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Generation of Functional Liver Sinusoidal Endothelial Cells from Human Pluripotent Stem-Cell-Derived Venous Angioblasts.
Cell Stem Cell ( IF 23.9 ) Pub Date : 2020-07-07 , DOI: 10.1016/j.stem.2020.06.007
Blair K Gage 1 , Jeff C Liu 2 , Brendan T Innes 3 , Sonya A MacParland 4 , Ian D McGilvray 5 , Gary D Bader 3 , Gordon M Keller 6
Affiliation  

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 β (TGF-β) 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.



中文翻译:

从人多能干细胞衍生的成血管成血管细胞生成功能性肝窦内皮细胞。

肝窦窦内皮细胞(LSEC)形成高度专门化的微脉管系统,在肝功能和疾病中起关键作用。为了更好地理解这一作用,我们制定了一种策略,首先优化动脉和静脉血管母细胞和衍生内皮细胞的规格,从而从人多能干细胞(hPSC)生成LSEC。缺氧,环状AMP(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反应更快,更强壮,在体外上调LSEC标记和功能。新生儿进行肝内移植后,静脉成血管细胞移植到肝脏中,并生成具有清除功能和主要人类LSEC分子特征的成熟,有窗孔的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VIII因子(FVIII)。用hPSC衍生的LSEC对鼠肝进行人源化,为研究这种关键肝细胞类型的生物学特性提供了一个易于处理的系统。

更新日期:2020-08-06
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