The Shh/Gli1 signaling pathway regulates regeneration via transcription factor Olig1 expression after focal cerebral ischemia in rats

ABSTRACT

Objective

Ischemic stroke is a major cause of death in the global population, with a high disability and mortality rate. Lack of regenerative ability is considered to be the fundamental cause. This study aims to determine the effect of Shh pathway, which mediates regenerative signaling in response to CNS injury, on myelin repair and Olig1 expression in focal ischemic lesions in the rat.

Methods

A model of middle cerebral artery occlusion (MCAO) was established using the intraluminal suture method where the middle cerebral artery (MCA) was restricted for 120 min. Cyclopamine, a specific inhibitor of Shh, or saline was administered 12h after MCAO surgery and lasted for 7d. After MCA occlusion, male Sprague-Dawley rats were randomly allocated to cyclopamine- or saline-treated groups. A group of no-injection animals after MCAO were used as control. The Shh signaling pathway, myelinogenesis-related factor MBP and Olig1 were tested using immunohistochemistry and RT-PCR assay.

Results

The levels of Shh and its component Gli1 were elevated from 1d up to 14d following ischemia, indicating that the Shh-Gli1 axis was broadly reactivated. Treatment with cyclopamine can partially block the Shh signaling pathway, prevent myelin repair, and decrease the Olig1 expression following ischemic stroke.

Conclusion

That blockade of Shh signaling concurrently with the creation of a lesion aggravated ischemic myelin damage, probably via its downstream effects on Olig1 transcription. Shh plays a contributory role during regeneration in the CNS, thereby providing promising new therapeutic strategies to assist in recovery from ischemic stroke.

KEWORDS:

• Rat
• oligodendrocyte precursor cells (OPCs)
• Shh
• remyelination
• differentiation
• Olig1
• brain ischemia

Acknowledgments

The authors would like to thank Professor Yue Lu at Peking University School of Nursing for technical assistance.

Authors’ contributions

HZ and YZ conceived and designed the study. XG and XW performed the experiments. XW analyzed the data and drafted the manuscript. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

The animal-related experiments were approved by Animal Welfare Committee of Dalian Medical University and followed the guidelines for Animal Care and Use adapted from NIH, USA.

Patients consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by grants from The National Natural Science Foundation of China (grant no. 30570626, no. 81371355 and no. 81671191) and The Beijing Natural Science Foundation (grant no. 7082028) [7082028].

Notes on contributors

Hong Zhao

Hong Zhao, Doctor's degree, born in 1978, graduated from Beijing Friendship Hospital affiliated to Capital Medical University in 2009, now worked in Dalian Municipal Central Hospital and majored in the pathogenesis of cerebrovascular disease.

Xiao-Yu Gao

Xiaoyu Gao, Doctor's degree, graduated from Beijing Friendship Hospital affiliated to Capital Medical University, now worked in Yuhuangding Hospital.

Xiao-Jun Wu

Xiaojun WU, master degree, graduated from Dalian Medical University, now worked in Anshan Hospital.

Yong-Bo Zhang

Yongbo Zhang, Ph.D. Department of Neurology, Beijing Friendship Hospital affiliated to Capital Medical University, who chaired The National Natural Science Foundation of China (grant no. 30570626, no. 81371355 and no. 81671191) and The Beijing Natural Science Foundation (grant no. 7082028).

Xun-Fen Wang

Xunfen Wang, master degree, Dalian Medical University.