Concise Review: Modeling Central Nervous System Diseases Using Induced Pluripotent Stem Cells

Abstract

Induced pluripotent stem cells (iPSCs) offer an opportunity to delve into the mechanisms underlying development while also affording the potential to take advantage of a number of naturally occurring mutations that contribute to either disease susceptibility or resistance. Just as with any new field, several models of screening are being explored, and innovators are working on the most efficient methods to overcome the inherent limitations of primary cell screens using iPSCs. In the present review, we provide a background regarding why iPSCs represent a paradigm shift for central nervous system (CNS) disease modeling. We describe the efforts in the field to develop more biologically relevant CNS disease models, which should provide screening assays useful for the pharmaceutical industry. We also provide some examples of successful uses for iPSC-based screens and suggest that additional development could revolutionize the field of drug discovery. The development and implementation of these advanced iPSC-based screens will create a more efficient disease-specific process underpinned by the biological mechanism in a patient-and disease-specific manner rather than by trial-and-error. Moreover, with careful and strategic planning, shared resources can be developed that will enable exponential advances in the field. This will undoubtedly lead to more sensitive and accurate screens for early diagnosis and allow the identification of patient-specific therapies, thus, paving the way to personalized medicine. STEM CELLS

Comparative neurotoxicity screening in human iPSC-derived neural stem cells, neurons and astrocytes

“…For example, iPSC can be engineered in multiple ways to investigate how genetic alterations modulate physiological and disease processes. These engineered tools can be further applied in disease pertinent cellular lineages as well as developing isogenic and reporter lines (Zeng et al, 2014; Zhu et al, 2011). Our neural lineage-specific luciferase reporters will simplify the cytotoxicity assay using neurons or astrocytes and will also allow for an evaluation of the ability of chemicals to adversely affect the differentiation process.…”

Mitochondrial Alterations by PARKIN in Dopaminergic Neurons Using PARK2 Patient-Specific and PARK2 Knockout Isogenic iPSC Lines

“…Indeed, a recent iPSC-based study showed that PARK2 controlled dopamine utilization in iPSC-derived dopaminergic neurons ( Jiang et al., 2012 ). Likewise, advances in gene targeting ( Cathomen and Joung, 2008; Urnov et al., 2010; Zeng et al., 2014 ) allow us to develop the corresponding models in an isogenic background.…”

Induced Pluripotent Stem Cells in Huntington’s Disease: Disease Modeling and the Potential for Cell-Based Therapy

“…First, iPSCs can be derived directly from skin cells of HD patients (Fig. 1), avoiding ethical concerns resulting from blastocyst destruction in the process of obtaining human ESCs [51]. Besides, iPSCs generated from individual patients would be a better source for cell replacement therapy than ESCs that would inevitably lead to immune rejection issues [52].…”