Carlson Morgan E, O'Connor Matthew S, Hsu Michael, Conboy Irina M
Department of Bioengineering, University of California at Berkeley, Berkeley, California.
Front Biosci. 2007 Sep 1;12:5143-56. doi: 10.2741/2554.
The Notch pathway is a signaling network essential for proper organ development in an embryo, and is indispensable for tissue regeneration in the adult. This key regulatory signaling network is evolutionarily conserved in all metazoans and is continually utilized for the building, maintenance and repair of diverse organs and tissues. Importantly, dysfunctions in the Notch pathway have been demonstrated to result in oncogenic transformation, such as in lymphoid cancers, and have been linked to the pathogenesis of several inherited human diseases. Therefore, the ability to regulate Notch signaling intensity both positively and negatively has a very high therapeutic relevance. Adapting this pathway for tissue engineering applications has great potential to spear-head the development of smart biomaterials to deliberately control cell-fate decisions and lead to designer ex vivo morphogenesis. This review describes the components of Notch-specific signal transduction, presents the role of the Notch signaling network in constructing and repairing multiple organ systems, summarizes the Notch-related pathologies, outlines current advances in the deliberate modulation of the Notch pathway in bioengineering applications, and introduces future perspectives on the use of Notch pathway manipulations as a powerful universal tool in tissue engineering and in the orchestration of stem cell responses. This review also summarizes the existing bioengineering methods most suitable for the deliberate manipulation of Notch signaling, such as smart biomaterials able to pattern Notch ligands or to create gradients of Notch agonists and antagonists. Such methods will likely facilitate the engineering and dynamic remodeling of tissues composed of stem, progenitor and differentiated cells derived from an initially equivalent cell population.
Notch信号通路是胚胎期器官正常发育所必需的信号网络，对成体组织再生也不可或缺。这一关键的调控信号网络在所有后生动物中都具有进化保守性，并且持续用于各种器官和组织的构建、维持及修复。重要的是，已证实Notch信号通路功能失调会导致致癌转化，如在淋巴癌中，并且与几种人类遗传性疾病的发病机制有关。因此，正向和负向调节Notch信号强度的能力具有很高的治疗相关性。将该通路应用于组织工程领域，对于率先开发智能生物材料以刻意控制细胞命运决定并实现体外设计形态发生具有巨大潜力。本综述描述了Notch特异性信号转导的组成部分，介绍了Notch信号网络在构建和修复多个器官系统中的作用，总结了与Notch相关的病理学，概述了生物工程应用中对Notch通路进行刻意调控的当前进展，并介绍了将Notch通路操作作为组织工程及调控干细胞反应的强大通用工具的未来前景。本综述还总结了最适合刻意调控Notch信号的现有生物工程方法，如能够对Notch配体进行图案化或产生Notch激动剂和拮抗剂梯度的智能生物材料。这些方法可能会促进由最初等同的细胞群体衍生而来的干细胞、祖细胞和分化细胞所组成组织的工程化和动态重塑。
