Effect of Valproic Acid on Promoting the Differentiation of Human Embryonic Stem Cells Into Cholangiocyte-Like Cells.

IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING
Shuai Deng, Xiaoyu Zhao, Ziyan Kou, Yanlun Zhu, Xuerao Zhang, Hon Fai Chan
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引用次数: 0

Abstract

Cholangiocytes form a complex 3D network of bile ducts in the liver and contribute to liver function. The damage or destruction of cholangiocytes can lead to biliary diseases, and the shortage of cholangiocytes remains an obstacle for drug development targeting biliary diseases. Valproic acid (VPA) is a potent activator of Notch signaling pathway that is essential for cholangiocyte differentiation. Here, we report a VPA-based approach for cholangiocyte differentiation of human pluripotent stem cells. VPA activated Notch2 expression and upregulated HES-1, HEY-1, and Sox9 gene expression in hESC-derived hepatoblast. After 7 days treatment, VPA promoted successful differentiation of hepatoblast into cholangiocytes expressing cholangiocyte marker genes (AE2, AQP1, CFTR) and proteins (CK19 and CK7). In addition, the differentiated cholangiocytes formed bile duct-like structures after implantation into the spleen of NOD/SCID mice. Our results suggested that VPA can promote hESC differentiation to cholangiocyte-like cells. The induced cholangiocytes may serve as a potential cell source for both in vitro modeling and regenerative therapy of cholangiopathies. The findings can also support further development of small-molecule based differentiation protocols for cholangiocyte production.

丙戊酸促进人胚胎干细胞向胆管细胞样细胞分化的作用。
胆管细胞在肝脏中形成一个复杂的三维胆管网络,并有助于肝功能。胆管细胞的损伤或破坏可导致胆道疾病,胆管细胞的缺乏仍然是针对胆道疾病的药物开发的障碍。丙戊酸(VPA)是胆管细胞分化所必需的Notch信号通路的有效激活剂。在这里,我们报告了一种基于vpa的方法用于人类多能干细胞的胆管细胞分化。VPA在hesc源性肝母细胞中激活Notch2表达,上调HES-1、HEY-1和Sox9基因表达。治疗7天后,VPA促进肝母细胞成功分化为表达胆管细胞标记基因(AE2、AQP1、CFTR)和蛋白(CK19、CK7)的胆管细胞。此外,分化的胆管细胞植入NOD/SCID小鼠脾脏后形成胆管样结构。我们的结果表明,VPA可以促进hESC向胆管细胞样细胞分化。诱导的胆管细胞可作为胆管病变体外建模和再生治疗的潜在细胞来源。这些发现还可以支持进一步开发基于小分子的胆管细胞分化方案。
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来源期刊
Stem Cells Translational Medicine
Stem Cells Translational Medicine CELL & TISSUE ENGINEERING-
CiteScore
12.90
自引率
3.30%
发文量
140
审稿时长
6-12 weeks
期刊介绍: STEM CELLS Translational Medicine is a monthly, peer-reviewed, largely online, open access journal. STEM CELLS Translational Medicine works to advance the utilization of cells for clinical therapy. By bridging stem cell molecular and biological research and helping speed translations of emerging lab discoveries into clinical trials, STEM CELLS Translational Medicine will help move applications of these critical investigations closer to accepted best patient practices and ultimately improve outcomes. The journal encourages original research articles and concise reviews describing laboratory investigations of stem cells, including their characterization and manipulation, and the translation of their clinical aspects of from the bench to patient care. STEM CELLS Translational Medicine covers all aspects of translational cell studies, including bench research, first-in-human case studies, and relevant clinical trials.
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