Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China.
Nat Commun. 2023 Apr 15;14(1):2157. doi: 10.1038/s41467-023-37928-5.
Hirschsprung disease is characterized by the absence of enteric neurons caused by the defects of enteric neural crest cells, leading to intestinal obstruction. Here, using induced pluripotent stem cell-based models of Hirschsprung and single-cell transcriptomic analysis, we identify a gene set of 118 genes commonly dysregulated in all patient enteric neural crest cells, and suggest HDAC1 may be a key regulator of these genes. Furthermore, upregulation of RNA splicing mediators and enhanced alternative splicing events are associated with severe form of Hirschsprung. In particular, the higher inclusion rate of exon 9 in PTBP1 and the perturbed expression of a PTBP1-target, PKM, are significantly enriched in these patient cells, and associated with the defective oxidative phosphorylation and impaired neurogenesis. Hedgehog-induced oxidative phosphorylation significantly enhances the survival and differentiation capacity of patient cells. In sum, we define various factors associated with Hirschsprung pathogenesis and demonstrate the implications of oxidative phosphorylation in enteric neural crest development and HSCR pathogenesis.
先天性巨结肠症的特征是肠神经嵴细胞缺陷导致肠神经元缺失，从而引发肠梗阻。在这里，我们使用基于诱导多能干细胞的先天性巨结肠症模型和单细胞转录组分析，确定了一组在所有患者肠神经嵴细胞中普遍失调的 118 个基因，并且提示 HDAC1 可能是这些基因的关键调节因子。此外，RNA 剪接介体的上调和增强的选择性剪接事件与先天性巨结肠症的严重形式有关。特别是，PTBP1 外显子 9 的更高包含率和 PTBP1 靶标 PKM 的表达失调在这些患者细胞中显著富集，并与氧化磷酸化功能缺陷和神经发生受损有关。 Hedgehog 诱导的氧化磷酸化显著增强了患者细胞的存活和分化能力。总之，我们定义了与先天性巨结肠症发病机制相关的各种因素，并证明了氧化磷酸化在肠神经嵴发育和先天性巨结肠症发病机制中的意义。
