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Research Article

Bone mesenchymal stem cell-derived exosome-loaded injectable hydrogel for minimally invasive treatment of spinal cord injury

    Jiyun Cheng‡

    School of Basic Medicine & Public Health, Jinan University, Guangzhou, 510630, China

    ‡Authors contributed equally

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    ,
    Zheng Chen‡

    Department of Stomatology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

    ‡Authors contributed equally

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    ,
    Can Liu‡

    Department of Orthopedic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    ‡Authors contributed equally

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    ,
    Mei Zhong

    Intensive Care Unit, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510630, China

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    ,
    Shihuan Wang

    Child Developmental & Behavioral Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

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    ,
    Yongjian Sun

    *Author for correspondence:

    E-mail Address: nysysyj@163.com

    Department of Pediatric Orthopedic, Center for Orthopedic Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou, 510515, China

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    ,
    Huiquan Wen

    **Author for correspondence:

    E-mail Address: wenhq5@mail.sysu.edu.cn

    Department of Radiology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China

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    &
    Tao Shu

    ***Author for correspondence:

    E-mail Address: shutao2019@126.com

    Department of Spine Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, China

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    Published Online:30 Jun 2021https://doi.org/10.2217/nnm-2021-0025

    Abstract

    Aim: Bone mesenchymal stem cell-derived exosomes (Exos) have been shown to exert therapeutic effects in spinal cord injury (SCI). In this study, we aimed to apply bioengineering approaches to promote Exo retention and their sustained release for SCI repair. Materials & methods: 3D gelatin methacrylate hydrogel (GelMA) was used as a transplanted Exo delivery system (GelMA-Exos). The viability, proliferation, and differentiation of neural stem cells cultured on hydrogel were assessed. Further, GelMA-Exos was injected into the damaged lesions to assess its repair potential. Results: GelMA hydrogel enhanced the retention of Exos, which promoted the neuronal differentiation and extension in vitro. Furthermore, GelMA-Exos promoted neurogenesis and attenuated glial scars in the damaged lesions. Conclusion: The injectable Exo-loaded 3D hydrogel induced neurological functional recovery post SCI.

