Telomerase reverse transcriptase (TERT) promotes neurogenesis after hypoxic-ischemic brain damage in neonatal rats

ABSTRACT

Objective

Neonatal hypoxic-ischemic encephalopathy (HIE) endangers quality of life in children, and curative attempts are rarely effective. Neurogenesis plays an important role in neural repair following brain damage. This study aimed to investigate the role of telomerase reverse transcriptase (TERT) in neurogenesis after neonatal hypoxic-ischemic brain damage (HIBD).

Methods

Neonatal HIBD models were established in vivo (Sprague-Dawley rats, 7 days old) and in vitro (cultured neural stem cells, NSCs). Lentivirus and adenovirus transfection was used to induce TERT overexpression. Expression of TERT was detected by quantitative real-time PCR and immunofluorescence staining. NSCs apoptosis and proliferation were measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and cell counting assays, respectively. Migration and differentiation of NSCs were assessed by western blotting and immunofluorescence staining. Morris water maze test and modified neurological severity scores were conducted to evaluate the neurological function of rats.

Results

Overexpression of TERT attenuated apoptosis of NSCs; promoted proliferation, migration, and differentiation of NSCs; and induced myelination in the brains of neonatal rats after HIBD. Moreover, it reduced the impairment of learning, memory, and neurological function after HIBD in neonatal rats. In vitro findings indicated that the expression of Gli1 was increased after OGD, and overexpression of TERT further increased the expression of Gli1 in NSCs after OGD.

Discussion

TERT promotes neurogenesis and decreases neurological function injury after HIBD in neonatal rats. This neuroprotective pathway may provide a basis for developing therapeutic strategies for neonatal HIE. Furthermore, TERT may represent a target during neural injury and repair in patients with various diseases affecting the nervous system.

KEYWORDS:

• Hypoxic-ischemic brain damage
• neurogenesis
• neonate
• telomerase reverse transcriptase

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

Author contributions

Jiao Li implemented the project and contributed to analysis and writing manuscript.

Hai-ting Liu contributed to neurobehavioral experiments.

Jing Zhao contributed to most of in vitro experiments.

Hong-Ju Chen contributed to most of the in vivo experiments.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and material

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

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant 81501302, to Jiao Li; the Science and Technology Bureau of Sichuan Province under Grant 2021YFS0247 and 2022YFS0360; and the New Bud foundation of West China Second University Hospital, Sichuan University under Grants Kx105 to Jiao Li and Kx097 to Haiting Liu. The National Natural Science Foundation of China contributed to the design of the study and the New Bud foundation of West China Second University Hospital, Sichuan University contributed to the collection, analysis and interpretation of data, the writing of the report, and the decision to submit the article for publication.

Notes on contributors

Jiao Li

Jiao Li, MD/PHD, has been engaged in the clinical and basic research in pediatrics for 12 years, especially neurology and neonatology. She has presided over one National Natural Science Foundation of China, and participated in a number of National Natural Science Foundations in China as a primary participant. She focuses on the basic research of hypoxic-ischemic brain damage in neonate and has published several related articles.

Hai-Ting Liu

Hai-ting Liu, MD/PHD, has been engaged in clinical and basic research in pediatrics for 18 years, especially neonatology, and participated in several National Natural Science Foundations in China. She is an expert in neonatal diseases and specializes in neurobehavioral experiments.

Jing Zhao

Jing Zhao, MD/PHD, has been engaged in clinical and basic research in pediatrics for 11 years, especially neonatology, and participated in several National Natural Science Foundations in China. She specializes in in vitro experiments as part of basic research concerning neonatal diseases.

Hong-Ju Chen

Hong-ju Chen, MD/PHD, has worked as a postdoctoral fellow for 4 years and has been engaged in basic research in pediatrics for 13 years, especially neurology. She has presided over one National Natural Science Foundation of China, and participated in a number of National Natural Science Foundations in China as a primary participant. She focuses on the basic research of neurological diseases and has published several related articles.