Generation and Use of iPSC derived Microglia to Study Neurodegenerative Diseases

Microglia play critical roles in brain development, homeostasis, and neurological disorders. Recent genetic studies have shown that polymorphisms in several microglial-enriched genes are associated with altered risk of developing Alzheimer’s disease (AD), the leading cause of age-related dementia. However, the study of human microglia has been hindered by the considerable challenges of isolating sufficient numbers of viable microglia from human brain tissue.

To address this challenge, Dr. Mathew Blurton-Jones (University of California, Irvine) and colleagues asked whether patient-derived induced pluripotent stem cells (iPSCs) could be used to produce large numbers of human microglia. Guided by prior studies of mouse microglial ontology, the group developed a two-step protocol to differentiate iPSCs first into primitive hematopoietic progenitors and then via exposure to brain-related growth factors into microglia-like cells (iMGLs). The resulting iMGLs exhibit whole-transcriptome gene expression profiles that are very similar to brain-derived human microglia. Functional assessments also demonstrate that iMGLs secrete cytokines and migrate in response to appropriate stimuli and robustly phagocytose CNS substrates. iMGLs were also used to examine the effects of beta-amyloid fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning.

To begin to examine interactions between microglia and other brain cells, Dr. Blurton-Jones’ group also transplanted iMGLs into transgenic mice and human brain organoids. Together, these findings demonstrate that iMGLs can be used to study microglial function and provide important new insight into human neurological disease.

In this webinar, Dr. Blurton-Jones will discuss the development and validation of his group's microglia differentiation approach, provide examples of the type of genetic and functional studies that can be performed using this approach, and discuss how his lab is moving forward with using iPSC-microglia to better understand the development and potential treatment of AD.

What you will learn in this webinar:
Why iPSC-derived microglia may be useful for study Alzheimer’s disease and other brain disorders.
Methods for differentiating iPSCs into microglia.
The types of functional experiments that can be performed with iPSC-microglia.
The remaining challenges and promising new approaches to study microglia in vivo.

Speaker:
Mathew Blurton-Jones
Director
UC-Irvine Alzheimer’s Disease Research Center Induced Pluripotent Stem Cell (iPSC) Core

Original Broadcast: December 5th, 2017