎儿细胞可以存活并整合到宿主大脑中，从而重建丢失的电路并减轻疾病的运动症状。迄今为止，这两种神经退行性疾病的临床试验已经证明了原理的证明。然而，迫切需要确定 C. M. Kelly 生物医学科学，卡迪夫健康科学学院，卡迪夫城市大学，卡迪夫，英国电子邮件：ckelly@cardiffmet.ac.uk M. A. Caldwell (*) 三一学院神经科学研究所，都柏林三一学院，都柏林，爱尔兰电子邮件：Maeve.Caldwell@tcd.ie © Springer International Publishing AG，Springer Nature 的一部分2018 L. Buzanska（编辑），人类神经干细胞，细胞分化的结果和问题 66，https://doi.org/10.1007/978-3-319-93485-3_1 3 个替代细胞来源，可用于使这种方法更加可行。目前，细胞的来源是在有限的时间窗口内（即这些神经元出生前后）采集的原代人类胎儿组织。具体而言，对于 PD，该时间为受孕后 4-6 周，对于 HD，则稍晚，为受孕后 8-12 周。这种有限的时间窗口极大地限制了大规模临床应用的可行性。此外，每位患者都需要多个供体，这一问题因 PD 的双侧移植需要来自大约 6 个胎儿的细胞而变得更加复杂，而收集该组织的时间限制为 7 天（从而导致协调细胞收集、手术和细胞病理筛选的后勤问题），而且很难标准化。因此，需要找到一种新的细胞来源来实现这一目标。事实上，对于任何类型的细胞被考虑作为细胞替代疗法，有许多关键问题需要解决：（1）细胞的生物学应该被完全定义； (2) 应该能够以临床有用的数量扩增和储存这些细胞； (3)应具有可靠的分化潜能，即传代后神经源潜能必须保持稳定； (4) 移植后必须能够恢复功能； (5) 不得随时间发生恶变。为此目的，ES 和 iPS 细胞正在被广泛探索。 ES 和 iPS 细胞是多能细胞来源，因此需要在体外进行操作，以首先将它们引导至神经元命运，然后引导至细胞类型特异性表型。另一种方法是寻求识别已经定型为神经谱系（即组织特异性）的干细胞，此外，还来自更受限制的谱系，例如纹状体前体细胞，从纹状体前体细胞中可能更容易驱动明确的纹状体表型，如 HD 所需。此外，如果这些细胞能够在冷冻保存中存活，这将缓解当前与安排神经外科手术相关的实际限制，并且还允许至少对细胞进行一定程度的标准化，而这对于原代胎儿组织来说目前还无法实现。具体来说，胎儿组织只能在短时间内（最多 8 天）可靠地保存在培养物中（使用培养基来减少代谢过程，即“冬眠”），这段时间不足以对组织进行全面的质量控制（Hurelbrink 等，2000）。此外，这些细胞的多能性质意味着它们在移植后不太可能产生快速生长的肿瘤，这是与多能衍生的神经细胞相关的持续风险。本章的重点将放在发育中和成人大脑中发现的具有“神经干细胞”特征的细胞。在发育中和成年的大脑中，有一些具有干细胞样特征的神经细胞群。根据定义，“神经干细胞”描述了一种多能干细胞，可以自我更新并产生一个或多个神经或神经胶质谱系。此外，术语“神经祖细胞”和“神经前体细胞”是指仅限于未指定的神经细胞的谱系，或者如果进一步沿着发育途径，则指定为大脑亚区域。干细胞群不仅存在于整个发育过程中，还存在于成体组织中，它们可能持续活跃，例如皮肤不断更新的干细胞，或者可能基本上处于静止状态，但如果条件合适，它们能够被触发增殖，就像成体中枢神经系统中的某些细胞群一样。不可能是 4 C. M. Kelly 和 M. A. Caldwell

