Modeling the Inflammatory Response of Traumatic Brain Injury Using Human Induced Pluripotent Stem Cell Derived
Aftab Alam1, Tanya Singh2, Saeed Kayhanian1
1Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
Abstract:
The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. The iPSC-derived microglia were exposed to interleukin (IL)-1β, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF) in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72h time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1β (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses with our previous studies of iPSC-derived neuronal and astrocyte cultures and the in vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, compared with astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.
Insights
Human microglia, key immune cells in the brain, show significant cytokine responses to traumatic brain injury (TBI) related signals. This study characterizes these microglial responses to specific TBI cytokines.
Area of Science:
- Neuroscience
- Immunology
- Stem Cell Biology
Background:
- Neuroinflammation, driven by microglia, significantly contributes to secondary injury after traumatic brain injury (TBI).
- Understanding microglial responses to TBI-associated cytokines is crucial for developing targeted therapies.
Purpose of the Study:
- To characterize the downstream cytokine secretome of human induced pluripotent stem cell (iPSC)-derived microglia stimulated with TBI-relevant cytokines.
- To compare microglial responses to those of iPSC-derived neurons and astrocytes, and to in vivo TBI data.
Main Methods:
- Human iPSC-derived microglia were stimulated with five specific cytokines (IL-1β, IL-4, IL-6, IL-10, TNF) at clinically relevant concentrations.
- Downstream cytokine release was measured over 72 hours using a 37-cytokine panel.
- Responses were compared across different cytokine concentrations, time points, and cell types (microglia, astrocytes, neurons).
Main Results:
- Microglial secretome exhibited concentration- and time-dependent cytokine responses.
- Tumor necrosis factor (TNF) and interleukin-1β (IL-1β) were the strongest inducers of downstream cytokine release.
- iPSC-derived microglia demonstrated broader and more potent cytokine responses compared to iPSC-derived astrocytes and neurons.
Conclusions:
- This study provides a comprehensive dataset of human microglial cytokine responses in a TBI context.
- The findings highlight the significant role of microglia in TBI-induced neuroinflammation.
- This research serves as a foundation for future studies investigating the complex neuroinflammatory network post-TBI.
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