干细胞与神经营养因子联合用于脊髓损伤修复的研究进展
Advances in Combined Stem Cell and Neurotrophic Factor Therapies for Spinal Cord Injury Repair
DOI: 10.12677/acm.2025.15113334, PDF,   
作者: 熊治霖：吉首大学医学院，湖南 吉首；刘超杰：张家界市人民医院脊柱外科，湖南 张家界；胡观成*：张家界市人民医院神经外科，湖南 张家界
关键词: 脊髓损伤；干细胞；神经营养因子；外泌体；生物材料；电刺激；临床转化；Spinal Cord Injury； Stem Cells； Neurotrophic Factors； Exosomes； Biomaterials； Rehabilitation； Clinical Translation
摘要: 目的：系统梳理干细胞与神经营养因子(neurotrophic factors, NTFs)联合应用于脊髓损伤(spinal cord injury, SCI)修复的研究现状，明确协同机制、技术突破与临床转化瓶颈，为后续研究提供方向。方法：检索近年国内外核心文献，从SCI病理特征、单一成分作用局限、联合治疗机制、载体技术创新及临床转化挑战等维度展开分析。主要发现神经干细胞(neural stem cells, NSCs)、诱导神经干细胞(induced neural stem cells, iNSCs)及其外泌体，与脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)、神经营养素-3 (neurotrophin-3, NT-3)、胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor, GDNF)等联合时，可通过免疫微环境调控、损伤区域基质重塑、轴突定向生长及髓鞘再生四重机制发挥作用。挑战：现存问题包括：细胞来源与制备工艺异质性导致疗效差异较高；干细胞潜在肿瘤原性缺乏5年以上长期随访数据；NTFs递送的时空精度不足；临床前试验设计无统一标准(如损伤节段、评价指标不统一)，制约结果可比性。结论：倡导构建“干细胞–NTFs–生物材料–康复干预”一体化治疗体系，重点优化亚急性/慢性期(损伤后2~8周)的细胞–因子剂量配比及时序方案，需通过多中心、大样本量的随机对照临床试验验证安全性与有效性，推动SCI修复从基础研究向临床应用转化。
Abstract: Spinal cord injury (SCI) leads to irreversible neurological deficits and remains a major challenge in regenerative medicine. Recent research has highlighted the potential synergy between stem cells and neurotrophic factors (NTFs) in promoting neuronal survival, axonal regeneration, and functional recovery. This review outlines current advances in combinatorial strategies involving neural stem cells, mesenchymal stem cells, Schwann cells, and exosome-based approaches with NTFs such as brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and glial cell line-derived neurotrophic factor (GDNF). The underlying mechanisms include immune modulation, extracellular matrix remodeling, axon guidance, and remyelination, which collectively contribute to microenvironmental restoration after SCI. Furthermore, we discuss emerging biomaterial-assisted delivery systems that enable controlled and sustained release, as well as their role in enhancing cell survival and integration. Despite promising preclinical findings, major challenges persist, including manufacturing heterogeneity, long-term safety, and standardized clinical trial design. Future research should focus on integrating cellular, molecular, and rehabilitative interventions to establish programmable, stage-specific therapeutic frameworks that bridge basic science and clinical translation.
文章引用：熊治霖, 刘超杰, 胡观成. 干细胞与神经营养因子联合用于脊髓损伤修复的研究进展[J]. 临床医学进展, 2025, 15(11): 2176-2185. https://doi.org/10.12677/acm.2025.15113334

参考文献

[1] Zhang, J., Liu, Y., Zhang, Y., Li, Y., et al. (2023) The Role of Immune Cells and Associated Immunological Factors in Spinal Cord Injury. Frontiers in Immunology, 14, Article 642839.
