Self-Healing COCu-Tac Hydrogel Enhances iNSCs Transplantation for Spinal Cord Injury by Promoting Mitophagy via the FKBP52/AKT Pathway

Advanced Science, 2025 · DOI: 10.1002/advs.202407757 · Published: November 25, 2024

Spinal Cord Injury Regenerative Medicine Biomedical

Simple Explanation

This study addresses the challenges of neural regeneration after spinal cord injury by developing a self-healing hydrogel (COCu-Tac) that releases tacrolimus to enhance the transplantation of induced neural stem cells (iNSCs). The hydrogel's sustained release of tacrolimus promotes axonal growth and improves mitochondrial quality in iNSCs and neurons by targeting FKBP52 to enhance mitophagy via the FKBP52/AKT pathway. This advanced system shows significant efficacy in promoting neural regeneration and restoring motor function after spinal cord injury in animal models.

Study Duration

6 Weeks

Participants

Adult female Sprague–Dawley rats

Evidence Level

Not specified

Key Findings

1
The COCu-Tac hydrogel promotes the survival and neuronal differentiation of transplanted iNSCs without systemic immunosuppression, leading to improved outcomes compared to iNSCs alone.
2
Tacrolimus released from the hydrogel selectively targets FKBP52 over FKBP51, inhibiting AKT phosphorylation in iNSCs, thereby promoting mitophagy and enhancing mitochondrial quality control.
3
The COCu-Tac-iNSCs hydrogel significantly boosts the regeneration of nerve fibers through mitophagy, leading to functional recovery in SCI rats.

Research Summary

This study introduces a novel COCu-Tac-iNSCs transplantation system to address challenges in cell-based therapies for spinal cord injury, such as graft rejection and mitochondrial dysfunction. The self-healing hydrogel with controlled tacrolimus release targets FKBP52 to induce mitophagy in transplanted iNSCs, improving cell survival by addressing loss of ECM, graft rejection, and energy metabolism disturbances. In animal models, the advanced iNSCs transplantation therapy significantly contributed to neural regeneration and functional recovery, indicating its potential for clinical translation.

Practical Implications

Enhanced iNSC Transplantation

The COCu-Tac hydrogel improves the survival and differentiation of transplanted iNSCs, offering a more effective approach for spinal cord injury treatment.

Targeted Immunosuppression

Local, sustained release of tacrolimus minimizes systemic side effects while promoting neural regeneration and reducing graft rejection.

Mitophagy Promotion

The hydrogel's ability to enhance mitophagy via the FKBP52/AKT pathway supports mitochondrial quality control and improves cellular viability in the injured spinal cord.

Study Limitations

1
The study duration was limited to 6 weeks post-spinal cord injury, not capturing long-term ECM remodeling and neural circuit reconstruction.
2
Potential neurotoxicity from tacrolimus remains a concern, requiring further exploration of long-term effects on local tissue homeostasis.
3
The study did not fully specify the types of CD13-positive cells post-transplantation or the regulatory effects of microglial activation.

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