Human iPSC co-culture model to investigate the interaction between microglia and motor neurons
Björn F Vahsen1,2, Elizabeth Gray1, Ana Candalija1
1Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
Abstract:
Motor neuron diseases such as amyotrophic lateral sclerosis are primarily characterized by motor neuron degeneration with additional involvement of non-neuronal cells, in particular, microglia. In previous work, we have established protocols for the differentiation of iPSC-derived spinal motor neurons and microglia. Here, we combine both cell lineages and establish a novel co-culture of iPSC-derived spinal motor neurons and microglia, which is compatible with motor neuron identity and function. Co-cultured microglia express key identity markers and transcriptomically resemble primary human microglia, have highly dynamic ramifications, are phagocytically competent, release relevant cytokines and respond to stimulation. Further, they express key amyotrophic lateral sclerosis-associated genes and release disease-relevant biomarkers. This novel and authentic human model system facilitates the study of physiological motor neuron-microglia crosstalk and will allow the investigation of non-cell-autonomous phenotypes in motor neuron diseases such as amyotrophic lateral sclerosis.
Insights
Researchers developed a new co-culture model using human induced pluripotent stem cell-derived motor neurons and microglia. This model authentically replicates motor neuron-microglia interactions, crucial for studying neurodegenerative diseases like amyotrophic lateral sclerosis.
Area of Science:
- Neuroscience
- Cell Biology
- Stem Cell Research
Background:
- Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), involve motor neuron degeneration and non-neuronal cell participation, especially microglia.
- Previous research established methods for differentiating induced pluripotent stem cells (iPSCs) into spinal motor neurons and microglia separately.
Purpose of the Study:
- To establish a novel co-culture system combining iPSC-derived spinal motor neurons and microglia.
- To create an authentic human model for studying motor neuron-microglia interactions in the context of neurodegenerative diseases.
Main Methods:
- Co-culturing of iPSC-derived spinal motor neurons and microglia.
- Assessment of microglial identity markers, transcriptomic profiles, morphology, phagocytic activity, cytokine release, and response to stimulation.
- Analysis of ALS-associated gene expression and biomarker release in co-cultured microglia.
Main Results:
- The co-culture system maintained motor neuron identity and function.
- Co-cultured microglia exhibited characteristics of primary human microglia, including dynamic ramifications and phagocytic competence.
- Microglia released relevant cytokines and biomarkers associated with ALS, and expressed key ALS-related genes.
Conclusions:
- A novel and authentic human co-culture model of iPSC-derived motor neurons and microglia was successfully established.
- This model system enables the study of physiological motor neuron-microglia crosstalk.
- It facilitates the investigation of non-cell-autonomous mechanisms in motor neuron diseases like ALS.
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