[2] Tang, H., Gu, Y., Jiang, L., Zheng, G., Pan, Z. and Jiang, X. (2022) The Role of Immune Cells and Associated Immunological Factors in the Immune Response to Spinal Cord Injury. Frontiers in Immunology, 13, Article 1070540. [Google Scholar] [CrossRef] 
[3] Andriot, T., Ghosh, M. and Pearse, D.D. (2025) Engineered Healing: Syner-gistic Use of Schwann Cells and Biomaterials for Spinal Cord Regeneration. International Journal of Molecular Sciences, 26, Article 7922. [Google Scholar] [CrossRef] 
[4] Chung, H.J., Chung, W.H., Lee, J.H., Chung, D.J., et al. (2016) Expression of Neu-rotrophic Factors in Injured Spinal Cord after Transplantation of Human-Umbilical Cord Blood Stem Cells in Rats. Journal of Veteri-nary Science, 17, 97-102. [Google Scholar] [CrossRef] 
[5] Ma, D., Fu, C., Li, F., Ruan, R., Lin, Y., Li, X., et al. (2024) Functional Biomaterials for Modulating the Dysfunctional Pathological Microenvironment of Spinal Cord Injury. Bioactive Ma-terials, 39, 521-543. [Google Scholar] [CrossRef] 
[6] Li, H., Yi, R., Fan, Y., Zhan, G. and Xiao, T. (2025) Overexpression of miRNA-216 in Exosomes Derived from Umbilical Cord Mesenchymal Stem Cells Promotes Angiogenesis and Improves Functional Recovery after Spinal cord Injury. Iranian Journal of Basic Medical Sciences, 28, 1344-1353.
[7] Zipser, C.M., Cragg, J.J., Guest, J.D., Fehlings, M.G., Jutzeler, C.R., Anderson, A.J., et al. (2022) Cell-Based and Stem-Cell-Based Treatments for Spinal Cord Injury: Evidence from Clinical Trials. The Lancet Neurology, 21, 659-670. [Google Scholar] [CrossRef] 
[8] Martin, J.R., Cleary, D., Abraham, M.E., Mendoza, M., Cabrera, B., Ja-mieson, C., et al. (2024) Long-Term Clinical and Safety Outcomes from a Single-Site Phase 1 Study of Neural Stem Cell Transplanta-tion for Chronic Thoracic Spinal Cord Injury. Cell Reports Medicine, 5, Article 101841. [Google Scholar] [CrossRef] 
[9] Hosseini, S.M., Borys, B. and Karimi-Abdolrezaee, S. (2024) Neural Stem Cell Therapies for Spinal Cord Injury Repair: An Update on Recent Preclinical and Clinical Advances. Brain, 147, 766-793. [Google Scholar] [CrossRef] 
[10] Ribeiro, B.F., da Cruz, B.C., de Sousa, B.M., Correia, P.D., David, N., Rocha, C., et al. (2023) Cell Therapies for Spinal Cord Injury: A Review of the Clinical Trials and Cell-Type Therapeutic Potential. Brain, 146, 2672-2693. [Google Scholar] [CrossRef] 
[11] Li, Y., Kumamaru, H., Vokes, T.J., Tran, A.N., Shevinsky, C.A., Graham, L., et al. (2024) An Improved Method for Generating Human Spinal Cord Neural Stem Cells. Experimental Neurology, 376, Article 114779. [Google Scholar] [CrossRef] 
[12] Ralph, P.C., Choi, S., Baek, M.J. and Lee, S.J. (2024) Regenerative Medicine Approaches for the Treatment of Spinal Cord Injuries: Progress and Challenges. Acta Biomaterialia, 189, 57-72. [Google Scholar] [CrossRef] 
