Generation of Functional Liver Sinusoidal Endothelial Cells from Human Pluripotent Stem-Cell-Derived Venous Angioblasts
Generation of Functional Liver Sinusoidal Endothelial Cells from Human Pluripotent Stem-Cell-Derived Venous Angioblasts
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DOI：
10.1016/j.stem.2020.06.007
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发表时间：
2020-08-06
期刊：
影响因子：
23.9
通讯作者：
Keller, Gordon M.
中科院分区：
文献类型：
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作者：
Gage, Blair K.;Liu, Jeff C.;Keller, Gordon M.
肝窦内皮细胞（LSEC）形成高度专业化的微血管系统，在肝功能和疾病中发挥着关键作用。为了更好地理解这一作用，我们开发了一种策略，通过首先优化动脉和静脉成血管细胞和衍生内皮细胞群的规格，从人多能干细胞（hPSC）中产生LSEC。通过缺氧、环腺苷酸（cAMP）激动和转化生长因子β（TGF-β）抑制诱导LSEC样命运显示，静脉内皮细胞比动脉细胞对体外上调LSEC标志物和功能的反应更迅速和更强烈。在新生儿肝内移植后，静脉成血管细胞植入肝脏并产生具有清道夫功能和原代人LSEC分子特征的成熟有孔LSEC。当移植到成年小鼠的肝脏中时，成血管细胞有效地产生了成熟的LSEC，并产生了强大的因子VIII（FVIII）。用hPSC衍生的LSEC对鼠肝脏进行人源化提供了用于研究这种关键肝细胞类型的生物学的易处理的系统。
Liver sinusoidal endothelial cells (LSECs) form a highly specialized microvasculature that plays a critical role in liver function and disease. To better understand this role, we developed a strategy to generate LSECs from human pluripotent stem cells (hPSCs) by first optimizing the specification of arterial and venous angioblasts and derivative endothelial populations. Induction of a LSEC-like fate by hypoxia, cyclic AMP (cAMP) agonism, and transforming growth factor beta (TGF-beta) inhibition revealed that venous endothelial cells responded more rapidly and robustly than the arterial cells to upregulate LSEC markers and functions in vitro. Upon intrahepatic transplantation in neonates, venous angioblasts engrafted the liver and generated mature, fenestrated LSECs with scavenger functions and molecular profiles of primary human LSECs. When transplanted into the liver of adult mice, angioblasts efficiently gave rise to mature LSECs with robust factor VIII (FVIII) production. Humanization of the murine liver with hPSC-derived LSECs provides a tractable system for studying the biology of this key liver cell type.