Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells.
Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells.
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DOI：
10.1016/j.stemcr.2021.09.004
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发表时间：
2021-11-09
影响因子：
5.9
通讯作者：
Gadue P
中科院分区：
文献类型：
--
作者：
Mukherjee S;French DL;Gadue P
Tbx 3已被确定为小鼠肝脏发育的调节因子，但其在人类肝脏发育中的功能仍然未知。使用CRISPR/Cas9基因组编辑产生TBX 3突变体人多能干细胞（PSC）系。在肝细胞分化过程中，TBX 3缺失导致肝脏分化受损和胰腺基因表达上调，包括PDX 1。其他胰腺基因，包括NEUROG 3和NKX2.2，在TBX 3突变肝母细胞中显示出更开放的染色质。使用胰腺分化方案，缺乏TBX 3的细胞产生更多的胰腺祖细胞，并且以肝脏基因表达为代价具有增强的胰腺基因表达特征。这些数据突出了TBX 3在前肠模式化过程中调节肝脏和胰腺结构域的潜在作用，其意义在于增强从PSC产生胰腺祖细胞。TBX 3缺失型PSC具有受损的肝细胞分化能力TBX 3缺失型肝细胞具有胰腺基因的异常表达，包括PDX 1 TBX 3缺失型PSC具有增强的分化为胰腺祖细胞的能力TBX 3缺失导致许多胰腺基因的染色质可及性增加Mukherjee et al.描述了TBX 3在前肠发育过程中对肝与胰腺结构域形成模式的潜在作用。使用肝细胞分化方案的TBX 3无效PSC的分化显示受损的肝细胞基因表达和胰腺基因如PDX 1的上调表达和染色质可及性。使用胰腺分化方案，TBX 3无效PSC在胰腺祖细胞生成中具有增加的效率。
Tbx3 has been identified as a regulator of liver development in the mouse, but its function in human liver development remains unknown. TBX3 mutant human pluripotent stem cell (PSC) lines were generated using CRISPR/Cas9 genome editing. TBX3 loss led to impaired liver differentiation and an upregulation of pancreatic gene expression, including PDX1, during a hepatocyte differentiation protocol. Other pancreatic genes, including NEUROG3 and NKX2.2, displayed more open chromatin in the TBX3 mutant hepatoblasts. Using a pancreatic differentiation protocol, cells lacking TBX3 generated more pancreatic progenitors and had an enhanced pancreatic gene expression signature at the expense of hepatic gene expression. These data highlight a potential role of TBX3 in regulating hepatic and pancreatic domains during foregut patterning, with implications for enhancing the generation of pancreatic progenitors from PSCs. TBX3 null PSCs have impaired hepatocyte differentiation capacity TBX3 null hepatocytes have aberrant expression of pancreatic genes, including PDX1 TBX3 null PSCs have enhanced differentiation capacity into pancreatic progenitors Loss of TBX3 leads to increased chromatin accessibility of many pancreatic genes Mukherjee et al. describe a potential role of TBX3 in patterning hepatic versus pancreatic domains during foregut development. Differentiation of TBX3 null PSCs using a hepatocyte differentiation protocol display impaired hepatocyte gene expression and upregulated expression and chromatin accessibility of pancreatic genes such as PDX1. Using a pancreatic differentiation protocol, TBX3 null PSCs have increased efficiency in pancreatic progenitor generation.
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