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Updated: Jun 17, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Single-cell and Spatial Transcriptomics Reveals Ferroptosis as The Most Enriched Programmed Cell Death Process in
Lingui Gu1, Hualin Chen1, Ruxu Geng2
1Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Insights
Intracerebral hemorrhage (ICH) triggers ferroptosis, a programmed cell death, primarily in oligodendrocytes. Targeting microglial lipocalin-2 (LCN2) offers a neuroprotective strategy against ICH-induced damage.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Intracerebral hemorrhage (ICH) is a severe stroke with limited treatments.
- Programmed cell death (PCD) encompasses multiple pathways, including ferroptosis, crucial for tissue homeostasis.
- Understanding PCD modalities post-ICH is vital for developing effective therapies.
Purpose of the Study:
- To investigate programmed cell death (PCD) gene expression in the rat brain after intracerebral hemorrhage (ICH).
- To identify the predominant PCD mechanism and affected cell types following hemorrhagic stroke.
- To elucidate molecular pathways driving cell death and neurological deficits post-ICH.
Main Methods:
- Single-cell RNA sequencing and spatial transcriptomics were employed to analyze gene expression.
- Rats underwent induced intracerebral hemorrhage to model stroke.
- Analysis focused on programmed cell death-related genes and cellular interactions.
Main Results:
- Ferroptosis was identified as the primary PCD pathway after ICH, affecting mature oligodendrocytes.
- Ferroptosis onset was observed as early as 1 hour post-ICH, peaking at 24 hours.
- A lipocalin-2 (LCN2)-microglia to oligodendrocyte signaling pathway involving CSF1/CSF1R was implicated in ferroptosis induction.
Conclusions:
- Ferroptosis is the principal PCD mechanism in intracerebral hemorrhage, initiating rapidly.
- Targeting microglial LCN2 expression presents a potential therapeutic avenue to mitigate oligodendrocyte damage and neurological deficits.
- This study offers a novel neuroprotective strategy for intracerebral hemorrhage treatment.
Abstract:
Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Programmed cell death (PCD) is crucial for immunological balance, and includes necroptosis, pyroptosis, apoptosis, ferroptosis, and necrosis. However, the distinctions between these programmed cell death modalities after ICH remain to be further investigated. We used single-cell transcriptome (single-cell RNA sequencing) and spatial transcriptome (spatial RNA sequencing) techniques to investigate PCD-related gene expression trends in the rat brain following hemorrhagic stroke. Ferroptosis was the main PCD process after ICH, and primarily affected mature oligodendrocytes. Its onset occurred as early as 1 hour post-ICH, peaking at 24 hours post-ICH. Additionally, ferroptosis-related genes were distributed in the hippocampus and choroid plexus. We also elucidated a specific interaction between lipocalin-2 (LCN2)-positive microglia and oligodendrocytes that was mediated by the colony stimulating factor 1 (CSF1)/CSF1 receptor pathway, leading to ferroptosis induction in oligodendrocytes and subsequent neurological deficits. In conclusion, our study highlights ferroptosis as the primary PCD mechanism, emerging as early as 1 hour post-ICH. Early therapeutic intervention via the suppression of microglial LCN2 expression may alleviate ferroptosis-induced damage in oligodendrocytes and associated neurological deficits, thus offering a promising neuroprotective strategy following ICH.
