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The aOECs Facilitate the Neuronal Differentiation of Neural Stem Cells in the Inflammatory Microenvironment Through Up-Regulation of Bioactive Factors and Activation of Wnt3/β-Catenin Pathway

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Abstract

The therapeutic application of neural stem cells (NSCs) in the central nerve system (CNS) injury is a promising strategy for combating irreversible neuronal loss. However, a variety of obvious inflammatory responses following nerve injury rapidly create an unfavorable microenvironment for survival and neuronal differentiation of NSCs in lesion area, limiting the efficacy of NSC-based therapy for CNS injury. It remained unknown how to effectively increase the neuronal differentiation efficiency of NSCs through transplantation. Here, we demonstrated that curcumin (CCM)-activated olfactory ensheathing cells (aOECs) effectively promoted neuronal differentiation of NSCs in the activated microglial inflammatory condition, and co-transplantation of aOECs and NSCs improved neurological recovery of rats after spinal cord injury (SCI), as evidenced by higher expression levels of neuronal markers and lower expression levels of glial markers in the differentiated cells, greater number of Tuj-1-positive cells as well as higher Basso, Beattie, and Bresnahan (BBB) locomotor scale, compared to the corresponding controls. Pathologically, hematoxylin and eosin (HE) staining and immunostaining also showed that aOECs remarkably enhanced the in vivo neuronal differentiation of NSCs and migration, and nerve repair. Further analysis revealed that the underlying mechanisms of aOECs potentiating the neuronal conversion of NSCs under inflammatory environment were tightly associated with up-regulation of anti-inflammatory cytokines and neurotrophic factors in OECs, and importantly, the activation of Wnt3/β-catenin pathway was likely involved in the mechanisms underlying the observed cellular events. Therefore, this study provides a promising strategy for SCI repair by co-transplantation of aOECs and NSCs.

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All data supporting the conclusions of this article are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to acknowledge Jing An, Xiaohui Wang, and Lingling Zhang for the excellent technical assistance. We would like to thank Dr. Huiming Xu for critical reading of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (grant no. 82071551, 82060238, and 81830077), the Natural Science Foundation of Shaanxi province (grant no. 2020JM-686), the key research and development program in Ning xia Hui Autonomous Region (grant no. 2022BEG02032).

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  1. Yuqing He and Yizhen Jiang contributed equally to the work.

Authors and Affiliations

  1. School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China

    Yuqing He, Hao Yang & Juan Liu

  2. Basic Medical School Academy, Shaanxi University of Traditional Chinese Medicine, Xianyang, 712046, China

    Yizhen Jiang

  3. Ningxia Hui Autonomous Region Hospital and Research Institute of Traditional Chinese Medicine, Yinchuan, 750021, China

    Lianwei Dong

  4. Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an 710054, China

    Chao Jiang

  5. Translational Medicine Center, Hong Hui Hospital, Xi’an Jiao Tong University, Xi’an 710054, China

    Yuqing He, Lingling Zhang, Gaorong Zhang & Hao Yang

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Contributions

HY and JL conceived the study and designed the work. YH, YJ, LD, and LZ performed the experiments. YJ, LD, and CJ collected and analyzed the data. YH, JL, and HY performed data analysis and interpretation. YH and HY wrote the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Hao Yang or Juan Liu.

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All animal procedures were performed in agreement with the National Institutes of Health guidelines and were approved by the Institutional Ethical Review Committee of Hong Hui Hospital affiliated by Xi’an Jiaotong University (No. 201712004). Written informed consent was obtained from all participants involved in this study.

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He, Y., Jiang, Y., Dong, L. et al. The aOECs Facilitate the Neuronal Differentiation of Neural Stem Cells in the Inflammatory Microenvironment Through Up-Regulation of Bioactive Factors and Activation of Wnt3/β-Catenin Pathway. Mol Neurobiol 60, 789–806 (2023). https://doi.org/10.1007/s12035-022-03113-w

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