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Overexpressed ski efficiently promotes neurorestoration, increases neuronal regeneration, and reduces astrogliosis after traumatic brain injury

Gene Therapy volume 30, pages 75–87 (2023)Cite this article

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Abstract

Traumatic brain injury (TBI) survivors suffer from long-term disability and neuropsychiatric sequelae due to irreparable brain tissue destruction. However, there are still few efficient therapies to promote neurorestoration in damaged brain tissue. This study aimed to investigate whether the pro-oncogenic gene ski can promote neurorestoration after TBI. We established a ski-overexpressing experimental TBI mouse model using adenovirus-mediated overexpression through immediate injection after injury. Hematoxylin-eosin staining, MRI-based 3D lesion volume reconstruction, neurobehavioral tests, and analyses of neuronal regeneration and astrogliosis were used to assess neurorestorative efficiency. The effects of ski overexpression on the proliferation of cultured immature neurons and astrocytes were evaluated using imaging flow cytometry. The Ski protein level increased in the perilesional region at 3 days post injury. ski overexpression further elevated Ski protein levels up to 14 days post injury. Lesion volume was attenuated by approximately 36–55% after ski overexpression, with better neurobehavioral recovery, more newborn immature and mature neurons, and less astrogliosis in the perilesional region. Imaging flow cytometry results showed that ski overexpression elevated the proliferation rate of immature neurons and reduced the proliferation rate of astrocytes. These results show that ski can be considered a novel neurorestoration-related gene that effectively promotes neurorestoration, facilitates neuronal regeneration, and reduces astrogliosis after TBI.

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Fig. 1: Dynamics of the lesion cavity volume after moderate TBI.
Fig. 2: Spatiotemporal protein level and distribution of Ski after TBI.
Fig. 3: Overexpression of exogenous ski after adenovirus-mediated transfection.
Fig. 4: Reduced lesion cavity volume after ski-overexpressing adenovirus treatment.
Fig. 5: Mitigated neurobehavioral deficits after ski-overexpressing adenovirus treatment.
Fig. 6: Increased number of newborn neurons after ski-overexpressing adenovirus treatment.
Fig. 7: Reduced astrogliosis after ski-overexpressing adenovirus treatment.
Fig. 8: Changes in the proliferation of immature neurons after ski overexpression in vitro.
Fig. 9: Changes in the proliferation of astrocytes after ski overexpression in vitro.

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Data availability

Data are available on request due to privacy/ethical restrictions. The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

We thank Jin Bo and Dr Tong Hai-Peng from the Department of Radiology, Research Institute of Surgery and Daping Hospital for their technical assistance in MRI analysis. We thank the Department of Pathology, Research Institute of Surgery and Daping Hospital for their assistance in collecting and processing pathological specimens.

Funding

The research fund of the State Key Laboratory of Trauma, Burn and Combined Injury of China (No. SKLZZ20111) supported the purchase of reagents and experimental animals, the collection, analysis, and interpretation of data, and the writing of the manuscript.

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  1. These authors contributed equally: Yu Zhai, Shi-Yang Ye.

Authors and Affiliations

  1. The Molecular Biology Centre, State Key Laboratory of Trauma, Burn and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University (The Third Military Medical University), Chongqing, People’s Republic of China

    Yu Zhai, Shi-Yang Ye, Qiu-Shi Wang, Ren-Ping Xiong, Sheng-Yu Fu, Hao Du, Ya-Wei Xu, Yan Peng, Zhi-Zhong Huang, Nan Yang, Yan Zhao, Ya-Lei Ning, Ping Li & Yuan-Guo Zhou

  2. Department of Pathology, Research Institute of Surgery and Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, People’s Republic of China

    Qiu-Shi Wang

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YZhai and S-YY: carried out experiments, performed statistical analysis, and drafted the manuscript. YZhao, Y-LN, PL, and Y-GZ: designed and oversaw the experiments, interpreted the data, and reviewed the manuscript. HD, Z-ZH: carried out a significant proportion of the supplementary experiments. Q-SW: performed the preparation of paraffin sections, and analyses of neuropathological characterization. R-PX: performed the western blot experiments and corresponding statistical analysis. Y-WX: assisted in the neurobehavioral examination. S-YF, YP, and NY: assisted in making animal models, and the injection of Adv. All authors read and approved the final manuscript.

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Correspondence to Ping Li or Yuan-Guo Zhou.

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Zhai, Y., Ye, SY., Wang, QS. et al. Overexpressed ski efficiently promotes neurorestoration, increases neuronal regeneration, and reduces astrogliosis after traumatic brain injury. Gene Ther 30, 75–87 (2023). https://doi.org/10.1038/s41434-022-00320-x

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  • DOI: https://doi.org/10.1038/s41434-022-00320-x

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