Presenilin-1 controls the growth and differentiation of endothelial progenitor cells through its β-catenin-binding region
Presenilin-1 controls the growth and differentiation of endothelial progenitor cells through its β-catenin-binding region
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DOI：
10.1016/j.cellbi.2005.11.003
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发表时间：
2006-03-01
影响因子：
3.9
通讯作者：
Furukawa, K
中科院分区：
文献类型：
--
作者：
Nakajima, M;Ogawa, M;Furukawa, K
早老素-1（PS1）是一个基因，负责早发性家族性阿尔茨海默病的发展。在小鼠中靶向破坏PS1基因表明PSI可能参与血管生成。我们利用体外胚胎干细胞培养系统制备了PS1缺失的内皮祖细胞，并研究了PS1在内皮细胞谱系中的作用。利用该系统，从PS1缺陷的ES细胞产生Flk-1（+）E-cadherin（-）EPC，并且缺乏PS1的EPC以及野生型EPC生长以形成由OP 9基质细胞层支持的VE-钙粘蛋白（+）内皮集落。虽然PS1缺陷型EPC的内皮细胞集落显示出与野生型EPC相似的形态，但PS1缺陷型EPC与野生型EPC相比形成了大量的集落。增强的集落形成能力的PS1缺陷的EPC减弱野生型人PS1的诱导。为了区分PS 1的多种活性的集落形成能力，我们使用了两种类型的人PS 1突变体：一种（hPS 1D 257 A）在残基257处具有天冬氨酸至丙氨酸突变，其损害PS 1的蛋白水解活性，另一种（hPS 1Delta cat）缺失β-连环蛋白结合所必需的胞质环序列的氨基酸340-371。hPS 1D 257 A显示出调节PS1缺陷型EPC的集落形成能力的活性，而hPS 1Delta cat没有显示出这种活性。这些结果表明，PS1通过β-catenin结合区调控内皮祖细胞的生长和分化，内皮细胞系中PS1功能的缺陷可能导致血管病变的发生。(C)2005年国际细胞生物学联合会。由爱思唯尔有限公司出版。保留所有权利。
Presenilin-1 (PS1) is a gene responsible for the development of early-onset familial Alzheimer's disease. Targeted disruption of the PS1 gene in mice suggested that PSI might be involved in angiogenesis. We have used an in vitro embryonic stem (ES) cell culture system to prepare endothelial progenitor cells (EPC) lacking PS1 and investigated the roles of PSI in endothelial cell lineage. With this system, Flk-1(+) E-cadherin(-) EPC were generated from PS1-deficient ES cells, and the EPC lacking PS1 as well as wild-type EPC grew to form VE-cadherin(+) endothelial colonies supported by a layer of OP9 stromal cells. Although the endothelial colonies from PS1-deficient EPC showed morphology similar to those from wild-type EPC, the PS1-deficient EPC formed a large number of the colonies compared to wild-type EPC. The enhanced colony-forming ability of PS1-deficient EPC was attenuated by the inductions of wild-type human PS1. To differentiate multiple activities of PS1 for colony-forming ability, we used two types of human PS1 mutants: one (hPS1D257A) with the aspartate to alanine Mutation at residue 257 that impairs the proteolytic activity of PS1, and the other (hPS1 Delta cat) deleting amino acids 340-371 of the cytosolic loop sequence essential for beta-catenin binding. hPS1D257A showed activity to regulate the colony-forming ability of PS1-deficient EPC, while hPS1 Delta cat failed to exhibit this activity. These results suggest that PS1 regulates the growth and differentiation of endothelial progenitor cells through its beta-catenin-binding, region and that the defect of PS1 function in endothelial cell lineage Could contribute to the induction of vascular pathology. (C) 2005 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.