    Papers of special note have been highlighted as: • of interest

    References

    • 1. Hutson TH, Di Giovanni S. The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration. Nat. Rev. Neurol. 15(12), 732–745 (2019).
      MedlineGoogle Scholar
    • 2. Koffler J, Zhu W, Qu X et al. Biomimetic 3D-printed scaffolds for spinal cord injury repair. Nat. Med. 25(2), 263–269 (2019).
      Medline CASGoogle Scholar
    • 3. Hong LTA, Kim YM, Park HH et al. An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling. Nat. Commun. 8(1), 533 (2017).
      MedlineGoogle Scholar
    • 4. Li L, Xiao B, Mu J et al. A MnO2 Nanoparticle-dotted hydrogel promotes spinal cord repair via regulating reactive oxygen species microenvironment and synergizing with mesenchymal stem cells. ACS Nano 13(12), 14283–14293 (2019).
      Medline CASGoogle Scholar
    • 5. Zhou L, Fan L, Yi X et al. Soft conducting polymer hydrogels cross-linked and doped by tannic acid for spinal cord injury repair. ACS Nano 12(11), 10957–10967 (2018).
      Medline CASGoogle Scholar
    • 6. Mckay CA, Pomrenke RD, Mclane JS et al. An injectable, calcium responsive composite hydrogel for the treatment of acute spinal cord injury. ACS Appl. Mater. Interfaces 6(3), 1424–1438 (2014).
      Medline CASGoogle Scholar
    • 7. Fan L, Liu C, Chen X et al. Directing induced pluripotent stem cell derived neural stem cell fate with a three-dimensional biomimetic hydrogel for spinal cord injury repair. ACS Appl. Mater. Interfaces 10(21), 17742–17755 (2018). • An injectable biomimetic hydrogel could direct differentiation of endogenous neural stem cells.
      Medline CASGoogle Scholar
    • 8. Fuhrmann T, Tam RY, Ballarin B et al. Injectable hydrogel promotes early survival of induced pluripotent stem cell-derived oligodendrocytes and attenuates longterm teratoma formation in a spinal cord injury model. Biomaterials 83, 23–36 (2016).
      Medline CASGoogle Scholar
    • 9. Li X, Zhang C, Haggerty AE et al. The effect of a nanofiber-hydrogel composite on neural tissue repair and regeneration in the contused spinal cord. Biomaterials 245, 119978 (2020).
      Medline CASGoogle Scholar
    • 10. Wang C, Yue H, Feng Q, Xu B, Bian L, Shi P. Injectable nanoreinforced shape-memory hydrogel system for regenerating spinal cord tissue from traumatic injury. ACS Appl. Mater. Interfaces 10(35), 29299–29307 (2018).
      Medline CASGoogle Scholar
    • 11. Tukmachev D, Forostyak S, Koci Z et al. Injectable extracellular matrix hydrogels as scaffolds for spinal cord injury repair. Tissue Eng. Part A 22(3–4), 306–317 (2016).
      Medline CASGoogle Scholar
    • 12. Wassenaar JW, Braden RL, Osborn KG, Christman KL. Modulating in vivo degradation rate of injectable extracellular matrix hydrogels. J. Mater. Chem. B 4(16), 2794–2802 (2016).
      Medline CASGoogle Scholar
    • 13. Rose JC, Camara-Torres M, Rahimi K, Kohler J, Moller M, De Laporte L. Nerve cells decide to orient inside an injectable hydrogel with minimal structural guidance. Nano Lett. 17(6), 3782–3791 (2017).
      Medline CASGoogle Scholar
    • 14. Bonnet M, Trimaille T, Brezun JM et al. Motor and sensitive recovery after injection of a physically cross-linked PNIPAAm-g-PEG hydrogel in rat hemisectioned spinal cord. Mater. Sci. Eng. C Mater. Biol. Appl. 107, 110354 (2020).
      Medline CASGoogle Scholar
    • 15. He Z, Zang H, Zhu L et al. An anti-inflammatory peptide and brain-derived neurotrophic factor-modified hyaluronan-methylcellulose hydrogel promotes nerve regeneration in rats with spinal cord injury. Int. J. Nanomedicine 14, 721–732 (2019).
      MedlineGoogle Scholar
    • 16. Zhao YZ, Jiang X, Xiao J et al. Using NGF heparin-poloxamer thermosensitive hydrogels to enhance the nerve regeneration for spinal cord injury. Acta Biomater. 29, 71–80 (2016).
      Medline CASGoogle Scholar
    • 17. An H, Li Q, Wen J. Bone marrow mesenchymal stem cells encapsulated thermal-responsive hydrogel network bridges combined photo-plasmonic nanoparticulate system for the treatment of urinary bladder dysfunction after spinal cord injury. J. Photochem. Photobiol. B. 203, 111741 (2020).
      Medline CASGoogle Scholar
    • 18. Boido M, Ghibaudi M, Gentile P, Favaro E, Fusaro R, Tonda-Turo C. Chitosan-based hydrogel to support the paracrine activity of mesenchymal stem cells in spinal cord injury treatment. Sci. Rep. 9(1), 6402 (2019).
      Medline CASGoogle Scholar
    • 19. Sun G, Li G, Li D et al. hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Mater. Sci. Eng. C Mater. Biol. Appl. 89, 194–204 (2018).
      Medline CASGoogle Scholar
    • 20. Wang C, Wang M, Xia K et al. A bioactive injectable self-healing anti-inflammatory hydrogel with ultralong extracellular vesicles release synergistically enhances motor functional recovery of spinal cord injury. Bioact. Mater. 6(8), 2523–2534 (2021).