[13] Zou, Y., Ma, D., Shen, H., Zhao, Y., Xu, B., Fan, Y., et al. (2020) Aligned Collagen Scaffold Combination with Human Spinal Cord-Derived Neural Stem Cells to Improve Spinal Cord Injury Repair. Biomateri-als Science, 8, 5145-5156. [Google Scholar] [CrossRef] 
[14] Yu, T., Yang, L., Zhou, Y., Wu, M. and Jiao, J. (2024) Exosome-Mediated Repair of Spinal Cord Injury: A Promising Therapeutic Strategy. Stem Cell Research & Therapy, 15, Article No. 6. [Google Scholar] [CrossRef] 
[15] Cao, Y., Zhu, S., Yu, B. and Yao, C. (2022) Single-Cell RNA Sequencing for Traumatic Spinal Cord Injury. The FASEB Journal, 36, e22656. [Google Scholar] [CrossRef] 
[16] Malvandi, A.M., Rastegar-Moghaddam, S.H., Ebrahimzadeh-Bideskan, S., Lombardi, G., Ebrahimzadeh-Bideskan, A. and Mohammadipour, A. (2022) Targeting miR-21 in Spinal Cord Injuries: A Game-Changer? Molecular Medicine, 28, Article No. 118. [Google Scholar] [CrossRef] 
[17] Marangon, D., Castro e Silva, J.H., Cerrato, V., Boda, E. and Lecca, D. (2024) Oligodendrocyte Progenitors in Glial Scar: A Bet on Remyelination. Cells, 13, Article 1024. [Google Scholar] [CrossRef] 
[18] Ray, S., Al-Sammarraie, N. and Mahmood, M. (2023) Neuroprotective Role of Nog-gin in Spinal Cord Injury. Neural Regeneration Research, 18, 492-496. [Google Scholar] [CrossRef] 
[19] Xiong, T., Xiao, X., Zhao, H., Yang, W., Gao, X., Yang, K., et al. (2025) The Key to Spinal Cord Recovery: Harnessing P21 Inhibition to Boost Neural Stem/Progenitor Cell Proliferation. ACS Nano, 19, 27406-27423. [Google Scholar] [CrossRef] 
[20] Shao, A., Tu, S., Lu, J. and Zhang, J. (2019) Crosstalk between Stem Cell and Spinal Cord Injury: Pathophysiology and Treatment Strategies. Stem Cell Research & Therapy, 10, Article No. 238. [Google Scholar] [CrossRef] 
[21] Li, C., Luo, Y. and Li, S. (2024) The Roles of Neural Stem Cells in Myelin Regeneration and Repair Therapy after Spinal Cord Injury. Stem Cell Research & Therapy, 15, Article No. 204. [Google Scholar] [CrossRef] 
[22] Marei, H.E. (2025) Stem Cell Therapy: A Revolutionary Cure or a Pandora’s Box. Stem Cell Research & Therapy, 16, Article No. 255. [Google Scholar] [CrossRef] 
[23] Mohammad, S., Roy, A., Karatzas, A., Sarver, S.L., Anagnostopoulos, I. and Chowdhury, F. (2024) Deep Learning Powered Identification of Differen-tiated Early Mesoderm Cells from Pluripotent Stem Cells. Cells, 13, Article 534. [Google Scholar] [CrossRef] 
[24] Ferrini, F., Salio, C., Boggio, E.M. and Merighi, A. (2021) Interplay of BDNF and GDNF in the Mature Spinal Somatosensory System and Its Potential Therapeutic Relevance. Current Neuropharmacology, 19, 1225-1245. [Google Scholar] [CrossRef] 
[25] Cheng, C., Li, Q., Lin, G., Opara, E.C. and Zhang, Y. (2023) Neu-robiological Insights into Lower Urinary Tract Dysfunction: Evaluating the Role of Brain-Derived Neurotrophic Factor. American Journal of Clinical and Experimental Urology, 11, 559-577.
