Recombinant Laminins Drive the Differentiation and Self-Organization of hESC-Derived Hepatocytes.
Recombinant Laminins Drive the Differentiation and Self-Organization of hESC-Derived Hepatocytes.
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DOI：
10.1016/j.stemcr.2015.10.016
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发表时间：
2015-12-08
影响因子：
5.9
通讯作者：
Hay DC
中科院分区：
文献类型：
--
作者：
Cameron K;Tan R;Schmidt-Heck W;Campos G;Lyall MJ;Wang Y;Lucendo-Villarin B;Szkolnicka D;Bates N;Kimber SJ;Hengstler JG;Godoy P;Forbes SJ;Hay DC
干细胞衍生的体细胞代表了基础科学和转化科学的无限资源。尽管前景光明，但仍有重大障碍需要克服。我们的重点是人类肝脏的主要细胞类型——肝细胞的产生。目前的方案产生可变的肝细胞群，这是在分化过程中使用未定义成分的产物。这是扩展和应用的一个重大障碍。为了解决这个问题，我们设计了一个明确的分化过程，使用重组层粘连蛋白底物来提供指导。我们证明有效的肝细胞规格，细胞组织，和显著改善细胞功能和表型。这在一定程度上是由于抑制了控制细胞增殖和迁移、多能干细胞自我更新、成纤维细胞和结肠规范的不利基因调控网络。我们相信这代表了一个重大的进步，使干细胞肝细胞更接近生物医学应用。我们设计了一个在规定条件下的肝细胞分化过程，肝细胞表型在两种层粘胶蛋白异构体上得到改善和稳定，层粘胶蛋白支持的分化抑制不适当的基因网络层粘胶蛋白表面递送的肝细胞与成人肝细胞更相似。在这篇文章中，Hay和同事证明，在规定条件下，用gmp级hESC细胞系产生肝细胞是可能的。重组层粘连蛋白的使用显著改善了干细胞来源的肝细胞表型，其性质更接近于原代成人肝细胞。
Stem cell-derived somatic cells represent an unlimited resource for basic and translational science. Although promising, there are significant hurdles that must be overcome. Our focus is on the generation of the major cell type of the human liver, the hepatocyte. Current protocols produce variable populations of hepatocytes that are the product of using undefined components in the differentiation process. This serves as a significant barrier to scale-up and application. To tackle this issue, we designed a defined differentiation process using recombinant laminin substrates to provide instruction. We demonstrate efficient hepatocyte specification, cell organization, and significant improvements in cell function and phenotype. This is driven in part by the suppression of unfavorable gene regulatory networks that control cell proliferation and migration, pluripotent stem cell self-renewal, and fibroblast and colon specification. We believe that this represents a significant advance, moving stem cell-based hepatocytes closer toward biomedical application. We designed a hepatocyte differentiation process under defined conditions The hepatocyte phenotype is improved and stabilized on two laminin isoforms Laminin-supported differentiation suppresses inappropriate gene networks Laminin surfaces deliver hepatocytes with greater similarity to adult hepatocytes In this article, Hay and colleagues demonstrate that hepatocyte production is possible under defined conditions with GMP-grade hESC lines. The use of recombinant laminins significantly improved the stem cell-derived hepatocyte phenotype, which was closer in nature to primary adult hepatocytes.