Modeling the blood-brain barrier using stem cell sources.
Modeling the blood-brain barrier using stem cell sources.
复制标题
使用干细胞来源模拟血脑屏障。
DOI：
10.1186/2045-8118-10-2
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发表时间：
2013-01-10
影响因子：
7.3
通讯作者：
Shusta EV
中科院分区：
文献类型：
--
作者：
Lippmann ES;Al-Ahmad A;Palecek SP;Shusta EV
血脑屏障（BBB）是一种选择性的内皮界面，控制血流和脑间质空间之间的运输。在发育过程中，血脑屏障的产生是由于未成熟内皮细胞与神经祖细胞、神经元、放射状胶质细胞和周细胞之间复杂的多细胞相互作用的结果。随着大脑的发育，星形胶质细胞和周细胞进一步促进BBB诱导和BBB表型的维持。由于BBB的发展，维持和疾病状态在体内研究是困难和耗时的，研究人员经常利用体外模型进行简化的分析和更高的通量。体外形式还提供了一个筛选脑穿透疗法的平台。然而，来自成人组织，特别是人类来源的BBB模型受到有限的细胞可用性和模型保真度的阻碍。此外，BBB内皮如果不是不可能的话，也是非常难以从胚胎动物或人脑中分离的，限制了体外模拟BBB发育的能力。为了解决其中的一些缺点，干细胞研究的进展最近被用来提高我们对BBB发育和功能的理解。干细胞，这是由它们的自我更新扩展的能力定义，可以诱导形成各种体细胞类型，原则上可能是非常有吸引力的BBB建模应用。在这篇综述中，我们将描述如何神经祖细胞（NPC），在体外神经元，星形胶质细胞和少突胶质细胞的前体细胞，可用于研究血脑屏障诱导。接下来，我们将详细介绍这些相同的NPC如何分化为更成熟的神经元和星形胶质细胞群体，并描述它们在成人BBB共培养建模中的用途。最后，我们将描述我们最近在将人多能干细胞（hPSC）分化为具有强大BBB特征的内皮细胞方面所做的努力，并详细说明这些细胞最终如何用于研究BBB的发育和维持，模拟神经系统疾病和筛选神经药物。
The blood–brain barrier (BBB) is a selective endothelial interface that controls trafficking between the bloodstream and brain interstitial space. During development, the BBB arises as a result of complex multicellular interactions between immature endothelial cells and neural progenitors, neurons, radial glia, and pericytes. As the brain develops, astrocytes and pericytes further contribute to BBB induction and maintenance of the BBB phenotype. Because BBB development, maintenance, and disease states are difficult and time-consuming to study in vivo, researchers often utilize in vitro models for simplified analyses and higher throughput. The in vitro format also provides a platform for screening brain-penetrating therapeutics. However, BBB models derived from adult tissue, especially human sources, have been hampered by limited cell availability and model fidelity. Furthermore, BBB endothelium is very difficult if not impossible to isolate from embryonic animal or human brain, restricting capabilities to model BBB development in vitro. In an effort to address some of these shortcomings, advances in stem cell research have recently been leveraged for improving our understanding of BBB development and function. Stem cells, which are defined by their capacity to expand by self-renewal, can be coaxed to form various somatic cell types and could in principle be very attractive for BBB modeling applications. In this review, we will describe how neural progenitor cells (NPCs), the in vitro precursors to neurons, astrocytes, and oligodendrocytes, can be used to study BBB induction. Next, we will detail how these same NPCs can be differentiated to more mature populations of neurons and astrocytes and profile their use in co-culture modeling of the adult BBB. Finally, we will describe our recent efforts in differentiating human pluripotent stem cells (hPSCs) to endothelial cells with robust BBB characteristics and detail how these cells could ultimately be used to study BBB development and maintenance, to model neurological disease, and to screen neuropharmaceuticals.