[26] Albu, S., Kumru, H., Coll, R., Vives, J., Vallés, M., Benito-Penalva, J., et al. (2021) Clinical Effects of Intrathecal Administration of Expanded Wharton Jelly Mesenchymal Stromal Cells in Patients with Chronic Complete Spinal Cord Injury: A Randomized Controlled Study. Cytotherapy, 23, 146-156. [Google Scholar] [CrossRef] 
[27] Zhang, Y., Zhang, C., Gao, K., Li, K., Fu, M. and Lv, C. (2025) The Application Prospects and Challenges of Mesenchymal Stem Cell-Derived Exosomes in Spinal Cord Injury Repair. Current Stem Cell Research & Therapy, 20, 1-13. [Google Scholar] [CrossRef] 
[28] Xia, Y., Yang, R., Wang, H., Hou, Y., Li, Y., Zhu, J., et al. (2022) Biomaterials Delivery Strategies to Repair Spinal Cord Injury by Modulating Macrophage Phenotypes. Journal of Tissue Engi-neering, 13, 1-18. [Google Scholar] [CrossRef] 
[29] Jiang, D., Ding, Y., Hu, S., Wei, G., Trujillo, C., Yang, Z., et al. (2025) Broad-Spectrum Downregulation of Inflammatory Cytokines by Polydopamine Nanoparticles to Protect the Injured Spinal Cord. Acta Biomaterialia, 193, 559-570. [Google Scholar] [CrossRef] 
[30] Szymoniuk, M., Litak, J., Sakwa, L., Dryla, A., Zezuliński, W., Czyżewski, W., et al. (2022) Molecular Mechanisms and Clinical Application of Multipotent Stem Cells for Spinal Cord Injury. Cells, 12, Article 120. [Google Scholar] [CrossRef] 
[31] Ghosh, M. and Pearse, D.D. (2023) Schwann Cell-Derived Exosomal Vesicles: A Promising Therapy for the Injured Spinal Cord. International Journal of Molecular Sciences, 24, Article 17317. [Google Scholar] [CrossRef] 
[32] Balçıkanlı, Z., Culha, I., Dilsiz, P., Aydin, M.S., Ates, N., Beker, M.C., et al. (2022) Lithium Promotes Long-Term Neurological Recovery after Spinal Cord Injury in Mice by Enhancing Neuronal Survival, Gray and White Matter Remodeling, and Long-Distance Axonal Regeneration. Frontiers in Cellular Neuroscience, 16, Article 1012523. [Google Scholar] [CrossRef] 
[33] Tashiro, S., Shibata, S., Nagoshi, N., Zhang, L., Yamada, S., Tsuji, T., et al. (2024) Do Pharmacological Treatments Act in Collaboration with Rehabilitation in Spinal Cord Injury Treatment? A Review of Preclin-ical Studies. Cells, 13, Article 412. [Google Scholar] [CrossRef] 
[34] Rahbaran, M., Zekiy, A.O., Bahramali, M., Jahangir, M., Mardasi, M., Sakhaei, D., et al. (2022) Therapeutic Utility of Mesenchymal Stromal Cell (MSC)-Based Approaches in Chronic Neurodegeneration: A Glimpse into Underlying Mechanisms, Current Status, and Prospects. Cellular & Molecular Biology Letters, 27, Article No. 56. [Google Scholar] [CrossRef] 
[35] Zheng, B. and Tuszynski, M.H. (2023) Regulation of Axonal Regeneration after Mammalian Spinal Cord Injury. Nature Reviews Molecular Cell Biology, 24, 396-413. [Google Scholar] [CrossRef] 
[36] Lee, S., Nam, H., Joo, K.M. and Lee, S.H. (2022) Advances in Neural Stem Cell Therapy for Spinal Cord Injury: Safety, Efficacy, and Future Perspectives. Neurospine, 19, 946-960. [Google Scholar] [CrossRef] 
[37] Hu, X., Xu, W., Ren, Y., Wang, Z., He, X., Huang, R., et al. (2023) Spinal Cord Injury: Molecular Mechanisms and Therapeutic Interventions. Signal Transduction and Targeted Therapy, 8, Article No. 245. [Google Scholar] [CrossRef] 
[38] Gilbert, E.A.B., Lakshman, N., Lau, K.S.K. and Morshead, C.M. (2022) Reg-ulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair. Cells, 11, Article 846. [Google Scholar] [CrossRef] 
[39] Saijo, Y., Nagoshi, N., Kawai, M., Kitagawa, T., Suematsu, Y., Ozaki, M., et al. (2024) Human-Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Ex Vivo Gene Therapy with Synaptic Organizer CPTX for Spinal Cord Injury. Stem Cell Reports, 19, 383-398. [Google Scholar] [CrossRef] 
[40] Aderinto, N., Abdulbasit, M.O. and Olatunji, D. (2023) Stem Cell-Based Combinatorial Therapies for Spinal Cord Injury: A Narrative Review of Current Research and Future Directions. Annals of Medicine & Surgery, 85, 3943-3954. [Google Scholar] [CrossRef] 
[41] Yu, L., Zhang, W., Li, F., et al. (2024) Exosome-Based Delivery of Neu-rotrophic Factors for Spinal Cord Injury Repair: A Review. Stem Cell Research & Therapy, 15, Article 58.
