Synthetic dynamic hydrogels promote degradation-independent in vitro organogenesis
Synthetic dynamic hydrogels promote degradation-independent in vitro organogenesis
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DOI：
10.1038/s41563-021-01136-7
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发表时间：
2021-11-15
期刊：
影响因子：
41.2
通讯作者：
Lutolf, Matthias P.
中科院分区：
文献类型：
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作者：
Chrisnandy, Antonius;Blondel, Delphine;Lutolf, Matthias P.
上皮类器官最有效地从小鼠肿瘤来源的重建细胞外基质水凝胶中生长，其不明确的组成，批次间的可变性和免疫原性限制了临床应用。在类器官培养中取代这种定义不清的基质的努力主要集中在由共价交联的亲水大分子组成的非适应性水凝胶上。然而，在这种弹性凝胶中，由组织膨胀引起的过大的力严重限制了类器官的生长和形态发生。化学或酶降解方案可以部分缓解这一问题，但由于其不可逆性，长期适用性有限。在这里，我们报告了一个合成水凝胶家族，通过可逆氢键介导的动态重排促进广泛的类器官形态发生。这些可调节的基质可以放松压力，从而通过增加对称性破坏和依赖于yes相关蛋白1的Paneth细胞形成，促进肠道干细胞上皮中有效的隐窝出芽。因此，这些定义良好的凝胶为培养复杂的体外形态发生提供了有前途的多功能基质。研究了细胞外基质应力松弛对肠道类器官形成的影响。研究表明，应力松弛的合成基质通过增加对称破坏和小生境细胞形成来促进隐窝萌发。
Epithelial organoids are most efficiently grown from mouse-tumour-derived, reconstituted extracellular matrix hydrogels, whose poorly defined composition, batch-to-batch variability and immunogenicity limit clinical applications. Efforts to replace such ill-defined matrices for organoid culture have largely focused on non-adaptable hydrogels composed of covalently crosslinked hydrophilic macromolecules. However, the excessive forces caused by tissue expansion in such elastic gels severely restrict organoid growth and morphogenesis. Chemical or enzymatic degradation schemes can partially alleviate this problem, but due to their irreversibility, long-term applicability is limited. Here we report a family of synthetic hydrogels that promote extensive organoid morphogenesis through dynamic rearrangements mediated by reversible hydrogen bonding. These tunable matrices are stress relaxing and thus promote efficient crypt budding in intestinal stem-cell epithelia through increased symmetry breaking and Paneth cell formation dependent on yes-associated protein 1. As such, these well-defined gels provide promising versatile matrices for fostering elaborate in vitro morphogenesis.The influence of stress relaxation of the extracellular matrix on the formation of intestinal organoids was investigated. It was shown that a stress-relaxing synthetic matrix promotes crypt budding through increased symmetry breaking and niche cell formation.