H4K12 Lactylation Activated-Spp1 in Reprogrammed Microglia Improves Functional Recovery After Spinal Cord Injury

IF 4.8 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2025-02-12 DOI:10.1111/cns.70232

Xiaokun Wang, Geliang Zhou, Junjun Xiong, Wu Ye, Yu Gao, Haofan Wang, Dishui Pan, Yongjun Luo, Zheng Zhou

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Abstract

Background

Spinal cord injury (SCI) is a severe condition leading to significant disability and high mortality. The role of the secreted phosphoprotein 1 (SPP1) signaling pathway in SCI, which is quickly activated after injury, is critical for intercellular communication but remains poorly understood.

Aims

This study aimed to explore the function and regulatory mechanisms of the SPP1 signaling pathway in SCI and investigate its potential as a therapeutic target for improving functional recovery after injury.

Materials and Methods

Single-cell RNA sequencing (scRNA-seq) was employed to identify ligands and receptors of the SPP1 signaling pathway, particularly in microglia/macrophages. Recombinant SPP1 (rSPP1) was used in vitro and in vivo to assess its effects on neuronal maturation, mitochondrial energy in axons, and functional recovery after SCI. Pseudotime analysis was conducted to examine the role of Spp1 in microglial activation and proliferation. DNA-pulldown and in vitro experiments were performed to investigate the upstream regulatory proteins of Spp1.

Results

The SPP1 signaling pathway is primarily localized in microglia after SCI, with rSPP1 promoting neuronal maturation and enhancing mitochondrial function in axons. Injection of rSPP1 into the injured spinal cord resulted in significant improvement in functional recovery. Pseudotime analysis indicated that Spp1 is involved in the activation and proliferation of microglia. Histone H4 lysine 12 lactylation (H4K12la) was found to promote the transcription of Spp1 in reprogrammed microglia postinjury.

Discussion

Our findings reveal a novel regulatory mechanism involving Spp1 in SCI, particularly its role in microglial activation, mitochondrial function, and glycolytic reprogramming. This new insight provides a deeper understanding of its contribution to the injury response.

Conclusion

This study uncovers a previously unreported mechanism of Spp1 in SCI, offering a potential therapeutic target for SCI.

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.