<br>肠道类器官发育中的自组织和对称性破坏,Nature

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肠道类器官发育中的自组织和对称性破坏
Nature ( IF 50.5 ) Pub Date : 2019-04-24 , DOI: 10.1038/s41586-019-1146-y
Denise Serra _{1,

2} , Urs Mayr _{1,

2} , Andrea Boni _{1,

3} , Ilya Lukonin _{1,

2} , Markus Rempfler ₁ , Ludivine Challet Meylan ₁ , Michael B Stadler _{1,

4} , Petr Strnad _{1,

3} , Panagiotis Papasaikas _{1,

4} , Dario Vischi ₁ , Annick Waldt ₅ , Guglielmo Roma ₅ , Prisca Liberali _{1,

2}

Affiliation

肠类器官是复杂的三维结构，通过概括源自单个肠干细胞的细胞群的自组织能力来模拟肠道的细胞类型组成和组织组织。这个过程中至关重要的是第一个对称性破坏事件，其中对称球体中只有一小部分相同的细胞分化为潘氏细胞，潘氏细胞产生干细胞生态位并导致隐窝和绒毛等不对称结构。在这里，我们结合单细胞定量基因组和成像方法来表征单细胞肠道类器官的发育。我们证明它们的发育遵循由转录调节因子 YAP1 瞬时激活驱动的再生过程。 YAP1 的细胞间变异出现在对称球体中，启动 Notch 和 DLL1 激活，并驱动对称性破坏事件和第一个潘氏细胞的形成。我们的研究结果揭示了暴露在均匀的生长促进环境中的单细胞如何具有产生紧急自组织行为的内在能力，从而导致复杂的多细胞不对称结构的形成。基于单细胞的成像和测序方法用于表征类器官发育和肠道再生过程，这是由 YAP1 瞬时激活驱动的。

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Self-organization and symmetry breaking in intestinal organoid development

Intestinal organoids are complex three-dimensional structures that mimic the cell-type composition and tissue organization of the intestine by recapitulating the self-organizing ability of cell populations derived from a single intestinal stem cell. Crucial in this process is a first symmetry-breaking event, in which only a fraction of identical cells in a symmetrical sphere differentiate into Paneth cells, which generate the stem-cell niche and lead to asymmetric structures such as the crypts and villi. Here we combine single-cell quantitative genomic and imaging approaches to characterize the development of intestinal organoids from single cells. We show that their development follows a regeneration process that is driven by transient activation of the transcriptional regulator YAP1. Cell-to-cell variability in YAP1, emerging in symmetrical spheres, initiates Notch and DLL1 activation, and drives the symmetry-breaking event and formation of the first Paneth cell. Our findings reveal how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behaviour that results in the formation of complex multicellular asymmetric structures.Single-cell-based imaging and sequencing approaches are used to characterize organoid development and the intestinal regeneration process, which is driven by transient activation of YAP1.

更新日期：2019-04-24

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