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

Zhixin Li, Kathy Nga-Chu Lui, Sin-Ting Lau, Frank Pui-Ling Lai, Peng Li, Patrick Ho-Yu Chung, Kenneth Kak-Yuen Wong, Paul Kwong-Hing Tam, Maria-Mercedes Garica-Barcelo, Chi-Chung Hui, Pak Chung Sham and Elly Sau-Wai Ngan ()
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Zhixin Li: The University of Hong Kong
Kathy Nga-Chu Lui: The University of Hong Kong
Sin-Ting Lau: The University of Hong Kong
Frank Pui-Ling Lai: The University of Hong Kong
Peng Li: The Seventh Affiliated Hospital of Sun Yat-sen University
Patrick Ho-Yu Chung: The University of Hong Kong
Kenneth Kak-Yuen Wong: The University of Hong Kong
Paul Kwong-Hing Tam: The University of Hong Kong
Maria-Mercedes Garica-Barcelo: The University of Hong Kong
Chi-Chung Hui: University of Toronto
Pak Chung Sham: The University of Hong Kong
Elly Sau-Wai Ngan: The University of Hong Kong

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37928-5

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