Neural stem cells isolated from the developing and adult brain are an ideal source of cells for use in clinical applications such as cell replacement therapy. The clear advantage of these cells over the more commonly utilised embryonic and pluripotent stem cells is that they are already neurally committed. Of particular importance is the fact that these cells don’t require the same level of in vitro culture that can be cost and labour intensive. Foetal neural stem cells can be readily derived from the foetal brain and expand in culture over time. Similarly, adult stem cells have been explored for their potential in vitro and in vivo animal models. In this chapter we identify the progress made in developing these cells as well as the advantages of taking them forward for clinical use. Neural stem cells may be derived from several sources, and the focus of attention in recent years has been on those from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. These cells can be readily differentiated down a neural lineage from where they can be further directed into the different cell types of the nervous system. One therapeutic approach for which these cells have been extensively explored is cell replacement therapy (CRT). CRT aims to replace the cells that have been lost due to disease process. Neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD), where there is focal cell loss, are ideal candidates for this type of approach. It has been shown that primary human foetal cells transplanted into the diseased brain can survive and integrate into the host brain, thereby recreating the lost circuitry and alleviating the motor symptoms of the disease. Proof of principle has been shown in clinical trials to date for both neurodegenerative diseases; however, there is an urgent need to identify an C. M. Kelly Biomedical Science, Cardiff School of Health Sciences, Cardiff Metropolitan University, Cardiff, UK e-mail: ckelly@cardiffmet.ac.uk M. A. Caldwell (*) Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland e-mail: Maeve.Caldwell@tcd.ie © Springer International Publishing AG, part of Springer Nature 2018 L. Buzanska (ed.), Human Neural Stem Cells, Results and Problems in Cell Differentiation 66, https://doi.org/10.1007/978-3-319-93485-3_1 3 alternative cell source that can be used to make this approach more viable. Currently, the source of cells is primary human foetal tissue taken within a restricted time window, around the time of birth of these neurons. Specifically, for PD this would be 4–6 weeks postconception and slightly later for HD, 8–12 weeks postconception. This restricted time window places significant constraints on the feasibility of largescale clinical application. In addition several donors are required per patient, an issue compounded by the fact that bilateral transplants in PD require cells from approximately six foetuses and the time line for collecting this tissue is restricted to 7 days (thus causing logistical problems for coordinating cell collection, surgery and pathological screening of cells) and they are difficult to standardise. Hence, there is a need to identify a new source of cells that would make this possible. Indeed, for any type of cells to be considered as a cell replacement therapy, there are a number of critical issues that should be addressed: (1) the biology of the cells should be completely defined; (2) it should be possible to both expand and store these cells in clinically useful quantities; (3) they should have a reliable differentiation potential, i.e. their neurogenic potential must remain stable after passaging; (4) they must be able to restore function following transplantation; and (5) they must not undergo malignant transformation over time. ES and iPS cells are being extensively explored for this purpose. ES and iPS cells are a pluripotent source of cells and thus require manipulation in vitro to direct them firstly to a neuronal fate and furthermore to a cell type-specific phenotype. An alternative approach is to seek to identify stem cells that are already committed to a neural lineage (i.e. tissue-specific) and, furthermore, from an even more restricted lineage, for example, striatal precursors from which it may be easier to drive an explicitly striatal phenotype, as required for HD. In addition, if these cells could survive cryopreservation, this would ease current practical constraints associated with scheduling the neurosurgery and would also permit at least some standardisation of the cells, which cannot currently be achieved for primary foetal tissue. Specifically, foetal tissue can only be reliably held in culture (using media to reduce metabolic processes, i.e. ‘hibernation’) for a short period of time (up to 8 days) which is an insufficient period of time to permit full quality control of the tissue (Hurelbrink et al. 2000). Furthermore, the multipotential nature of these cells means they are less likely to give rise to fast-growing tumours following grafting, a constant risk associated with pluripotent-derived neural cells. The focus of this chapter will be on those cells found in the developing and adult brain that have ‘neural stem cell’ characteristics. Within the developing and adult brain, there are populations of neural cells that have stem cell-like characteristics. By definition ‘neural stem cell’ describes a multipotent stem cell that can self-renew and give rise to one or multiple neural or glial lineages. Furthermore, the terms ‘neural progenitor cell’ and ‘neural precursor cell’ refer to a lineage restricted to an unspecified neural cell or, if further down the developmental pathway, specified to a brain subregion. As well as being present throughout development, stem cell populations are present in adult tissues, where they may be continually active, such as stem cells that underlie the constant renewal of the skin, or may be largely quiescent but capable of being triggered to proliferate if the conditions are right, as for some populations in the adult CNS. It cannot be 4 C. M. Kelly and M. A. Caldwell

Results and Problems in Cell Differentiation

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