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Transcriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation

Li Z, Lui KN, Lau ST, Lai FP, Li P, Chung PH, Wong KK, Tam PK, Garica-Barcelo MM, Hui CC, Sham PC, Ngan ES
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.
Not Epub
Organism or Cell Type: 
cell culture: Hirschsprung disease enteric neural crest cells (HSCR-ENCC) from iPSCs
Delivery Method: 
Endo-Porter PEG