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Journal Article Epublish 12 citations

PubMed: 36782279 DOI: 10.1186/s41232-023-00263-9

IFN-γ-STAT1-mediated CD8 T-cell-neural stem cell cross talk controls astrogliogenesis after spinal cord injury.

Inflamm Regen 43(1):12

Authors: Jingyu Wang, Lintao Xu, Deqing Peng, Yongjian Zhu, Zhaowen Gu, Ying Yao, Heyangzi Li, Xi Cao, Chun-Yan Fu, Mingzhi Zheng, Xinghui Song, Yueming Ding, Yueliang Shen, Jinjie Zhong, Ying-Ying Chen, Jue Hu, Lin-Lin Wang

Affiliations

  • Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310009, China.
  • Department of Neurosurgery, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital Hangzhou Medical College), Hangzhou, Zhejiang, China.
  • Department of Neurointensive Care Unit, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • Department of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • School of Basic Medical Sciences & Forensic Medicine of Hangzhou Medical College, Hangzhou, 310053, China.
  • Central Laboratory, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
  • School of Medicine, Zhejiang University City College, Hangzhou, 310015, China.
  • Department of Basic Medicine Sciences and Department of Obstetrics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • Department of Basic Medicine Sciences and Department of Obstetrics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • School of Basic Medical Sciences & Forensic Medicine of Hangzhou Medical College, Hangzhou, 310053, China.
  • Department of Basic Medicine Sciences and Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Abstract

BACKGROUND

Spinal cord injury (SCI) causes nearly all patients to suffer from protracted disabilities. An emerging therapeutic strategy involving the recruitment of endogenous neural stem cells (NSCs) has been developed. However, endogenous NSCs in the adult spinal cord differentiate into mostly astrocytes after traumatic injury, forming glial scars, which is a major cause of regeneration failure in SCI. Thus, understanding which factors drive the activation and differentiation of endogenous NSCs after SCI is critical for developing therapeutic drugs.

METHODS

The infiltration, state, and location of CD8 T cells in spinal cord after traumatic injury were analyzed by flow cytometry and immunofluorescence (IF) staining. The Basso Mouse Scale (BMS) scores and rotarod testing were used for motor behavioral analysis. NSCs were co-cultured with CD8 T cells. EdU assay was used to detect proliferative cells. Western blotting was used to analyze the expression levels of STAT1, p-STAT1, and p27. ChIP-seq and ChIP-qRT-PCR analyses were used to detect the downstream of STAT1. Nestin-CreERT2::Ai9 transgenic mice were used to genetic lineage tracing of Nestin NSCs after SCI in vivo.

RESULTS

A prolonged increase of activated CD8 T cells occurs in the injured spinal cords. The behavioral analysis demonstrated that the administration of an anti-CD8 antibody promotes the recovery of locomotor function. Then, we discovered that CD8 T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1 pathway in vitro. ChIP-seq and ChIP-qRT-PCR analysis revealed that STAT1 could directly bind to the promoters of astrocyte marker genes GFAP and Aldh1l1. Genetic lineage tracing of Nestin NSCs demonstrated that most NSCs differentiated into astrocytes following SCI. Depleting CD8 T cells reduced the differentiation of NSCs into astrocytes and instead promoted the differentiation of NSCs into oligodendrocytes.

CONCLUSION

In conclusion, CD8 T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1-GFAP/Aldhl1l axis. Our study identifies INF-γ as a critical mediator of CD8 T-cell-NSC cross talk and a potential node for therapeutic intervention in SCI.

MeSH

Therapeutics, Microscopy, Electron, Scanning Transmission, T-Lymphocytes, Spine, Astrocytes, Spinal Cord Injuries, Neural Stem Cells

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