The limited capacity of the adult central nervous system (CNS) to regenerate damaged neural circuits remains a major obstacle to functional recovery following ischemic stroke. Although rehabilitative training promotes neuroplasticity and partial restoration of motor function, its efficacy is constrained by the age-associated decline in the intrinsic regenerative potential of corticospinal neurons.

In a recent study published in Genes & Diseases, researchers from Children's Hospital of Soochow University, Suzhou Industrial Park Center for Disease Control and Prevention, Medical College of Soochow University, The Second Affiliated Hospital of Soochow University, Guangzhou Medical University, The Fourth Affiliated Hospital of Soochow University, University of Electronic Science and Technology of China, and The Second Hospital and Yuying Children's Hospital of Wenzhou Medical University investigated whether epigenetic rejuvenation of corticospinal neurons through the ectopic expression of the transcription factors Oct4, Sox2, and Klf4 (OSKTFs) enhances rehabilitation-induced axonal remodeling and improves functional recovery following photothrombotic ischemic stroke. By combining partial cellular reprogramming with rehabilitative training, the study explored a novel strategy to restore neuronal plasticity without compromising neuronal identity.

Using an intersectional viral strategy with adeno-associated viral vectors, the researchers selectively expressed OSKTFs in corticospinal neurons of adult mice to induce partial cellular reprogramming. Methodologically, the study employed a doxycycline (Dox)-inducible system to temporally control the expression of OSKTFs, allowing direct comparison between treated and control groups.

Molecular characterization demonstrated that OSKTF expression reversed age-associated epigenetic features without altering neuronal identity, corticospinal projections, or normal motor function. Following photothrombotic ischemic stroke, mice underwent rehabilitative training to evaluate whether rejuvenated corticospinal neurons exhibited enhanced structural plasticity and functional recovery.

The authors observed that OSKTF-mediated rejuvenation alone produced modest improvements in corticospinal tract collateral sprouting and skilled motor recovery after stroke. However, when combined with rehabilitative training, it markedly enhanced corticospinal tract (CST) axon sprouting from the intact hemisphere into denervated spinal regions, resulting in significantly greater recovery of skilled locomotor function than either intervention alone. These findings indicate that neuronal rejuvenation amplifies the regenerative effects of rehabilitation by increasing the intrinsic growth capacity of adult corticospinal neurons rather than directly restoring lost neural circuits.

Mechanistic investigations revealed that the regenerative effects of OSKTFs were dependent on activation of the mTOR signaling pathway. Pharmacological inhibition of mTOR abolished both CST axon sprouting and the associated functional improvements, confirming its essential role in neuronal regeneration. Furthermore, selective chemogenetic silencing of the newly sprouted corticospinal neurons eliminated the behavioral benefits despite OSKTF treatment and rehabilitation. These findings establish that functional improvement results from the formation of new compensatory neural connections rather than from nonspecific effects of gene expression or rehabilitation alone.

In conclusion, this study demonstrates that partial epigenetic rejuvenation of corticospinal neurons through OSKTF expression enhances rehabilitation-associated CST axon sprouting and promotes functional recovery following photothrombotic ischemic stroke. By identifying mTOR-dependent axonal remodeling as the underlying mechanism, the findings highlight the therapeutic potential of combining neuronal rejuvenation with rehabilitative training to improve neural circuit repair and functional recovery after stroke.

Reference

Title of the original paper: Rejuvenation of corticospinal neurons enhances rehabilitation-associated corticospinal tract axon sprouting and functional recovery post photothrombotic ischemic stroke in mice
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.102000

Funding Information:
National Natural Science Foundation of China (No. 82471742, 82271739, 82171703, 82271405)
National Key R&D Program Project (China) (No. 2024YFC2707700)
Natural Science Foundation of Jiangsu Province, China (No. BK20200207)
Jiangsu Provincial Key Medical Discipline (China) (No. ZDXKA2016013)
Training Program Foundation for Health Talents of Gusu (China) (No. GSWS2020052, GSWS2019049)
Project of Suzhou Science and Technology Development Plan (China) (No. SKY2021008, SYS2020154)
Suzhou Science, Education and Health and Technology Project (China) (No. KJXW2018018)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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