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Low-Stiffness Hydrogels Promote Peripheral Nerve Regeneration Through the Rapid Release of Exosomes.

ABSTRACT: A hydrogel system loaded with mesenchymal stem cell-derived exosome (MSC-Exos) is an attractive new tool for tissue regeneration. However, the effect of the stiffness of exosome-loaded hydrogels on tissue regeneration is unclear. Here, the role of exosome-loaded hydrogel stiffness, during the regeneration of injured nerves, was assessed in vivo. The results showed that the photocrosslinkable hyaluronic acid methacrylate hydrogel stiffness plays an important role in repairing nerve injury. Compared with the stiff hydrogels loaded with exosomes, soft hydrogels loaded with exosomes showed better repair of injured peripheral nerves. The soft hydrogel promoted nerve repair by quickly releasing exosomes to inhibit the infiltration of macrophages and the expression of the proinflammatory factors IL-1β and TNF-α in injured nerves. Our work revealed that exosome-loaded hydrogel stiffness plays an important role in tissue regeneration by regulating exosome release behavior and provided important clues for the clinical application of biological scaffold materials.

SUBMITTER: Liu Z

PROVIDER: S-EPMC9260118 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Low-Stiffness Hydrogels Promote Peripheral Nerve Regeneration Through the Rapid Release of Exosomes.

Liu Zhixiao Z Tong Hua H Li Jian J Wang Ling L Fan Xiaoyi X Song Honghao H Yang Mei M Wang Haowei H Jiang Xin X Zhou Xuhui X Yuan Hongbin H Wang Yue Y

Frontiers in bioengineering and biotechnology 20220623

A hydrogel system loaded with mesenchymal stem cell-derived exosome (MSC-Exos) is an attractive new tool for tissue regeneration. However, the effect of the stiffness of exosome-loaded hydrogels on tissue regeneration is unclear. Here, the role of exosome-loaded hydrogel stiffness, during the regeneration of injured nerves, was assessed <i>in vivo</i>. The results showed that the photocrosslinkable hyaluronic acid methacrylate hydrogel stiffness plays an important role in repairing nerve injury. ...[more]

PMID: 35814007

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Project description:BackgroundSchwann cell-like cells (SCLCs), differentiated from mesenchymal stem cells, have shown promising outcomes in the treatment of peripheral nerve injuries in preclinical studies. However, certain clinical obstacles limit their application. Hence, the primary aim of this study was to investigate the role of exosomes derived from SCLCs (SCLCs-exo) in peripheral nerve regeneration.MethodsSCLCs were differentiated from human amniotic mesenchymal stem cells (hAMSCs) in vitro and validated by immunofluorescence, real-time quantitative PCR and western blot analysis. Exosomes derived from hAMSCs (hAMSCs-exo) and SCLCs were isolated by ultracentrifugation and validated by nanoparticle tracking analysis, WB analysis and electron microscopy. A prefabricated nerve graft was used to deliver hAMSCs-exo or SCLCs-exo in an injured sciatic nerve rat model. The effects of hAMSCs-exo or SCLCs-exo on rat peripheral nerve injury (PNI) regeneration were determined based on the recovery of neurological function and histomorphometric variation. The effects of hAMSCs-exo or SCLCs-exo on Schwann cells were also determined via cell proliferation and migration assessment.ResultsSCLCs significantly expressed the Schwann cell markers glial fibrillary acidic protein and S100. Compared to hAMSCs-exo, SCLCs-exo significantly enhanced motor function recovery, attenuated gastrocnemius muscle atrophy and facilitated axonal regrowth, myelin formation and angiogenesis in the rat model. Furthermore, hAMSCs-exo and SCLCs-exo were efficiently absorbed by Schwann cells. However, compared to hAMSCs-exo, SCLCs-exo significantly promoted the proliferation and migration of Schwann cells. SCLCs-exo also significantly upregulated the expression of a glial cell-derived neurotrophic factor, myelin positive regulators (SRY-box transcription factor 10, early growth response protein 2 and organic cation/carnitine transporter 6) and myelin proteins (myelin basic protein and myelin protein zero) in Schwann cells.ConclusionsThese findings suggest that SCLCs-exo can more efficiently promote PNI regeneration than hAMSCs-exo and are a potentially novel therapeutic approach for treating PNI.

