Probing disorders of the nervous system using reprogramming approaches

Abstract

The groundbreaking technologies of induced pluripotency and lineage conversion have generated a genuine opportunity to address fundamental aspects of the diseases that affect the nervous system. These approaches have granted us unrestricted access to the brain and spinal cord of patients and have allowed for the study of disease in the context of human cells, expressing physiological levels of proteins and under each patient's unique genetic constellation. Along with this unprecedented opportunity have come significant challenges, particularly in relation to patient variability, experimental design and data interpretation. Nevertheless, significant progress has been achieved over the past few years both in our ability to create the various neural subtypes that comprise the nervous system and in our efforts to develop cellular models of disease that recapitulate clinical findings identified in patients. In this Review, we present tables listing the various human neural cell types that can be generated and the neurological disease modeling studies that have been reported, describe the current state of the field, highlight important breakthroughs and discuss the next steps and future challenges.

Keywords: directed differentiation; disease modeling; neurologic disorder; neuronal development.

Figure 1. You can model only what you can make

A number of different human neural cells can be efficiently generated by directed differentiation (DD) from pluripotent stem cells, or by lineage conversion (LC) from somatic cell types.

Figure 2. Developing stem cell-based models of neurological disorders

Patient-specific iPSCs should be properly quality controlled for genomic integrity and pluripotent potential, while gene editing techniques allow for the generation of isogenic controls in cases where the disease-causing allele is known. Simple cell autonomous or more sophisticated multi-cellular and 3D disease models can be developed depending on the hypothesis being addressed. Neuronal maturity increases with the complexity of the cellular system, while methods for effectively aging neurons are lacking.

Figure 3. Patient stratification based on the molecular pathways that are affected

Reprogramming and stem cell-based disease modeling can be utilized to address the level of heterogeneity by defining the molecular mechanisms that lead to disease in different patients. This novel classification of patients could lead to rationally targeted clinical trials and personalized therapeutic approaches.