Synthetic Molecules that Protect Cells from Anoikis and Their Use in Cell Transplantation
Synthetic Molecules that Protect Cells from Anoikis and Their Use in Cell Transplantation
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DOI：
10.1002/anie.201405829
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发表时间：
2014-10-13
影响因子：
16.6
通讯作者：
Uesugi, Motonari
中科院分区：
文献类型：
--
作者：
Frisco-Cabanos, Heidie L.;Watanabe, Mizuki;Uesugi, Motonari
细胞移植中遇到的主要问题之一是由于移植诱导的细胞凋亡（称为失巢凋亡）导致的移植细胞的低水平存活。本研究报告的化学合成和生物学评价的水溶性分子，保护悬浮细胞从失巢凋亡。合成分子结合并诱导整联蛋白和硫酸乙酰肝素结合的多配体蛋白聚糖簇，这两类受体对细胞外基质介导的细胞存活很重要。分子生物学分析表明，这样的分子延长悬浮的NIH 3 T3细胞的存活，至少部分地，通过促进细胞表面上的多配体蛋白聚糖-4和整联蛋白1的聚集，导致小的GTd-Rac-1和Akt的活化。使用动物疾病模型的体内实验证明了分子改善细胞移植的能力。簇诱导分子可以为设计用于基于细胞的治疗的新合成工具提供起点。
One of the major problems encountered in cell transplantation is the low level of survival of transplanted cells due to detachment-induced apoptosis, called anoikis. The present study reports on the chemical synthesis and biological evaluation of water-soluble molecules that protect suspended cells from anoikis. The synthetic molecules bind to and induce clusters of integrins and heparan-sulfate-bound syndecans, two classes of receptors that are important for extracellular matrix-mediated cell survival. Molecular biological analysis indicates that such molecules prolong the survival of suspended NIH3T3 cells, at least in part, by promoting clustering of syndecan-4 and integrin 1 on the cell surface, leading to the activation of small GTPase Rac-1 and Akt. Invivo experiments using animal disease models demonstrated the ability of the molecules to improve cell engraftment. The cluster-inducing molecules may provide a starting point for the design of new synthetic tools for cell-based therapy.