Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, MIT, Cambridge, Massachusetts, USA.
Nat Chem Biol. 2013 Aug;9(8):514-20. doi: 10.1038/nchembio.1270. Epub 2013 Jun 2.
Cell-based therapies hold the potential to alleviate the growing burden of liver diseases. Such therapies require human hepatocytes, which, within the stromal context of the liver, are capable of many rounds of replication. However, this ability is lost ex vivo, and human hepatocyte sourcing has limited many fields of research for decades. Here we developed a high-throughput screening platform for primary human hepatocytes to identify small molecules in two different classes that can be used to generate renewable sources of functional human hepatocytes. The first class induced functional proliferation of primary human hepatocytes in vitro. The second class enhanced hepatocyte functions and promoted the differentiation of induced pluripotent stem cell-derived hepatocytes toward a more mature phenotype than what was previously obtainable. The identification of these small molecules can help address a major challenge affecting many facets of liver research and may lead to the development of new therapeutics for liver diseases.
基于细胞的疗法有可能缓解日益增长的肝脏疾病负担。此类疗法需要人肝细胞，这些细胞在肝脏基质环境中能够进行多次复制。然而，这种能力在体外丧失了，人肝细胞的来源在几十年来限制了许多研究领域。在这里，我们开发了一种用于原代人肝细胞的高通量筛选平台，以鉴定两种不同类别的小分子，这些小分子可用于生成可再生的功能性人肝细胞来源。第一类小分子在体外诱导原代人肝细胞的功能增殖。第二类小分子增强了肝细胞的功能，并促进诱导多能干细胞衍生的肝细胞向比以前更成熟的表型分化。这些小分子的鉴定可以帮助解决影响肝脏研究多个方面的一个主要挑战，并可能导致肝脏疾病的新疗法的开发。
