Fate mapping of Spp1 expression reveals age-dependent plasticity of disease-associated microglia-like cells after
Yangning Lan1, Xiaoxuan Zhang2, Shaorui Liu3
1College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Laboratory of Neuroimmunology, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
Abstract:
Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1（Spp1） to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1+ microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions.
Insights
Disease-associated microglia (DAM) exhibit different fates after brain injury. Neonatal microglia show plasticity and immune memory, unlike adult microglia, influencing neurological disorder outcomes.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Microglial reactivity is crucial in neurological disorders.
- The plasticity and fate of disease-associated microglia (DAM) are largely unknown.
Purpose of the Study:
- To investigate the plasticity and fate of DAM-like microglia during brain injury and recovery.
- To understand the long-term impact of neonatal brain injury on microglial function.
Main Methods:
- Established a lineage tracing system using secreted phosphoprotein 1 (Spp1) expression.
- Tracked Spp1+ microglia during stroke in juvenile and neonatal mouse models.
- Analyzed microglial state, integration, and immune response post-injury.
Main Results:
- Juvenile DAM-like microglia entered an irreversible state and were eliminated.
- Neonatal DAM-like microglia demonstrated plasticity, regained homeostasis, and integrated into the microglial network.
- Neonatal injury induced lasting intrinsic immune sensitization in microglia.
Conclusions:
- Neonatal microglia possess significant plasticity and innate immune memory.
- The fate of DAM-like microglia differs between juvenile and neonatal brain injury.
- Findings offer insights into microglial roles in neuropathological conditions.
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