Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA.
Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA.
Nat Commun. 2017 Apr 21;8:14662. doi: 10.1038/ncomms14662.
To date, reprogramming strategies for generating cell types of interest have been facilitated by detailed understanding of relevant developmental regulatory factors. However, identification of such regulatory drivers often represents a major challenge, as specific gene combinations may be required for reprogramming. Here we show that a computational systems approach can identify cell type specification genes (master regulators) that act synergistically, and demonstrate its application for reprogramming of fibroblasts to prostate tissue. We use three such master regulators (FOXA1, NKX3.1 and androgen receptor, AR) in a primed conversion strategy starting from mouse fibroblasts, resulting in prostate tissue grafts with appropriate histological and molecular properties that respond to androgen-deprivation. Moreover, generation of reprogrammed prostate does not require traversal of a pluripotent state. Thus, we describe a general strategy by which cell types and tissues can be generated even with limited knowledge of the developmental pathways required for their specification in vivo.
迄今为止，通过对相关发育调控因子的深入了解，已经实现了用于生成感兴趣细胞类型的重编程策略。然而，此类调控驱动因子的鉴定通常是一个重大挑战，因为重编程可能需要特定的基因组合。在这里，我们展示了一种计算系统方法，可以识别协同作用的细胞类型特化基因（主调控因子），并展示了其在将成纤维细胞重编程为前列腺组织中的应用。我们使用三种这样的主调控因子（FOXA1、NKX3.1 和雄激素受体 AR），从小鼠成纤维细胞开始采用预编程转换策略，从而产生具有适当组织学和分子特性的前列腺组织移植物，并且对雄激素剥夺有反应。此外，重编程的前列腺的产生不需要经过多能状态。因此，我们描述了一种通用策略，即使对体内特化所需的发育途径的了解有限，也可以生成细胞类型和组织。
