Modeling psychiatric disorders with patient-derived iPSCs

Abstract

Psychiatric disorders are heterogeneous disorders characterized by complex genetics, variable symptomatology, and anatomically distributed pathology, all of which present challenges for effective treatment. Current treatments are often blunt tools used to ameliorate the most severe symptoms, often at the risk of disrupting functional neural systems, thus there is a pressing need to develop rational therapeutics. Induced pluripotent stem cells (iPSCs) reprogrammed from patient somatic cells offer an unprecedented opportunity to recapitulate both normal and pathologic human tissue and organ development, and provides new approaches for understanding disease mechanisms and for drug discovery with higher predictability of their effects in humans. Here we review recent progress and challenges in using human iPSCs for modeling neuropsychiatric disorders and developing novel therapeutic strategies.

Figure 1. Diagram of disease modeling and drug development with human iPSCs

Patient specific iPSCs could be derived from skin biopsy of a patient with psychiatric disorders by ectopic co-expression of four Yamanaka factors. In cases in which the genetic mutation is known, isogenic iPSC lines, either correcting the mutation in the patient iPSCs or introducing the mutation into healthy control iPSCs, could be generated by genome editing techniques, such as CRISPR/Cas9 or TALEN. Human iPSCs could be further differentiated into the affected neuronal subtypes (for example, cortical glutamatergic neurons) for disease modeling in vitro. The identified phenotypes in patient iPSC-derived neurons could be used as readouts for high-throughput drug screening, which would facilitate the discovery of novel therapeutic compounds to treat psychiatric disorders.

Figure 2. Diagram of differentiation of neuronal subtypes and 3D organoids in vitro

Differentiation of disease-related neuronal subtypes or 3D organoids from hiPSCs have been established. By manipulating morphogen pathways such as BMP, TGFβ, WNT, SHH pathways as well as other growth factors such as FGFs, human iPSCs could be induced into brain region-specific neural progenitor cells (NPCs), including dorsal forebrain NPCs, ventral forebrain NPCs, midbrain floor plate NPCs, and hippocampal NPCs. These area-specific NPCs could be further differentiated into different neuronal subtypes for disease modeling and drug screening, including cortical glutamatergic neurons or cerebral organoids (TBR1⁺/CTIP2⁺/BRN2⁺/SATB2⁺), cortical GABAergic neurons (GABA⁺/GAD65/67⁺/VGAT⁺/SST⁺/PV⁺), midbrain DA neurons (TH⁺/NURR1⁺/PITX3⁺/DAT⁺), and hippocampal granule cells (PROX1⁺).