Modeling neurological diseases using iPSC-derived neural cells : iPSC modeling of neurological diseases

Abstract

Developing efficient models for neurological diseases enables us to uncover disease mechanisms and develop therapeutic strategies to treat them. Discovery of reprogramming somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the way of modeling human diseases, especially neurological diseases. Currently almost all types of neural cells, including but not limited to neural stem cells, neurons, astrocytes, oligodendrocytes and microglia, can be derived from iPSCs following developmental principles. These iPSC-derived neural cells provide valuable tools for studying neurological disease mechanisms, developing potential therapies, and deepening our understanding of the nervous system.

Keywords: Disease modeling; Neurological diseases; iPSC.

Fig 1. A schematic for iPSC modeling of neurological diseases

The logical path of modeling neurological diseases using patient-derived iPSCs mainly includes the following steps. First, iPSCs are generated from patients by reprogramming somatic cells using 4 Yamanaka factors, OCT4, SOX2, KLF4, and MYC. Isogenic iPSCs can be produced through gene editing technology, such as CRISPR/Cas9. iPSCs, including isogenic iPSCs, will be induced to neural cell type(s) of interest, for example, neurons. These iPSC-derived neural cells can be applied to disease-relevant phenotypes studies. Drugs can be developed to target specific phenotype identified in the previous step for disease therapy.

Fig 2. A schematic for neural cell differentiation from iPSCs

iPSCs can be induced to neural progenitor cells (NPCs) that possess multipotentcy to multiple neural lineages. With additional induction, NPCs can give rise to neurons, astrocytes and oligodendrocytes. Microglia can be induced from myeloid progenitors generated from iPSCs. Each neural cell type can be used to model relevant neurological diseases.