Gladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
J Cell Sci. 2012 Dec 1;125(Pt 23):5609-20. doi: 10.1242/jcs.096032.
Despite the great potential of stem cells for basic research and clinical applications, obstacles - such as their scarce availability and difficulty in controlling their fate - need to be addressed to fully realize their potential. Recent achievements of cellular reprogramming have enabled the generation of induced pluripotent stem cells (iPSCs) or other lineage-committed cells from more accessible and abundant somatic cell types by defined genetic factors. However, serious concerns remain about the efficiency and safety of current genetic approaches to cell reprogramming and traditional culture systems that are used for stem cell maintenance. As a complementary approach, small molecules that target specific signaling pathways, epigenetic processes and other cellular processes offer powerful tools for manipulating cell fate to a desired outcome. A growing number of small molecules have been identified to maintain the self-renewal potential of stem cells, to induce lineage differentiation and to facilitate reprogramming by increasing the efficiency of reprogramming or by replacing genetic reprogramming factors. Furthermore, mechanistic investigations of the effects of these chemicals also provide new biological insights. Here, we examine recent achievements in the maintenance of stem cells, including pluripotent and lineage-specific stem cells, and in the control of cell fate conversions, including iPSC reprogramming, conversion of primed to naïve pluripotency, and transdifferentiation, with an emphasis on manipulation with small molecules.
尽管干细胞在基础研究和临床应用方面具有巨大的潜力，但仍存在一些障碍，如来源稀少和难以控制其命运等，需要加以解决才能充分发挥其潜力。细胞重编程的最新进展使得人们能够通过特定的遗传因子，从更容易获得且更为丰富的体细胞核细胞类型中产生诱导多能干细胞（iPSCs）或其他定向分化的细胞。然而，目前的遗传方法和传统的细胞培养系统在细胞重编程的效率和安全性方面仍存在严重问题，这些系统被用于维持干细胞。作为一种互补方法，靶向特定信号通路、表观遗传过程和其他细胞过程的小分子为操纵细胞命运以达到预期结果提供了有力工具。越来越多的小分子被鉴定出来，可以维持干细胞的自我更新能力，诱导谱系分化，并通过提高重编程效率或取代遗传重编程因子来促进重编程。此外，对这些化学物质作用机制的研究也提供了新的生物学见解。在这里，我们研究了小分子在维持干细胞（包括多能干细胞和谱系特异性干细胞）和控制细胞命运转变（包括 iPSC 重编程、初始态多能性向 naive 多能性的转变以及转分化）方面的最新进展，重点介绍了小分子的操纵作用。