      Medline CASGoogle Scholar
    • 21. Waters R, Alam P, Pacelli S, Chakravarti AR, Ahmed RPH, Paul A. Stem cell-inspired secretome-rich injectable hydrogel to repair injured cardiac tissue. Acta Biomater. 69, 95–106 (2018).
      Medline CASGoogle Scholar
    • 22. Sun J, Zhang Y, Song X, Zhu J, Zhu Q. The healing effects of conditioned medium derived from mesenchymal stem cells on radiation-induced skin wounds in rats. Cell Transplant. 28(1), 105–115 (2019).
      MedlineGoogle Scholar
    • 23. Zhang K, Zhao X, Chen X et al. Enhanced therapeutic effects of mesenchymal stem cell-derived exosomes with an injectable hydrogel for hindlimb ischemia treatment. ACS Appl. Mater. Interfaces 10(36), 30081–30091 (2018).
      Medline CASGoogle Scholar
    • 24. Li L, Zhang Y, Mu J et al. Transplantation of human mesenchymal stem-cell-derived exosomes immobilized in an adhesive hydrogel for effective treatment of spinal cord injury. Nano Lett. 20(6), 4298–4305 (2020). • The exosomes from mesenchymal stem cells combined with hydrogel exert a beneficial therapeutic effect on spinal cord injury.
      Medline CASGoogle Scholar
    • 25. Rao F, Zhang D, Fang T et al. Exosomes from human gingiva-derived mesenchymal stem cells combined with biodegradable chitin conduits promote rat sciatic nerve regeneration. Stem Cells Int. 2019, 2546367 (2019).
      MedlineGoogle Scholar
    • 26. Brennan MA, Layrolle P, Mooney DJ. Biomaterials functionalized with MSC secreted extracellular vesicles and soluble factors for tissue regeneration. Adv. Funct. Mater. 30(37), doi:10.1002/adfm.201909125 (2020).
      MedlineGoogle Scholar
    • 27. Ahuja CS, Wilson JR, Nori S et al. Traumatic spinal cord injury. Nat. Rev. Dis. Primers 3, 17018 (2017).
      MedlineGoogle Scholar
    • 28. Liu S, Sandner B, Schackel T et al. Regulated viral BDNF delivery in combination with Schwann cells promotes axonal regeneration through capillary alginate hydrogels after spinal cord injury. Acta Biomater. 60, 167–180 (2017).
      MedlineGoogle Scholar
    • 29. Wang C, Gong Z, Huang X et al. An injectable heparin-Laponite hydrogel bridge FGF4 for spinal cord injury by stabilizing microtubule and improving mitochondrial function. Theranostics 9(23), 7016–7032 (2019).
      Medline CASGoogle Scholar
    • 30. Li LM, Han M, Jiang XC et al. Peptide-tethered hydrogel scaffold promotes recovery from spinal cord transection via synergism with mesenchymal stem cells. ACS Appl. Mater. Interfaces 9(4), 3330–3342 (2017).
      Medline CASGoogle Scholar
    • 31. Xu HL, Tian FR, Xiao J et al. Sustained-release of FGF-2 from a hybrid hydrogel of heparin-poloxamer and decellular matrix promotes the neuroprotective effects of proteins after spinal injury. Int. J. Nanomedicine 13, 681–694 (2018).
      Medline CASGoogle Scholar
    • 32. Agrawal NK, Allen P, Song YH et al. Oligonucleotide-functionalized hydrogels for sustained release of small molecule (aptamer) therapeutics. Acta Biomater. 102, 315–325 (2020).
      Medline CASGoogle Scholar
    • 33. Liu C, Fan L, Xing J et al. Inhibition of astrocytic differentiation of transplanted neural stem cells by chondroitin sulfate methacrylate hydrogels for the repair of injured spinal cord. Biomater. Sci. 7(5), 1995–2008 (2019).
      Medline CASGoogle Scholar
    • 34. Wang Q, He Y, Zhao Y et al. A thermosensitive heparin-poloxamer hydrogel bridges aFGF to treat spinal cord injury. ACS Appl. Mater. Interfaces 9(8), 6725–6745 (2017).
      Medline CASGoogle Scholar
    • 35. Huang JH, Yin XM, Xu Y 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 34(24), 3388–3396 (2017).
      MedlineGoogle Scholar
    • 36. Wang L, Pei S, Han L et al. Mesenchymal stem cell-derived exosomes reduce A1 astrocytes via downregulation of phosphorylated NFkappaB P65 subunit in spinal cord injury. Cell Physiol. Biochem. 50(4), 1535–1559 (2018).
      Medline CASGoogle Scholar
    • 37. Romanelli P, Bieler L, Scharler C et al. Extracellular vesicles can deliver anti-inflammatory and anti-scarring activities of mesenchymal stromal cells after spinal cord injury. Front. Neurol. 10, 1225 (2019). • Shows the role of mesenchymal stem cell exosomes in spinal cord injury repair by enhancing proliferation, attenuating scarring and modulating immune reactivity.
      MedlineGoogle Scholar
    • 38. Johnson CDL, Ganguly D, Zuidema JM et al. Injectable, magnetically orienting electrospun fiber conduits for neuron guidance. ACS Appl. Mater. Interfaces 11(1), 356–372 (2019).
      Medline CASGoogle Scholar
    • 39. Ghosh B, Nong J, Wang Z et al. A hydrogel engineered to deliver minocycline locally to the injured cervical spinal cord protects respiratory neural circuitry and preserves diaphragm function. Neurobiol. Dis. 127, 591–604 (2019).
      Medline CASGoogle Scholar