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论文标题：Highly efficient and expedited hepatic differentiation from human pluripotent stem cells by pure small-molecule cocktails

数字识别码：10.1186/s13287-018-0794-4

原文作者：Cong Du, Yuan Feng, Dongbo Qiu, Yan Xu, Mao Pang, Nan Cai, Andy Peng Xiang and Qi Zhang

人类诱导多能干细胞的出现为产生充足的各异的肝细胞带来了巨大希望。尽管之前已有工作通过基于病毒的转录因子和/或在分化过程中添加生长因子等技术在体外成功地从人多能干细胞产生了肝细胞，但病毒转导的安全性问题和细胞因子的高成本阻碍了其下游的应用。最近，由于具有优越的稳定性、安全性、细胞渗透性和成本效益，小分子的使用成为诱导细胞命运转变的一种有力工具。

在发表于Stem Cell Research & Therapy的Highly efficient and expedited hepatic differentiation from human pluripotent stem cells by pure small-molecule cocktails一文中，来自中山大学附属第三医院的Qi Zhang及其研究团队基于纯小分子鸡尾酒疗法，开发了一种新型高效的人类多能干细胞的肝细胞分化方案。这种方法依靠三步策略在短短的13天内，逐步诱导肝细胞的分化，包括定型内胚层分化、肝脏特化和肝细胞成熟。

图1. 诱导hPSC逐步分化为肝细胞的三阶段。

Cong Du et al.

分化的肝细胞样细胞在形态学上类似于基于生长因子法产生的肝细胞和原代肝细胞。这些细胞不仅在转录和蛋白水平上表达特异性肝脏标志物，还具有主要的肝功能，例如白蛋白产生、糖原储存、细胞色素P450的活性和吲哚菁绿的吸收和释放。

通过这种新颖的纯小分子鸡尾酒方法，可以实现人多能干细胞高效快速的肝细胞分化，这为体外研究人类肝脏发育的分子机制提供了一个经济有效的平台，在未来临床应用方面有巨大的潜力。

摘要：

Background

The advent of human-induced pluripotent stem cells holds great promise for producing ample individualized hepatocytes. Although previous efforts have succeeded in generating hepatocytes from human pluripotent stem cells in vitro by viral-based expression of transcription factors and/or addition of growth factors during the differentiation process, the safety issue of viral transduction and high cost of cytokines would hinder the downstream applications. Recently, the use of small molecules has emerged as a powerful tool to induce cell fate transition for their superior stability, safety, cell permeability, and cost-effectiveness.

Methods

In the present study, we established a novel efficient hepatocyte differentiation strategy of human pluripotent stem cells with pure small-molecule cocktails. This method induced hepatocyte differentiation in a stepwise manner, including definitive endoderm differentiation, hepatic specification, and hepatocyte maturation within only 13 days.

Results

The differentiated hepatic-like cells were morphologically similar to hepatocytes derived from growth factor-based methods and primary hepatocytes. These cells not only expressed specific hepatic markers at the transcriptional and protein levels, but also possessed main liver functions such as albumin production, glycogen storage, cytochrome P450 activity, and indocyanine green uptake and release.

Conclusions

Highly efficient and expedited hepatic differentiation from human pluripotent stem cells could be achieved by our present novel, pure, small-molecule cocktails strategy, which provides a cost-effective platform for in vitro studies of the molecular mechanisms of human liver development and holds significant potential for future clinical applications.

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期刊介绍:

Stem Cell Research & Therapy(https://stemcellres.biomedcentral.com/ ,4.963 -2-year Impact Factor, 5.382 -5-year Impact Factor) is the major forum for translational research into stem cell therapies. An international peer-reviewed journal, it publishes high-quality open access research articles with a special emphasis on basic, translational and clinical research into stem cell therapeutics and regenerative therapies, including animal models and clinical trials. The journal also provides reviews, viewpoints, commentaries, reports and methods.