One of the most crucial components of regenerative medicine is the controlled differentiation of embryonic or adult stem cells into the desired cell lineage. Although most of the reported protocols of stem cell differentiation involve the use of soluble growth factors, it is increasingly evident that stem cells also undergo differentiation when cultured in the appropriate microenvironment. When cultured in decellularized tissues, for instance, stem cells can recapitulate the morphogenesis and functional specialization of differentiated cell types with speed and efficiency that often surpass the traditional growth factor-driven protocols. This suggests that the tissue microenvironment (TME) provides stem cells with a holistic “instructive niche” that harbors signals for cellular reprogramming. The translation of this into medical applications requires the decoding of these signals, but this has been hampered by the complexity of TME. This problem is often addressed by a reductionist approach, in which cells are exposed to substrates decorated with simple, empirically designed geometries, textures, and chemical compositions (“bottom-up” approach). Although these studies are invaluable in revealing the basic principles of mechanotransduction mechanisms, their physiological relevance is often uncertain. This review examines the recent progress of an alternative, “top-down” approach, in which the TME is treated as a holistic biological entity. This approach is made possible by recent advances in systems biology and fabrication technologies that enable the isolation, characterization, and reconstitution of TME. It is hoped that these new techniques will elucidate the nature of niche signals so that they can be extracted, replicated, and controlled. This review summarizes these emerging techniques and how the data they generated are changing our view on TME.

中文翻译：

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用于干细胞分化的解构、复制和工程组织微环境。

再生医学最重要的组成部分之一是胚胎或成体干细胞受控分化为所需的细胞谱系。虽然大多数报道的干细胞分化方案都涉及使用可溶性生长因子，但越来越明显的是，干细胞在适当的微环境中培养时也会发生分化。例如，当在脱细胞组织中培养时，干细胞可以以通常超过传统生长因子驱动方案的速度和效率来重现分化细胞类型的形态发生和功能特化。这表明组织微环境 (TME) 为干细胞提供了一个整体的“指导性生态位”，其中包含细胞重编程的信号。将其转化为医疗应用需要对这些信号进行解码，但这受到了 TME 复杂性的阻碍。这个问题通常通过还原论方法来解决，其中细胞暴露于装饰有简单的、经验设计的几何形状、纹理和化学成分的基板（“自下而上”方法）。尽管这些研究在揭示机械转导机制的基本原理方面非常宝贵，但它们的生理相关性往往是不确定的。本综述考察了另一种“自上而下”方法的最新进展，其中 TME 被视为一个整体的生物实体。系统生物学和制造技术的最新进展使这种方法成为可能，这些技术使 TME 的分离、表征和重建成为可能。希望这些新技术能够阐明生态位信号的本质，以便它们可以被提取、复制和控制。本综述总结了这些新兴技术以及它们生成的数据如何改变我们对 TME 的看法。