ILC2 Instructs Neural Stem and Progenitor Cells to Potentiate Neurorepair After Stroke

Neurology Immunology Life Sciences Medicine
neurorepair ILC2 neural stem cells stroke neural progenitor cells brain injury therapeutic strategy

Academic Background

Stroke is one of the leading causes of adult disability globally, with the core issue being neuronal damage and neurological dysfunction. Although neurogenesis and neurorepair after stroke are considered crucial for recovery, the specific mechanisms remain incompletely understood. Recent studies have shown that immune cells play a significant role in post-stroke neurorepair, particularly Group 2 Innate Lymphoid Cells (ILC2s) among the Innate Lymphoid Cells (ILCs). ILC2s have demonstrated their importance in various physiological and pathological conditions, including tissue repair and immune regulation. However, the role of ILC2s in the central nervous system, especially in post-stroke neurorepair, remains understudied.

The aim of this study is to explore the potential role of ILC2s in post-stroke neurorepair and to elucidate the underlying mechanisms. The researchers hypothesized that ILC2s promote the proliferation of Neural Stem and Progenitor Cells (NSPCs) by secreting specific cytokines, such as Amphiregulin (AREG), thereby improving neurological recovery after stroke.

Source of the Paper

This paper was co-authored by Gaoyu Liu, Huachen Huang, Ying Wang, and others, with the research team affiliated with The First Affiliated Hospital of Chongqing Medical University, Tianjin Medical University, and The Seventh Affiliated Hospital of Sun Yat-sen University, among other institutions. The paper was published on June 4, 2025, in the journal Neuron, titled “ILC2 Instructs Neural Stem and Progenitor Cells to Potentiate Neurorepair After Stroke.” The study received funding from the National Natural Science Foundation of China and other sources.

Research Process

1. Establishment of Stroke Model and Dynamic Changes of ILC2s

The study first established a transient Middle Cerebral Artery Occlusion (MCAO) mouse model to simulate ischemic injury after stroke. Through flow cytometry analysis, the researchers found that ILC2s significantly increased during the recovery phase (days 7 to 28) after stroke, particularly in the lesion core and the Subventricular Zone (SVZ). Additionally, ILC2s exhibited enhanced cytokine production, especially IL-5 and IL-13, during the chronic phase after stroke.

2. Impact of ILC2 Deficiency on Neurological Function

To investigate the role of ILC2s after stroke, the researchers used ILC2-deficient mice (Rorafl/flIl7rcre/+). Compared to the control group, ILC2-deficient mice exhibited more severe neurological deficits after stroke, including significant declines in motor and cognitive functions. Through Magnetic Resonance Imaging (MRI) and Modified Neurological Severity Score (mNSS) assessments, the researchers confirmed impaired neurological recovery in ILC2-deficient mice after stroke.

3. ILC2s Promote Neural Stem Cell Proliferation via AREG

Further mechanistic studies revealed that ILC2s promote NSPC proliferation by secreting AREG. Through in vitro co-culture experiments, the researchers found that ILC2s significantly increased the size of neurospheres and the proliferative capacity of NSPCs. Additionally, experiments using AREG or an EGFR inhibitor (EGFR-in-70) further confirmed the critical role of the AREG-EGFR axis in ILC2-mediated neuroregeneration.

4. Transcriptomic Analysis of ILC2s

Using single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing, the researchers analyzed the transcriptomic changes of ILC2s after stroke. The results showed that brain ILC2s expressed genes related to neuroregeneration, particularly AREG. Moreover, the transcriptomic profile of brain ILC2s was significantly different from that of peripheral lymphoid tissue ILC2s, indicating unique immune functions of brain ILC2s.

5. Therapeutic Potential of AREG

To validate the therapeutic potential of AREG, the researchers administered AREG to mice on day 4 after stroke. The results showed that AREG significantly improved neurological recovery in ILC2-deficient mice and increased the proliferation of NSPCs and neuroblasts. Additionally, AREG administration reduced the lesion size after stroke, further supporting the important role of AREG in neurorepair.

Key Findings

  1. Dynamic Changes of ILC2s After Stroke: ILC2s significantly increased during the recovery phase after stroke, particularly in the lesion core and SVZ.
  2. Impact of ILC2 Deficiency on Neurological Function: ILC2-deficient mice exhibited more severe neurological deficits after stroke.
  3. ILC2s Promote Neural Stem Cell Proliferation via AREG: ILC2s promote NSPC proliferation by secreting AREG, with the AREG-EGFR axis playing a critical role in this process.
  4. Transcriptomic Profile of ILC2s: Brain ILC2s expressed genes related to neuroregeneration, particularly AREG.
  5. Therapeutic Potential of AREG: AREG significantly improved neurological recovery after stroke and promoted NSPC proliferation.

Conclusions and Significance

This study is the first to reveal the important role of ILC2s in post-stroke neurorepair and to elucidate the specific mechanism by which they promote neuroregeneration through the AREG-EGFR axis. This discovery provides a new therapeutic strategy for post-stroke neurorepair, namely enhancing ILC2 function or directly administering AREG to promote neuroregeneration and functional recovery. Additionally, the study highlights the differences in immune functions between brain ILC2s and peripheral ILC2s, laying the groundwork for further research on the role of ILC2s in the central nervous system.

Research Highlights

  1. Key Role of ILC2s in Post-Stroke Neurorepair: The study found that ILC2s promote NSPC proliferation by secreting AREG, thereby improving neurological recovery after stroke.
  2. Mechanistic Insight into the AREG-EGFR Axis: The study elucidated the specific mechanism by which AREG promotes neuroregeneration through the EGFR signaling pathway.
  3. Transcriptomic Profile of ILC2s: Brain ILC2s exhibit unique transcriptomic characteristics, significantly different from peripheral ILC2s.
  4. Therapeutic Potential of AREG: AREG administration significantly improved neurological recovery after stroke, demonstrating important clinical application value.

Additional Valuable Information

The study also found that ILC2s enhance the neuroregeneration process by promoting the proliferation and differentiation of NSPCs during the recovery phase after stroke. Furthermore, the study revealed interactions between ILC2s and other immune cells (e.g., regulatory T cells) after stroke, providing new directions for future immunotherapy research.

This study provides a new theoretical foundation and therapeutic strategy for post-stroke neurorepair, holding significant scientific and clinical importance.