Scientific Papers

Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial | Stem Cell Research & Therapy


  • David G, Mohammadi S, Martin AR, Cohen-Adad J, Weiskopf N, Thompson A, Freund P. Traumatic and nontraumatic spinal cord injury: pathological insights from neuroimaging. Nat Reviews Neurol. 2019;15(12):718–31.

    Article 

    Google Scholar
     

  • James SL, Theadom A, Ellenbogen RG, Bannick MS, Montjoy-Venning W, Lucchesi LR, et al. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the global burden of Disease Study 2016. Lancet Neurol. 2019;18(1):56–87.

    Article 

    Google Scholar
     

  • Ahuja CS, Wilson JR, Nori S, Kotter M, Druschel C, Curt A, Fehlings MG. Traumatic spinal cord injury. Nat Reviews Disease Primers. 2017;3(1):1–21.


    Google Scholar
     

  • Hayta E, Elden H. Acute spinal cord injury: a review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention. J Chem Neuroanat. 2018;87:25–31.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bradbury EJ, Burnside ER. Moving beyond the glial scar for spinal cord repair. Nat Commun. 2019;10(1):3879.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dalamagkas K, Tsintou M, Seifalian A, Seifalian AM. Translational regenerative therapies for chronic spinal cord injury. Int J Mol Sci. 2018;19(6):1776.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tashiro S, Tsuji O, Shinozaki M, Shibata T, Yoshida T, Tomioka Y, et al. Current progress of rehabilitative strategies in stem cell therapy for spinal cord injury: a review. NPJ Regenerative Med. 2021;6(1):81.

    Article 
    CAS 

    Google Scholar
     

  • Liau LL, Looi QH, Chia WC, Subramaniam T, Ng MH, Law JX. Treatment of spinal cord injury with mesenchymal stem cells. Cell Bioscience. 2020;10(1):1–17.

    Article 

    Google Scholar
     

  • Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109(10):1292–8.

    Article 
    PubMed 

    Google Scholar
     

  • Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8(9):726–36.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hofer HR, Tuan RS. Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res Ther. 2016;7:1–14.

    Article 

    Google Scholar
     

  • Sun G, Li G, Li D, Huang W, Zhang R, Zhang H, et al. hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Mater Sci Engineering: C. 2018;89:194–204.

    Article 
    CAS 

    Google Scholar
     

  • Kang J, Guo Y. Human umbilical cord mesenchymal stem cells derived exosomes promote neurological function recovery in a rat spinal cord Injury Model. Neurochem Res. 2022;47(6):1532–40.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ren Z, Qi Y, Sun S, Tao Y, Shi R. Mesenchymal stem cell-derived exosomes: hope for spinal cord injury repair. Stem Cells Dev. 2020;29(23):1467–78.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He C, Zheng S, Luo Y, Wang B. Exosome theranostics: biology and translational medicine. Theranostics. 2018;8(1):237.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shafei S, Khanmohammadi M, Heidari R, Ghanbari H, Taghdiri Nooshabadi V, Farzamfar S, et al. Exosome loaded alginate hydrogel promotes tissue regeneration in full-thickness skin wounds: an in vivo study. J Biomed Mater Res A. 2020;108(3):545–56.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yi H, Wang Y. A meta-analysis of exosome in the treatment of spinal cord injury. Open Med. 2021;16(1):1043–60.

    Article 
    CAS 

    Google Scholar
     

  • Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Translational Med. 2020;18(1):1–21.

    Article 

    Google Scholar
     

  • Herberts CA, Kwa MS, Hermsen HP. Risk factors in the development of stem cell therapy. J Translational Med. 2011;9:1–14.

    Article 

    Google Scholar
     

  • El Masry WS, Tsubo M, Katoh S, El Miligui YH, Khan A. Validation of the American spinal injury association (ASIA) motor score and the national acute spinal cord injury study (NASCIS) motor score. Spine. 1996;21(5):614–9.

