To develop stem cell (SC)-based models of central nervous system (CNS) diseases, it is important to focus on the roles of glia and their contributions toward disease progression. There are three main types of glial cells in the CNS: astrocytes are a ubiquitous glial subgroup that perform a wide range of functions in the CNS ranging from blood–brain barrier maintenance to synaptic support [1]. Mature oligodendrocytes (O4+) and oligodendrocyte progenitor cells (OPCs) are important for myelination of axons and signal transmission [2]. Microglia are the resident immune cells of the CNS and adopt different phenotypes based on changes in their microenvironment, providing surveillance of CNS pathologies such as damaged neurons, amyloid-β plaques, and other defects [3]. While much is known about the changes of glial functions during disease, there is still a gap in knowledge of key molecular mechanisms that result in gain or loss of function. SC-derived glia can be an important tool to study the glial interplay during CNS disease onset and allow for identification of glial targets for therapies. Human iPSCs (hiPSCs) represent a patient-derived source to model specific cellular changes attributed to CNS disease mimicking in vivo changes observed in patients 4, 5. This source can overcome the challenge of obtaining consistent human primary samples with confounding factors of age, disease stage, and time interval [4]. Thus, hiPSC technology with glial differentiation from patient cells is becoming a prevalent tool to develop personalized medicine [6]. It is important to determine ways to differentiate glial subtypes to generate SC-derived models of CNS disease progression and therapeutic screening.

As neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD), progress, the normal physiological functions, morphology, and molecular profiles of glia are altered 7, 8, 9. Changes to the CNS microenvironment activate glia to secrete inhibitory extracellular matrix (ECM) proteins and pro-inflammatory cytokines that are detrimental to axonal growth and neuronal survival 7, 8. These cues can also trigger loss of myelination that causes a decrease in signal transmission resulting in changes to brain function [9]. Understanding how glia respond or contribute to the progression of different CNS diseases is critical in providing treatment for these diseases.

Researchers have started to utilize differentiation from induced pluripotent stem cells (iPSCs) derived from patients with CNS disease and the same cells with genetic correction (or iPSCs from healthy individuals) to better model the genetic component of disease and changes to the CNS microenvironment in a quick, reproducible manner. These SC lines can be from patients with specific genetic mutations that might affect differentiated glia and their functions, allowing identification of glial roles in CNS diseases [9]. hiPSC-derived glia can help model specific pathological roles and the resulting altered functions of glia in response to disease.

Overall, iPSCs serve as an asset for the generation of the multiple glial cell types involved in various CNS diseases without the need for harvesting primary cells. These differentiated iPSC-derived cells can be used to uncover the roles of glia in the onset and progression of disease. However, it is crucial to understand the key morphogens and cues that drive differentiation from iPSCs into specific glial phenotypes, as well as how to adapt these protocols to reduce differentiation time, increase cell yield, and improve purity of the resulting cells to more efficiently model CNS disease. Understanding the mechanisms of gliogenesis during development can help to generate specific types of glia in vitro. Furthermore, proteomic and transcriptomic analyses can help characterize specific phenotypes and gene expression in SC-derived glia to choose as candidates for purification of the resulting cells, modeling certain CNS diseases, and monitoring changes during disease progression.