Project description:Despite microsurgical repair, recovery of function following peripheral nerve injury is slow and often incomplete. Outcomes could be improved by an increased understanding of the molecular biology of regeneration and by translation of experimental bioengineering strategies. Topographical cues have been shown to be powerful regulators of the rate and directionality of neurite regeneration, and in this study we investigated the downstream molecular effects of linear micropatterned structures in an organotypic explant model. Linear topographical cues enhanced neurite outgrowth and our results demonstrated that the mTOR pathway is important in regulating these responses. mTOR gene expression peaked between 48 and 72h, coincident with the onset of rapid neurite outgrowth and glial migration, and correlated with neurite length at 48h. mTOR protein was located to glia and in a punctate distribution along neurites. mTOR levels peaked at 72h and were significantly increased by patterned topography (p<0.05). Furthermore, the topographical cues could override pharmacological inhibition. Downstream phosphorylation assays and inhibition of mTORC1 using rapamycin highlighted mTORC2 as an important mediator, and more specific therapeutic target. Quantitative immunohistochemistry confirmed the presence of the mTORC2 component rictor at the regenerating front where it co-localised with F-actin and vinculin. Collectively, these results provide a deeper understanding of the mechanism of action of topography on neural regeneration, and support the incorporation of topographical patterning in combination with pharmacological mTORC2 potentiation within biomaterial constructs used to repair peripheral nerves.Statement of significancePeripheral nerve injury is common and functionally devastating. Despite microsurgical repair, healing is slow and incomplete, with lasting functional deficit. There is a clear need to translate bioengineering approaches and increase our knowledge of the molecular processes controlling nerve regeneration to improve the rate and success of healing. Topographical cues are powerful determinants of neurite outgrowth and represent a highly translatable engineering strategy. Here we demonstrate, for the first time, that microtopography potentiates neurite outgrowth via the mTOR pathway, with the mTORC2 subtype being of particular importance. These results give further evidence for the incorporation of microtopographical cues into peripheral nerve regeneration conduits and indicate that mTORC2 may be a suitable therapeutic target to potentiate nerve regeneration.

Project description:BackgroundEfficient and stable delivery of neurotrophic factors (NTFs) is crucial to provide suitable microenvironment for peripheral nerve regeneration. Neurotrophin-3 (NT-3) is an important NTF during peripheral nerve regeneration which is scarce in the first few weeks of nerve defect. Exosomes are nanovesicles and have been served as promising candidate for biocarrier. In this work, NT-3 mRNA was encapsulated in adipose-derived stem cell (ADSC)-derived exosomes (ExoNT-3). These engineered exosomes were applied as NT-3 mRNA carrier and then were loaded in nerve guidance conduit (ExoNT-3-NGC) to bridge rat sciatic nerve defect.MethodNT-3 mRNA was encapsulated in exosomes by forcedly expression of NT-3 mRNA in the donor ADSCs. ExoNT-3 were co-cultured with SCs in vitro; after 24 h of culture, the efficiency of NT-3 mRNA delivery was evaluated by qPCR, western blotting and ELISA. Then, ExoNT-3 were loaded in alginate hydrogel to construct the nerve guidance conduits (ExoNT-3-NGC). ExoNT-3-NGC were implanted in vivo to reconstruct 10 mm rat sciatic nerve defect. The expression of NT-3 was measured 2 weeks after the implantation operation. The sciatic nerve functional index (SFI) was examined at 2 and 8 weeks after the operation. Moreover, the therapeutic effect of ExoNT-3-NGC was also evaluated by morphology assay, immunofluorescence staining of regenerated nerves, function evaluation of gastrocnemius muscles after 8 weeks of implantation.ResultsThe engineered exosomes could deliver NT-3 mRNA to the recipient cells efficiently and translated into functional protein. The constructed NGC could realize stable release of exosomes at least for 2 weeks. After NGC implantation in vivo, ExoNT-3-NGC group significantly promote nerve regeneration and improve the function recovery of gastrocnemius muscles compared with control exosomes (Exoempty-NGC) group.ConclusionIn this work, NGC was constructed to allow exosome-mediated NT-3 mRNA delivery. After ExoNT-3-NGC implantation in vivo, the level of NT-3 could restore which enhance the nerve regeneration. Our study provide a potential approach to improve nerve regeneration.

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Low-Stiffness Hydrogels Promote Peripheral Nerve Regeneration Through the Rapid Release of Exosomes.

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Low-Stiffness Hydrogels Promote Peripheral Nerve Regeneration Through the Rapid Release of Exosomes.

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