    Article 
    PubMed 

    Google Scholar
     

  • Itzkovich M, Gelernter I, Biering-Sorensen F, Weeks C, Laramee M, Craven B, et al. The spinal cord independence measure (SCIM) version III: reliability and validity in a multi-center international study. Disabil Rehabil. 2007;29(24):1926–33.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Krogh K, Christensen P, Sabroe S, Laurberg S. Neurogenic bowel dysfunction score. Spinal Cord. 2006;44(10):625–31.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Akpinar P, Atici A, Ozkan F, Aktas I, Kulcu D, Sarı A, Durmus B. Reliability of the Modified Ashworth Scale and Modified Tardieu Scale in patients with spinal cord injuries. Spinal Cord. 2017;55(10):944–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • El-Kheir WA, Gabr H, Awad MR, Ghannam O, Barakat Y, Farghali HA, et al. Autologous bone marrow-derived cell therapy combined with physical therapy induces functional improvement in chronic spinal cord injury patients. Cell Transplant. 2014;23(6):729–45.

    Article 
    PubMed 

    Google Scholar
     

  • Vaquero J, Zurita M, Rico MA, Aguayo C, Bonilla C, Marin E, et al. Intrathecal administration of autologous mesenchymal stromal cells for spinal cord injury: safety and efficacy of the 100/3 guideline. Cytotherapy. 2018;20(6):806–19.

    Article 
    PubMed 

    Google Scholar
     

  • Cofano F, Boido M, Monticelli M, Zenga F, Ducati A, Vercelli A, Garbossa D. Mesenchymal stem cells for spinal cord injury: current options, limitations, and future of cell therapy. Int J Mol Sci. 2019;20(11):2698.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yeo RWY, Lai RC, Tan KH, Lim SK. Exosome: a novel and safer therapeutic refinement of mesenchymal stem cell. Exosomes Microvesicles. 2013;1:7.


    Google Scholar
     

  • van der Meel R, Fens MH, Vader P, Van Solinge WW, Eniola-Adefeso O, Schiffelers RM. Extracellular vesicles as drug delivery systems: lessons from the liposome field. J Controlled Release. 2014;195:72–85.

    Article 

    Google Scholar
     

  • Ha D, Yang N, Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sinica B. 2016;6(4):287–96.

    Article 

    Google Scholar
     

  • Hwang I, Shen X, Sprent J. Direct stimulation of naive T cells by membrane vesicles from antigen-presenting cells: distinct roles for CD54 and B7 molecules. Proc Natl Acad Sci. 2003;100(11):6670–5.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nazarenko I, Rana S, Baumann A, McAlear J, Hellwig A, Trendelenburg M, et al. Cell surface tetraspanin Tspan8 contributes to Molecular pathways of Exosome-Induced Endothelial Cell ActivationExosome-Induced endothelial cell activation. Cancer Res. 2010;70(4):1668–78.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lener T, Gimona M, Aigner L, Börger V, Buzas E, Camussi G, et al. Applying extracellular vesicles based therapeutics in clinical trials–an ISEV position paper. J Extracell Vesicles. 2015;4(1):30087.

    Article 
    PubMed 

    Google Scholar
     

  • Zheng G, Huang R, Qiu G, Ge M, Wang J, Shu Q, Xu J. Mesenchymal stromal cell-derived extracellular vesicles: regenerative and immunomodulatory effects and potential applications in sepsis. Cell Tissue Res. 2018;374:1–15.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang C-C, Kang M, Lu Y, Shirazi S, Diaz JI, Cooper LF, et al. Functionally engineered extracellular vesicles improve bone regeneration. Acta Biomater. 2020;109:182–94.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bari E, Perteghella S, Di Silvestre D, Sorlini M, Catenacci L, Sorrenti M, et al. Pilot production of mesenchymal stem/stromal freeze-dried secretome for cell-free regenerative nanomedicine: a validated GMP-compliant process. Cells. 2018;7(11):190.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Khorasanizadeh M, Yousefifard M, Eskian M, Lu Y, Chalangari M, Harrop JS, et al. Neurological recovery following traumatic spinal cord injury: a systematic review and meta-analysis. J Neurosurgery: Spine. 2019;30(5):683–99.

