Cell Aggregation Culture Induces Functional Differentiation of Induced Hepatocyte-like Cells through Activation of Hippo Signaling
Cell Aggregation Culture Induces Functional Differentiation of Induced Hepatocyte-like Cells through Activation of Hippo Signaling
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DOI：
10.1016/j.celrep.2018.09.010
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发表时间：
2018-10-02
期刊：
影响因子：
8.8
通讯作者：
Suzuki, Atsushi
中科院分区：
文献类型：
--
作者：
Yamamoto, Junpei;Udono, Miyako;Suzuki, Atsushi
直接谱系重编程的最新进展已经使得诱导的肝细胞样（iHep）细胞的产生成为可能，并揭示了它们作为肝细胞的替代物用于医学应用的潜力。然而，与原代肝细胞相比，iHep细胞的肝功能不足。在这里，我们表明，细胞聚集体的形成可以迅速诱导生长停滞和肝成熟的iHep细胞通过激活Hippo信号。在iHep细胞聚集体形成过程中，肌动蛋白重组和细胞间粘附诱导雅普失活，导致在不存在雅普/Tead/Chd 4转录阻遏物单位的情况下Hnf 1 α表达上调。然后，Hnf 1 α作为中心转录因子，调节iHep细胞聚集体中肝脏富集的基因表达，并诱导iHep细胞的功能分化。此外，iHep细胞聚集体在移植后有效地重建受损的肝组织并支持肝功能。因此，iHep细胞聚集体可以为肝病的基础研究和潜在疗法提供见解。
Recent progress in direct lineage reprogramming has enabled the generation of induced hepatocyte-like (iHep) cells and revealed their potential as an alternative to hepatocytes for medical applications. However, the hepatic functions of iHep cells are insufficient compared with those of primary hepatocytes. Here, we show that cell-aggregate formation can rapidly induce growth arrest and hepatic maturation of iHep cells through activation of Hippo signaling. During formation of iHep cell aggregates, Yap inactivation is induced by actin reorganization and intercellular adhesion, leading to upregulation of Hnf1 alpha expression in the absence of the Yap/Tead/Chd4 transcriptional repressor unit. Hnf1 alpha then acts as a central transcription factor that regulates liver-enriched gene expression in iHep cell aggregates and induces functional differentiation of iHep cells. Moreover, iHep cell aggregates efficiently reconstitute injured liver tissues and support hepatic function after transplantation. Thus, iHep cell aggregates may provide insights into basic research and potential therapies for liver diseases.