Microglia play key roles in neurodegenerative diseases, but working with microglia obtained from human brain tissue is difficult and unfeasible in drug discovery. CAMP4 recently published a study in Scientific Reports that assessed how closely microglia from human brain tissue resembled microglia-like cells derived from induced pluripotent stem cells (iPSCs).
In this Q&A, Gokul Ramaswami, Ph.D., lead author and principal data scientist at CAMP4, describes the study, its findings, and its relevance to companies and academics in the neurodegenerative disease space.
Q: What are microglia and what are the challenges in working with them?
A: Besides being the main immune cells in the brain and central nervous system (CNS), microglia help maintain the functions of normal neurons and synapses. They are also key drivers of neuroinflammation in Alzheimer’s disease (AD) and other neurodegenerative diseases. Microglia are therefore an important focus in developing new therapies for those diseases.
The problem is that it’s hard to isolate enough microglia from human brain tissue (ex vivo microglia) to do lots of experiments; plus, once cultured in a dish, the cells rapidly lose the phenotypes they had in the brain. These challenges have led researchers to seek other sources of microglia-like cells. One source is iPSCs that have been reprogrammed into a microglia-like state – what we call iMGLs in our study.
iMGLs can be easy to generate or obtain at scale, making them promising alternatives to other sources of microglia-like cells. But before using iMGLs as disease models, it’s important to establish how well they mimic the phenotypes and functions of “the real thing.”
Q: That’s what you set out to establish in this study, right?
A: Yes. We did this by comparing detailed transcriptional profiles of ex vivo microglia and iMGLs from a commercial supplier. We chose these iMGLs because they’re readily accessible to researchers – unlike other sources of microglia-like cells, which researchers typically have to make in their own labs.
We made the comparison in two main ways: at the bulk level, by looking at the entire population of cells in the dish; and at the single-cell level, to identify “clusters” or subpopulations of cells with different functional features of microglia.
We also treated the iMGLs with two LXR pathway agonists – a class of therapeutic agents in development for AD – and compared the treatment responses we saw with previously reported data for these and other LXR agonists in cellular and animal models of AD.
Q: How well did iMGLs stack up?
A: The transcriptional profiles of iMGLs and ex vivo microglia were very similar. The iMGLs also contained 11 different clusters corresponding to a range of phenotypic and functional states of microglia, including homeostatic maintenance and immune activation. These results showed iMGLs recapitulated many of the features and processes of their ex vivo counterparts.
In iMGLs treated with the LXR agonists, we observed changes in gene expression levels across various pathways – such as lipid metabolism, inflammation, and the cell cycle – that were consistent with the role of the LXR pathway in AD and the agonists’ known mechanism of action.
Overall, we demonstrated iMGLs are a promising and tractable alternative to ex vivo microglia for anyone doing drug discovery in neurodegenerative diseases.
Q: How do you envision other researchers and companies using your findings?
A: The host of data we generated from this “deep dive” into iMGLs is a resource for companies developing therapies for CNS disorders where microglia are relevant, and academic researchers involved in cell-based neural and neurodegenerative disease research.
More broadly, our study offers a systematic approach for making comparisons between ex vivo cells and alternative sources for any cell type, such as astrocytes and cardiomyocytes, that researchers want to use in their work.
Q: Are your findings relevant to CAMP4’s platform and/or pipeline?
A: The study stemmed from a 2020 drug discovery collaboration between CAMP4 and Biogen. We’re currently in early discovery research in several neurodegenerative diseases, and this publication sets the foundation for using iMGLs as a model for testing our therapies, if and when microglia are relevant to a disease target we’re pursuing.
Find the open-access paper titled “Transcriptional characterization of iPSC-derived microglia as a model for therapeutic development in neurodegeneration” in Scientific Reports.