Development of Patient-Specific Neurons in Schizophrenia Using Induced Pluripotent Stem Cells

Abstract

Induced pluripotent stem cell (iPSC) technology has the potential to transform regenerative medicine. It also offers a powerful tool for establishing in vitro models of disease, in particular, for neuropsychiatric disorders where live human neurons are essentially impossible to procure. Using iPSCs derived from three schizophrenia (SZ) patients, one of whom has 22q11.2del (velocardiofacial syndrome; VCFS), the authors developed a culture system to study SZ on a molecular and cellular level. SZ iPSCs were differentiated into functional, primarily glutamatergic neurons that were able to fire action potentials after ∼8 weeks in culture. Early differentiating neurons expressed a number of transcription factors/chromatin remodeling proteins and synaptic proteins relevant to SZ pathogenesis, including ZNF804A, RELN, CNTNAP2, CTNNA2, SMARCA2, and NRXN1. Although a small number of lines were developed in this preliminary study, the SZ line containing 22q11.2del showed a significant delay in the reduction of endogenous OCT4 and NANOG expression that normally occurs during differentiation. Constitutive expression of OCT4 has been observed in Dgcr8-deficient mouse embryonic stem cells (mESCs); DGCR8 maps to the 22q11.2-deleted region. These findings demonstrate that the method of inducing neural differentiation employed is useful for disease modeling in SZ and that the transition of iPSCs with 22q11.2 deletions towards a differentiated state may be marked by subtle changes in expression of pluripotency-associated genes.

Neural stem cells: mechanisms and modeling

“…The molecular and cellular mechanisms underlying the pathogenesis of SCZD remain unknown, largely because animal models are limited for the study of SCZD. Strikingly, fibroblasts of SCZD patients carrying mutations in DISC1 or other relevant genes have been recently successfully reprogrammed into iPSCs (Brennand et al, 2011;Chiang et al, 2011;Pedrosa et al, 2011). Brennand et al succeeded in recapitulating the phenotypes of SCZD, which were previously revealed by animal studies, in neurons derived from SCZD iPSCs, thus providing a shining example for the iPSC study of polygenic diseases.…”

Will Brain Cells Derived From Induced Pluripotent Stem Cells or Directly Converted From Somatic Cells (iNs) Be Useful for Schizophrenia Research?

“…Pedrosa et al 13 identified differences in gene expression in undifferentiated iPSCs, and in day 10 and day 32 derived neurons in both cases and controls. CNVs may also be introduced with increasing passage number.…”

“…17 iPSCs have also been established from a schizophrenia patient with a 22q11.2 deletion, a rare deletion of moderately large effect. 13 …”

“…Work is already underway on schizophrenia cases with the 22q11.2 deletion. 13 The use of age and sex-matched controls (22q11.2 cases without schizophrenia) would be preferable, but these constitute a very limited resource and may develop schizophrenia in the future. Genetic rescue, 8,22 however, would constitute a suitable control.…”

The potential of induced pluripotent stem cells in models of neurological disorders: implications on future therapy

“…By comparison, disease-specific iPSCs provide new prospects for disease-related R&D by enabling screening for genes and disease processes potentially modifiable by drugs identified through in vitro screening. Consequently, iPSCs have been successfully derived from patients with NDv disorders including schizophrenia [3][4][5][6][7][8][9][10][11], Down's syndrome [12][13][14][15][16][17][18][19][20][21], autism spectrum disorders (ASDs) including fragile X, Rett and Timothy syndromes [22][23][24][25][26][27][28][29][30][31][32][33][34][35], and epilepsy [36][37][38][39], as well as NDg disorders such as Alzheimer's disease [40][41][42][43][44][45][46][47][48], Parkinson's disease [49][50][51][52]…”