Impaired migration of autologous induced neural stem cells from patients with schizophrenia and implications for genetic risk for psychosis

Junhee Lee, Sehyeon Song, Juhee Lee, Jisoo Kang, Eun Kyung Choe, Tae Young Lee, Myong Wuk Chon, Minah Kim, Seong Who Kim, Myung Suk Chun, Mi Sook Chang, Jun Soo Kwon

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Stem cell technologies have presented explicit evidence of the neurodevelopmental hypothesis of schizophrenia. However, few studies investigated relevance of the schizophrenia genetic liability and the use of genetic reprogramming on pluripotent stem cells to the impaired neurodevelopment shown by stem cells. Therefore, this study sought to investigate the cellular phenotypes of induced neural stem cells (iNSCs) derived without genetic modification from patients with schizophrenia and from genetic high risk (GHR) individuals. Three patients with a diagnosis of schizophrenia, 3 GHR individuals who had two or more relatives with schizophrenia, and 3 healthy volunteers participated. iNSCs were derived using a small molecule-based lineage switch method, and their gene expression levels and migration capabilities were examined. Demographic characteristics were not different among the groups (age, χ2 = 5.637, P = .060; education, χ2 = 2.111, P = .348). All participants stayed well during the follow-up except one GHR individual who developed psychosis 1.5 years later. Migration capacity was impaired in iNSCs from patients with schizophrenia (SZ-iNSCs) compared to iNSCs from GHR individuals or controls (P < .001). iNSCs from a GHR individual who later developed schizophrenia showed migratory impairment that was similar to SZ-iNSCs. Gene expression levels of Sox2 in SZ-iNSCs were significantly lower than those in controls (P = .028). Defective migration in genetically unmodified SZ-iNSCs is the first direct demonstration of neurodevelopmental abnormalities in schizophrenia. Additionally, alterations in gene expression in SZ-iNSCs suggest mechanisms by which genetic liability leads to aberrant neurodevelopment.

Original languageEnglish
Pages (from-to)225-234
Number of pages10
JournalSchizophrenia Research
Volume246
DOIs
StatePublished - Aug 2022
Externally publishedYes

Keywords

  • Genetic high risk
  • Neurodevelopment
  • Neuronal migration
  • Schizophrenia
  • Stem cell

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