Induced pluripotent stem cells from ALS patients for disease modeling

Abstract

The ability to reprogram adult somatic cells into pluripotent stem cells that can differentiate into all three germ layers of the developing human has fundamentally changed the landscape of biomedical research. For a neurodegenerative disease like Amyotrophic Lateral Sclerosis (ALS), which does not manifest itself until adulthood and is a heterogeneous disease with few animal models, this technology may be particularly important. Induced pluripotent stem cells (iPSC) have been created from patients with several familial forms of ALS as well as some sporadic forms of ALS. These cells have been differentiated into ALS-relevant cell subtypes including motor neurons and astrocytes, among others. ALS-relevant pathologies have also been identified in motor neurons from these cells and may provide a window into understanding disease mechanisms in vitro. Given that this is a relatively new field of research, numerous challenges remain before iPSC methodologies can fulfill their potential as tools for modeling ALS as well as providing a platform for the investigation of ALS therapeutics. This article is part of a Special Issue entitled ALS complex pathogenesis.

Keywords: Astrocyte; Human; Motor neuron; Non-cell autonomous; Stem cell; iPSC.

Figure 1. Human iPSC from ALS patients differentiate into neural cell subtypes

Fibroblasts (or other tissues) from patients with familial ALS (FALS), sporadic ALS (SALS), and controls are genetically reprogrammed to form induced pluripotent stem cells (iPSC). Cells from varying ALS genotypes and phenotypes can subsequently be differentiated into motor neurons, astrocytes, or other non-neuronal (not shown) cells for further studies of disease. Gene correction methods exist to delete mutant genes from FALS patients to create control iPSC on the same genetic background of the ALS patient—thus allowing for patient-specific controls.

Figure 2. Opportunities for using iPSC from ALS patients

Once developed iPSC-derived neural cell subtypes can be of value for a number of lines of investigation. A. The examination of subcellular aggregates and other pathologies described in human autopsy tissues can be assessed in both familial ALS as well as sporadic ALS iPSC. B. Assays to assess physiological characteristics as well as biochemical profiles of iPSC-derived neural cells may bridge genotype/phenotype correlations. C. The capacity of ALS iPSC-derived neural cells to respond to a number of cellular stress paradigms may provide insight into environmental cascades relevant to disease. D. The capability of generating multiple neural cell types allows for understanding of interplay between normal and disease cell subtypes. E. iPSC-derived neural cell culture may be amenable to high throughput screening to allow for the study of potential neuroprotective compounds.