    PubMed 

    Google Scholar
     

  • Zhu Y, Soderblom C, Krishnan V, Ashbaugh J, Bethea J, Lee J. Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. Neurobiol Dis. 2015;74:114–25.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu GJ, Nagarajah R, Banati RB, Bennett MR. Glutamate induces directed chemotaxis of microglia. Eur J Neurosci. 2009;29(6):1108–18.

    Article 
    PubMed 

    Google Scholar
     

  • Tang P, Hou H, Zhang L, Lan X, Mao Z, Liu D, et al. Autophagy reduces neuronal damage and promotes locomotor recovery via inhibition of apoptosis after spinal cord injury in rats. Mol Neurobiol. 2014;49:276–87.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bellora F, Castriconi R, Dondero A, Reggiardo G, Moretta L, Mantovani A et al. The interaction of human natural killer cells with either unpolarized or polarized macrophages results in different functional outcomes. Proceedings of the National Academy of Sciences. 2010;107(50):21659-64.

  • Brown G. Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase. Biochem Soc Trans. 2007;35(5):1119–21.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009;29(43):13435–44.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brewer KL, Bethea JR, Yezierski RP. Neuroprotective effects of interleukin-10 following excitotoxic spinal cord injury. Exp Neurol. 1999;159(2):484–93.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • BETHEA JR, NAGASHIMA H, ACOSTA MC, BRICENO C, GOMEZ F, MARCILLO AE, et al. Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats. J Neurotrauma. 1999;16(10):851–63.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang L, Pei S, Han L, Guo B, Li Y, Duan R, et al. Mesenchymal stem cell-derived exosomes reduce A1 astrocytes via downregulation of phosphorylated NFκB P65 subunit in spinal cord injury. Cell Physiol Biochem. 2018;50(4):1535–59.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu C, Hu F, Jiao G, Guo Y, Zhou P, Zhang Y, et al. Dental pulp stem cell-derived exosomes suppress M1 macrophage polarization through the ROS-MAPK-NFκB P65 signaling pathway after spinal cord injury. J Nanobiotechnol. 2022;20(1):65.

    Article 
    CAS 

    Google Scholar
     

  • Xin W, Qiang S, Jianing D, Jiaming L, Fangqi L, Bin C, et al. Human bone marrow mesenchymal stem cell–derived exosomes attenuate blood–spinal cord barrier disruption via the TIMP2/MMP pathway after acute spinal cord injury. Mol Neurobiol. 2021;58:6490–504.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang J-H, Yin X-M, Xu Y, Xu C-C, Lin X, Ye F-B, et al. Systemic administration of exosomes released from mesenchymal stromal cells attenuates apoptosis, inflammation, and promotes angiogenesis after spinal cord injury in rats. J Neurotrauma. 2017;34(24):3388–96.

    Article 
    PubMed 

    Google Scholar
     

  • Zhang J, Cui Z, Feng G, Bao G, Xu G, Sun Y, et al. RBM5 and p53 expression after rat spinal cord injury: implications for neuronal apoptosis. Int J Biochem Cell Biol. 2015;60:43–52.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lin C-L, Wang J-Y, Huang Y-T, Kuo Y-H, Surendran K, Wang F-S. Wnt/β-catenin signaling modulates survival of high glucose–stressed mesangial cells. J Am Soc Nephrol. 2006;17(10):2812–20.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998;281(5381):1322–6.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen J, Zhang C, Li S, Li Z, Lai X, Xia Q. Exosomes derived from nerve stem cells loaded with FTY720 promote the recovery after spinal cord injury in rats by PTEN/AKT signal pathway. Journal of Immunology Research. 2021;2021.

  • Fan L, Dong J, He X, Zhang C, Zhang T. Bone marrow mesenchymal stem cells-derived exosomes reduce apoptosis and inflammatory response during spinal cord injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Hum Exp Toxicol. 2021;40(10):1612–23.

    Article 
    CAS 
    PubMed 

    Google Scholar
     



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