[42] Zhang, N., Hu, J., Liu, W., Cai, W., Xu, Y., Wang, X., et al. (2024) Advances in Novel Biomaterial-Based Strategies for Spinal Cord Injury Treatment. Mo-lecular Pharmaceutics, 21, 4764-4785. [Google Scholar] [CrossRef] 
[43] Baek, I. and Song, Y. (2024) Development of Combinatorial Therapeu-tics for Spinal Cord Injury Using Stem Cell Delivery. Journal of Visualized Experiments, 208, e66872. [Google Scholar] [CrossRef] 
[44] Sterner, R.C. and Sterner, R.M. (2023) Immune Response Following Traumatic Spinal Cord Injury: Pathophysiology and Therapies. Frontiers in Immunology, 13. [Google Scholar] [CrossRef] 
[45] Dorrian, D., Lawrence, J., Wang, J., et al. (2023) The Role of Electrical Stimulation in Spinal Cord Injury Rehabilitation: A Systematic Review and Meta-Analysis. Frontiers in Cellular Neuroscience, 17, Article 823029.
[46] Anjum, A., Yazid, M.D., Fauzi Daud, M., Idris, J., Ng, A.M.H., Selvi Naicker, A., et al. (2020) Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Re-covery Mechanisms. International Journal of Molecular Sciences, 21, Article 7533. [Google Scholar] [CrossRef] 
[47] Katari, V., Pasupuleti, S.K., Mullick, M., Lekkala, V.K.R. and Sen, D. (2024) Editori-al: Advanced Neural Stem Cell Therapies for Spinal Cord Injury. Frontiers in Pharmacology, 15, Article 1469553. [Google Scholar] [CrossRef] 
[48] Abolghasemi, R. and Davoudi-Monfared, E. (2025) Guide for Cell Therapy in Human Chronic Spinal Cord Injury. Tissue Engineering Part C: Methods, 31, 174-180. [Google Scholar] [CrossRef] 
[49] Liu, Y., Liu, J., Wang, Y., Zhang, Y., Peng, Z., Li, P., et al. (2025) Regulation of Neuroimmune Microenvironment by PLA/GO/Anti-TNF-α Composite to Enhance Neurological Repair after Spinal Cord Injury. Inter-national Journal of Nanomedicine, 20, 4919-4942. [Google Scholar] [CrossRef] 
[50] Fan, C., Yang, W., Zhang, L., Cai, H., Zhuang, Y., Chen, Y., et al. (2022) Restoration of Spinal Cord Biophysical Microenvironment for Enhancing Tissue Repair by Injury-Responsive Smart Hydrogel. Biomaterials, 288, Article 121689. [Google Scholar] [CrossRef] 
[51] Chen, H., Wang, W., Yang, Y., Zhang, B., Li, Z., Chen, L., et al. (2024) A Sequential Stimuli-Responsive Hydrogel Promotes Structural and Functional Recovery of Severe Spinal Cord Injury. Biomaterials, 316, Article 122995. [Google Scholar] [CrossRef] 
[52] Zhou, Z., Liu, Y., Chen, L., et al. (2024) Sustained Delivery of NT-3 and Curcumin Augments Microenvironment Remodeling for Spinal Cord Injury Repair. Regenerative Biomaterials, 11, rbae039.
