hPSC-derived sacral neural crest enables rescue in a severe model of Hirschsprung's disease

Yujie Fan, James Hackland, Arianna Baggiolini, Lin Y. Hung, Huiyong Zhao, Paul Zumbo, Polina Oberst, Andrew P. Minotti, Emiliano Hergenreder, Sarah Najjar, Zixing Huang, Nelly M. Cruz, Aaron Zhong, Mega Sidharta, Ting Zhou, Elisa de Stanchina, Doron Betel, Richard M. White, Michael Gershon, Kara Gross MargolisLorenz Studer

Research output: Contribution to journalArticlepeer-review


The enteric nervous system (ENS) is derived from both the vagal and sacral component of the neural crest (NC). Here, we present the derivation of sacral ENS precursors from human PSCs via timed exposure to FGF, WNT, and GDF11, which enables posterior patterning and transition from posterior trunk to sacral NC identity, respectively. Using a SOX2::H2B-tdTomato/T::H2B-GFP dual reporter hPSC line, we demonstrate that both trunk and sacral NC emerge from a double-positive neuro-mesodermal progenitor (NMP). Vagal and sacral NC precursors yield distinct neuronal subtypes and migratory behaviors in vitro and in vivo. Remarkably, xenografting of both vagal and sacral NC lineages is required to rescue a mouse model of total aganglionosis, suggesting opportunities in the treatment of severe forms of Hirschsprung's disease.

Original languageEnglish (US)
Pages (from-to)264-282.e9
JournalCell Stem Cell
Issue number3
StatePublished - Mar 2 2023


  • GDF11
  • Hirschsprung's disease
  • axial patterning
  • axial progenitors
  • cell therapy
  • directed differentiation
  • enteric nervous system
  • nervous system disorder
  • neural crest development
  • pluripotent stem cells
  • regenerative medicine
  • sacral neural crest

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology


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