BACKGROUND The human placenta is vital for fetal development, yet little is understood about how it forms successfully to ensure a healthy pregnancy or why this process is inadequate in 1 in 10 pregnancies, leading to miscarriage, intrauterine growth restriction or preeclampsia. Trophoblasts are placenta-specific epithelial cells that maximize nutrient exchange. All trophoblast lineages are thought to arise from a population of trophoblast stem cells (TSCs). However, whilst the isolation of murine TSC has led to an explosion in understanding murine placentation, the isolation of an analogous human TSC has proved more difficult. Consequently, alternative methods of studying human trophoblast lineage development have been employed, including human embryonic stem cells (hESCs), induced pluripotent stem cells (iPS) and transformed cell lines; but what do these proxy models tell us about what is happening during early placental development? OBJECTIVE AND RATIONALE In this systematic review, we evaluate current approaches to understanding human trophoblast lineage development in order to collate and refine these models and inform future approaches aimed at establishing human TSC lines. SEARCH METHODS To ensure all relevant articles were analysed, an unfiltered search of Pubmed, Embase, Scopus and Web of Science was conducted for 25 key terms on the 13th May 2016. In total, 47 313 articles were retrieved and manually filtered based on non-human, non-English, non-full text, non-original article and off-topic subject matter. This resulted in a total of 71 articles deemed relevant for review in this article. OUTCOMES Candidate human TSC populations have been identified in, and isolated from, both the chorionic membrane and villous tissue of the placenta, but further investigation is required to validate these as 'true' human TSCs. Isolating human TSCs from blastocyst trophectoderm has not been successful in humans as it was in mice, although recently the first reported TSC line (USFB6) was isolated from an eight-cell morula. In lieu of human TSC lines, trophoblast-like cells have been induced to differentiate from hESCs and iPS. However, differentiation in these model systems is difficult to control, culture conditions employed are highly variable, and the extent to which they accurately convey the biology of 'true' human TSCs remains unclear, particularly as a consensus has not been met among the scientific community regarding which characteristics a human TSC must possess. WIDER IMPLICATIONS Human TSC models have the potential to revolutionize our understanding of trophoblast differentiation, allowing us to make significant gains in understanding the underlying pathology of pregnancy disorders and to test potential therapeutic interventions on cell function in vitro. In order to do this, a collaborative effort is required to establish the criteria that define a human TSC to confirm the presence of human TSCs in both primary isolates and to determine how accurately trophoblast-like cells derived from current model systems reflect trophoblast from primary tissue. The in vitro systems currently used to model early trophoblast lineage formation have provided insights into early human placental formation but it is unclear whether these trophoblast-like cells are truly representative of primary human trophoblast. Consequently, continued refinement of current models, and standardization of culture protocols is essential to aid our ability to identify, isolate and propagate 'true' human TSCs from primary tissue.

中文翻译：

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干细胞对人类滋养细胞谱系分化的见解。

背景技术人胎盘对于胎儿的发育至关重要，但人们对其如何成功形成以确保健康怀孕或为什么这一过程在十分之一的怀孕中不足以导致流产，宫内生长受限或先兆子痫的了解甚少。滋养细胞是胎盘特异的上皮细胞，可最大化营养交换。人们认为所有滋养层谱系都来自滋养层干细胞（TSC）群体。但是，尽管分离鼠TSC导致理解鼠胎盘的爆炸式增长，但事实证明，分离相似人类TSC更加困难。因此，已经采用了研究人类滋养细胞谱系发育的替代方法，包括人类胚胎干细胞（hESCs），诱导多能干细胞（iPS）和转化细胞系。但是这些代理模型能告诉我们早期胎盘发育期间发生了什么？目的和理由在本系统综述中，我们评估了目前了解人类滋养层谱系发育的方法，以便整理和完善这些模型，并为旨在建立人类TSC谱系的未来方法提供信息。搜索方法为确保分析所有相关文章，于2016年5月13日对Pubmed，Embase，Scopus和Web of Science进行了25个关键术语的未经过滤的搜索。总共检索到47313篇文章，并基于非人类，非英语，非全文，非原创文章和主题外的主题。这样一来，共有71条被认为与本文章相关的文章。结果已在以下地区确定了人类TSC候选人群：并且从胎盘的绒毛膜和绒毛组织中分离出来，但是需要进一步研究以确认它们是“真正的”人类TSC。从胚泡滋养外胚层中分离人TSC在人类中并不像在小鼠中那样成功，尽管最近第一个报道的TSC品系（USFB6）是从八细胞桑ula中分离出来的。代替人类的TSC系，已经诱导了滋养细胞样细胞与hESCs和iPS分化。但是，这些模型系统的差异难以控制，采用的培养条件变化很大，并且它们在多大程度上准确传达“真正的”人类TSC生物学特性尚不清楚，特别是因为尚未达成科学界的共识关于人类TSC必须具备的特征。进一步的意义人类TSC模型有可能彻底改变我们对滋养层细胞分化的理解，从而使我们在了解妊娠失调的潜在病理学和测试体外细胞功能的潜在治疗性干预方面取得重大进展。为此，需要共同努力以建立定义人类TSC的标准，以确认两个分离株中都存在人类TSC，并确定源自当前模型系统的滋养层样细胞如何准确反映来自初级组织的滋养层。当前用于模拟早期滋养层谱系形成的体外系统提供了对人类早期胎盘形成的见解，但是尚不清楚这些滋养层样细胞是否真正代表原代人类滋养层。