[53] Liu, J., Yan, R., Wang, B., Chen, S., Hong, H., Liu, C., et al. (2024) Decellularized Extracellular Matrix Enriched with GDNF Enhances Neurogenesis and Remyelination for Improved Motor Recovery after Spinal Cord Injury. Acta Biomaterialia, 180, 308-322. [Google Scholar] [CrossRef] 
[54] Kirkeby, A., Main, H. and Carpenter, M. (2025) Pluripotent Stem-Cell-Derived Therapies in Clinical Trial: A 2025 Update. Cell Stem Cell, 32, 10-37. [Google Scholar] [CrossRef] 
[55] Montoto-Meijide, R., Meijide-Faílde, R., Díaz-Prado, S.M. and Monto-to-Marqués, A. (2023) Mesenchymal Stem Cell Therapy in Traumatic Spinal Cord Injury: A Systematic Review. International Journal of Molecular Sciences, 24, Article 1719. [Google Scholar] [CrossRef] 
[56] Li, S., Chen, G., Tong, K., Che, Y., Xie, Y., Shi, W., et al. (2025) Inhibition of Neuronal Necroptosis via Disruption of RIPK1-RIPK3 Interactions: The Role of Neural Stem Cell-Derived Exosomes in Spinal Cord Injury Recovery. Bioactive Materials, 51, 889-908. [Google Scholar] [CrossRef] 
[57] Kwon, Y.D., Won, J.S., Ma, X., Choi, Y.J., et al. (2025) Preclinical Effica-cy and Safety Assessments of Adult Human Neural Stem Cells (AhNSCs) for Spinal Cord Injury. Toxicology Reports, 14, Article 102048. [Google Scholar] [CrossRef] 
[58] He, W., Li, Z.Q., Gu, H.Y., et al. (2024) Targeted Therapy of Spinal Cord Injury: Inhibition of Apoptosis Is a Promising Therapeutic Strategy. Molecular Neurobiology, 61, 4222-4239. [Google Scholar] [CrossRef] 
[59] Feng, Y., Li, Y., Shen, P. and Wang, B. (2022) Gene-Modified Stem Cells for Spinal Cord Injury: A Promising Better Alternative Therapy. Stem Cell Reviews and Reports, 18, 2662-2682. [Google Scholar] [CrossRef] 
[60] Tashiro, S., Tsuji, O., Shinozaki, M., Shibata, T., Yoshida, T., Tomioka, Y., et al. (2021) Current Progress of Rehabilitative Strategies in Stem Cell Therapy for Spinal Cord Injury: A Review. npj Regenerative Med-icine, 6, Article No. 81. [Google Scholar] [CrossRef] 
[61] Bydon, M., Qu, W., Moinuddin, F.M., Hunt, C.L., Garlanger, K.L., Reeves, R.K., et al. (2024) Intrathecal Delivery of Adipose-Derived Mesenchymal Stem Cells in Traumatic Spinal Cord Injury: Phase I Trial. Nature Communications, 15, Article No. 2201. [Google Scholar] [CrossRef] 
[62] Brumbaugh, A.D., Podolsky, A., Kulzer, M.H., Spearman, M.P., Goldberg, M.F., Chang, W.M., et al. (2022) Stem Cell Induced Inflammatory Hypertrophy of the Cauda Equina. Radiology Case Reports, 17, 1601-1604. [Google Scholar] [CrossRef] 
[63] Grace, P.M., Rolan, P.E. and Hutchinson, M.R. (2021) Mediators of Neuro-pathic Pain; Focus on Spinal Microglia, CSF-1, BDNF and Wnt Signaling. Frontiers in Pain Research, 2, Article 698157.
[64] Alles, S.R.A., Odem, M.A., Lu, V.B., Cassidy, R.M. and Smith, P.A. (2021) Chronic BDNF Simultaneously Inhibits and Unmasks Superfi-cial Dorsal Horn Neuronal Activity. Scientific Reports, 11, Article No. 2249. [Google Scholar] [CrossRef] 
[65] U.S. FDA (2022) Principles of Premarket Pathways for Combination Prod-ucts: Guidance for Industry and FDA Staff.

为你推荐