Delineating cooperative effects of Notch and biomechanical signals on patterned liver differentiation.
Delineating cooperative effects of Notch and biomechanical signals on patterned liver differentiation.
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描述Notch和生物力学信号对模式化肝分化的协同作用。
DOI：
10.1038/s42003-022-03840-9
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发表时间：
2022-10-07
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
已使用具有限定的生物物理微环境的受控体外多细胞培养系统来阐明Notch信号传导在干细胞和祖细胞分化的时空调节中的作用。此外，结合Notch配体-受体相互作用特征的计算模型为Notch途径信号传导动力学提供了重要的见解。然而，Notch介导的细胞间信号传导和合作微环境线索之间的机制关系尚不清楚。在此，肝祖细胞分化模式被用作模型以系统地评估细胞力学和Notch信号传导的复杂相互作用，沿着鉴定指导祖细胞命运的组合机制。我们提出了一个综合的方法，对细胞微阵列平台内提供的定义的微尺度培养配置的计算细胞间信号模型。具体而言，基于细胞微阵列的实验用于验证和优化细胞间Notch信号传导模型的参数。该模型结合了实验建立的细胞微阵列结构域的多细胞尺寸、机械应力相关的活化参数以及基于Notch配体Jagged-1和Delta-like-1的作用的不同Notch受体-配体相互作用。总的来说，这些研究证明了机械转导相关成分，关键生长因子和Notch信号相互作用的空间控制，并指向E-钙粘蛋白在将细胞间机械梯度翻译为下游Notch信号中的可能作用。整合细胞微阵列，肝祖细胞分化模式的实验和计算数据，Notch信号和细胞力学之间的相互作用进行评估。
Controlled in vitro multicellular culture systems with defined biophysical microenvironment have been used to elucidate the role of Notch signaling in the spatiotemporal regulation of stem and progenitor cell differentiation. In addition, computational models incorporating features of Notch ligand-receptor interactions have provided important insights into Notch pathway signaling dynamics. However, the mechanistic relationship between Notch-mediated intercellular signaling and cooperative microenvironmental cues is less clear. Here, liver progenitor cell differentiation patterning was used as a model to systematically evaluate the complex interplay of cellular mechanics and Notch signaling along with identifying combinatorial mechanisms guiding progenitor fate. We present an integrated approach that pairs a computational intercellular signaling model with defined microscale culture configurations provided within a cell microarray platform. Specifically, the cell microarray-based experiments were used to validate and optimize parameters of the intercellular Notch signaling model. This model incorporated the experimentally established multicellular dimensions of the cellular microarray domains, mechanical stress-related activation parameters, and distinct Notch receptor-ligand interactions based on the roles of the Notch ligands Jagged-1 and Delta-like-1. Overall, these studies demonstrate the spatial control of mechanotransduction-associated components, key growth factor and Notch signaling interactions, and point towards a possible role of E-Cadherin in translating intercellular mechanical gradients to downstream Notch signaling. Integrating cellular microarrays, experimental and computational data for liver progenitor cell differentiation patterning, the interplay between Notch signaling and cellular mechanics is assessed.
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影响因子：
16.8
作者：
Bangru S;Arif W;Seimetz J;Bhate A;Chen J;Rashan EH;Carstens RP;Anakk S;Kalsotra A
通讯作者：
Kalsotra A
影响因子：
4.3
作者：
Agrawal S;Archer C;Schaffer DV
通讯作者：
Schaffer DV
影响因子：
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作者：
Buske, Peter;Przybilla, Jens;Galle, Joerg
通讯作者：
Galle, Joerg
影响因子：
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作者：
Brafman, David A.;Chien, Shu;Willert, Karl
通讯作者：
Willert, Karl
机械变构：Notch蛋白水解激活中力需求的证据。
影响因子：
11.8
作者：
Gordon, Wendy R.;Zimmerman, Brandon;He, Li;Miles, Laura J.;Huang, Jiuhong;Tiyanont, Kittichoat;McArthur, Debbie G.;Aster, Jon C.;Perrimon, Norbert;Loparo, Joseph J.;Blacklow, Stephen C.
通讯作者：
Blacklow, Stephen C.