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自修复COCu-Tac水凝胶通过FKBP52/AKT途径促进线粒体自噬增强诱导神经干细胞移植治疗脊髓损伤

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

作者信息

Tian Zhenming, Hu Han-Jian, Chan Chun Cheung, Hu Tian, Cai Chaoyang, Li Hong, Rong Limin, Jiang Gang-Biao, Liu Bin

机构信息

Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.

Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, 510630, China.

出版信息

Adv Sci (Weinh). 2025 Jan;12(3):e2407757. doi: 10.1002/advs.202407757. Epub 2024 Nov 25.

DOI:10.1002/advs.202407757
PMID:39587837
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11744648/
Abstract

In the realm of neural regeneration post-spinal cord injury, hydrogel scaffolds carrying induced neural stem cells (iNSCs) have demonstrated significant potential. However, challenges such as graft rejection and dysfunction caused by mitochondrial damage persist after transplantation, presenting formidable barriers. Tacrolimus, known for its dual role as an immunosuppressant and promoter of neural regeneration, holds the potential for enhancing iNSC transplantation. However, systemic administration of tacrolimus often comes with severe side effects. This study pioneers the development of a self-healing hydrogel with sustained-release tacrolimus (COCu-Tac), tailored specifically for iNSC transplantation after spinal cord injury. This research reveals that the sustained release of tacrolimus enhances axonal growth and improves mitochondrial quality control in iNSCs and neurons. Further analysis shows that tacrolimus targets FKBP52 rather than FKBP51, enhancing mitophagy via the FKBP52/AKT pathway. This advanced system demonstrates significant efficacy in promoting neural regeneration and restoring motor function following spinal cord injury.

摘要

在脊髓损伤后的神经再生领域，携带诱导神经干细胞（iNSCs）的水凝胶支架已显示出巨大潜力。然而，移植后诸如移植物排斥和线粒体损伤导致的功能障碍等挑战依然存在，构成了巨大障碍。他克莫司以其作为免疫抑制剂和神经再生促进剂的双重作用而闻名，具有增强iNSC移植的潜力。然而，全身施用他克莫司往往伴随着严重的副作用。本研究率先开发了一种具有他克莫司缓释功能的自愈水凝胶（COCu-Tac），专门为脊髓损伤后的iNSC移植量身定制。该研究表明，他克莫司的缓释增强了iNSCs和神经元的轴突生长并改善了线粒体质量控制。进一步分析表明，他克莫司靶向FKBP52而非FKBP51，通过FKBP52/AKT途径增强线粒体自噬。这一先进系统在促进脊髓损伤后的神经再生和恢复运动功能方面显示出显著疗效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/b5c4a39626c7/ADVS-12-2407757-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/57b6bd76a7e2/ADVS-12-2407757-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/4280eaa82a5f/ADVS-12-2407757-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/f66ebde80c9c/ADVS-12-2407757-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/08c4b1416fa7/ADVS-12-2407757-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/9a519ebf0d30/ADVS-12-2407757-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/b5c4a39626c7/ADVS-12-2407757-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/57b6bd76a7e2/ADVS-12-2407757-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/4be11bac62df/ADVS-12-2407757-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/483804dec655/ADVS-12-2407757-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/4111e25e2b02/ADVS-12-2407757-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/4280eaa82a5f/ADVS-12-2407757-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/f66ebde80c9c/ADVS-12-2407757-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/08c4b1416fa7/ADVS-12-2407757-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/9a519ebf0d30/ADVS-12-2407757-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89f9/11744648/b5c4a39626c7/ADVS-12-2407757-g009.jpg

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本文引用的文献

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Cellular and molecular mechanisms of cell damage and cell death in ischemia-reperfusion injury in organ transplantation.器官移植中缺血再灌注损伤的细胞损伤和细胞死亡的细胞和分子机制。
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Combined transplantation of hiPSC-NSC and hMSC ameliorated neuroinflammation and promoted neuroregeneration in acute spinal cord injury.人诱导多能干细胞-神经干细胞与骨髓间充质干细胞联合移植改善急性脊髓损伤的神经炎症反应和促进神经再生。
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Neural stem cell therapies for spinal cord injury repair: an update on recent preclinical and clinical advances.神经干细胞疗法治疗脊髓损伤修复：近期临床前和临床进展的更新。
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FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment.FKBP5 通过消除 PPAR-γ 来激活细胞自噬，从而塑造良性的髓鞘修复环境。
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Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor.冷冻电镜揭示了 Hsp90 和 FKBP 免疫亲和素如何共同调节糖皮质激素受体。
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