The Application of Human iPSCs in Neurological Diseases: From Bench to Bedside

Abstract

In principle, induced pluripotent stem cells (iPSCs) are generated from somatic cells by reprogramming and gaining the capacity to self-renew indefinitely as well as the ability to differentiate into cells of different lineages. Human iPSCs have absolute advantages over human embryonic stem cells (ESCs) and animal models in disease modeling, drug screening, and cell replacement therapy. Since Takahashi and Yamanaka first described in 2007 that iPSCs can be generated from human adult somatic cells by retroviral transduction of the four transcription factors, Oct3/4, Sox2, Klf4, and c-Myc, disease specific iPSC lines have sprung up worldwide like bamboo shoots after a spring rain, making iPSC one of the hottest and fastest moving topics in modern science. The craze for iPSCs has spread throughout main branches of clinical medicine, covering neurology, hematology, cardiology, endocrinology, hepatology, ophthalmology, and so on. Here in this paper, we will focus on the clinical application of human iPSCs in disease modeling, drug screening, and cell replacement therapy for neurological diseases.

Figure 1

Applications of human iPSCs and iPSC derived neural cells in neurological diseases. In principle, induced pluripotent stem cells (iPSCs) are generated from somatic cells by reprogramming and gaining the capacity to self-renew indefinitely as well as the ability to differentiate into cells of different lineages. Up to date, the main applications of iPSC products in neurological diseases have included disease modeling, drug screening, and cell replacement therapy, for which the successful reprogramming of somatic cells to iPSCs is the most fundamental step. By generating human-animal chimeras, 3D culture systems, and cerebral organoids with disease specific iPSCs and iPSC derived neural cells, researchers can have various systems for disease modeling and drug screening. By inducing disease relevant cell types into wild type (WT) iPSCs, researchers and clinicians can have normal cells for cell replacement therapy. Recently, the rapid development of genome editing technology, including TALEN, ZFN, and CRISPR, makes it possible for diseases with defined genetic disorders to switch phenotype between WT and mutant at the single cell level, providing a new strategy to create syngeneic WT cells for cell replacement therapy [103]. Overall, human iPSCs have a great potential for clinical applications in neurological diseases.

Figure 2

A strategy map towards clinical grade iPSCs. Strict standards should be set to ensure the safety of cell replacement therapy using iPSC products. These standards for clinical grade iPSCs must cover but are not limited to generation of iPSCs with minimal mutation, assessment for tumorigenicity and immunogenicity, cell type and dosage selection, length of treatment window, and posttranslation monitoring, which requires the cooperation of lab researchers, clinicians, and business industry.