Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Accelerate Functional Recovery After Spinal Cord Injury by Promoting the Phagocytosis of Macrophages to Clean Myelin Debris

Frontiers in Cell and Developmental Biology - Tập 9
Xiaolong Sheng1,2,3,4, Jinyun Zhao1,2,3,4, Miao Li5,1,2,3,4, Yan Xu6,2,3,4, Yi Zhou7,1,2,3,4, Jiaqi Xu1,2,3,4, Rundong He1,2,3,4, Hongbin Lü6,2,3,4, Tianding Wu1,2,3,4, Chunyue Duan1,2,3,4, Yong Cao1,2,3,4, Jianzhong Hu1,2,3,4
1Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
2Hunan Engineering Research Center of Sports and Health, Changsha, China
3Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
5Department of Orthopedics, Hunan Children’s Hospital, Changsha, China
6Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China
7Department of Pain, Institute of Pain Medicine, Third Xiangya Hospital of Central South University, Changsha, China

Tóm tắt

Macrophage phagocytosis contributes predominantly to processing central nervous system (CNS) debris and further facilitates neurological function restoration after CNS injury. The aims of this study were to evaluate the effect of bone marrow mesenchymal stem cells (BMSC)-derived exosomes (BMSC-Exos) on the phagocytic capability of macrophages to clear myelin debris and to investigate the underlying molecular mechanism during the spinal cord injury (SCI) process. This work reveals that monocyte-derived macrophages (MDMs) infiltrating into the SCI site could efficiently engulf myelin debris and process phagocytic material. However, the phagocytic ability of macrophages to clear tissue debris is compromised after SCI. The administration of BMSC-Exos as an approach for SCI treatment could rescue macrophage normal function by improving the phagocytic capability of myelin debris internalization, which is beneficial for SCI repair, as evidenced by better axon regrowth and increased hindlimb locomotor functional recovery in a rodent model. Examination of macrophage treatment with BMSC-Exos revealed that BMSC-Exos could promote the capacity of macrophages to phagocytose myelin debris in vitro and could create a regenerative microenvironment for axon regrowth. In addition, we confirmed that BMSC-Exo treatment resulted in improved phagocytosis of engulfed myelin debris by promoting the expression of macrophage receptor with collagenous structure (MARCO) in macrophages. The inhibition of MARCO with PolyG (a MARCO antagonist) impaired the effect of BMSC-Exos on the phagocytic capacity of macrophages and resulted in compromised myelin clearance at the lesion site, leading to further tissue damage and impaired functional healing after SCI. In conclusion, these data indicated that targeting the phagocytic ability of macrophages may have therapeutic potential for the improvement in functional healing after SCI. The administration of BMSC-Exos as a cell-free immune therapy strategy has wide application prospects for SCI treatment.

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Tài liệu tham khảo

Basso, 2006, Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains., J. Neurotrauma, 23, 635, 10.1089/neu.2006.23.635

Berghoff, 2021, Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis., Nat. Neurosci., 24, 47, 10.1038/s41593-020-00757-6

Cao, 2021, Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis., Stem Cell Res Ther., 12, 10.1186/s13287-020-02078-8

Cao, 2017, Three dimensional quantification of microarchitecture and vessel regeneration by synchrotron radiation microcomputed tomography in a rat model of spinal cord injury., J. Neurotrauma, 34, 1187, 10.1089/neu.2016.4697

Cignarella, 2020, TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis., Acta Neuropathol., 140, 513, 10.1007/s00401-020-02193-z

Cunha, 2020, Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis., J. Exp. Med., 217, 10.1084/jem.20191390

David, 2018, Myeloid cell responses after spinal cord injury., J. Neuroimmunol., 321, 97, 10.1016/j.jneuroim.2018.06.003

Doring, 2015, Stimulation of monocytes, macrophages, and microglia by amphotericin B and macrophage colony-stimulating factor promotes remyelination., J. Neurosci., 35, 1136, 10.1523/JNEUROSCI.1797-14.2015

Elomaa, 1998, Structure of the human macrophage MARCO receptor and characterization of its bacteria-binding region., J. Biol. Chem., 273, 4530, 10.1074/jbc.273.8.4530

Evans, 2014, High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury., Exp. Neurol., 254, 109, 10.1016/j.expneurol.2014.01.013

Feng, 2021, Emerging exosomes and exosomal MiRNAs in spinal cord injury., Front. Cell Dev. Biol., 9, 10.3389/fcell.2021.703989

Gensel, 2015, Macrophage activation and its role in repair and pathology after spinal cord injury., Brain Res., 1619, 1, 10.1016/j.brainres.2014.12.045

Grajchen, 2020, CD36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammation., J. Neuroinflammation, 17, 10.1186/s12974-020-01899-x

Gu, 2020, Bone marrow mesenchymal stem cell-derived exosomes improves spinal cord function after injury in rats by activating autophagy., Drug Des. Devel. Ther., 14, 1621, 10.2147/DDDT.S237502

Guo, 2016, Rescuing macrophage normal function in spinal cord injury with embryonic stem cell conditioned media., Mol. Brain, 9, 10.1186/s13041-016-0233-3

Hade, 2021, Mesenchymal stem cell-derived exosomes: applications in regenerative medicine., Cells, 10, 10.3390/cells10081959

He, 2018, Exosome theranostics: biology and translational medicine., Theranostics, 8, 237, 10.7150/thno.21945

Huang, , Clinical neurorestorative therapeutic guidelines for spinal cord injury (IANR/CANR version 2019)., J. Orthop. Translat., 20, 14, 10.1016/j.jot.2019.10.006

Huang, , Exosomes derived from miR-126-modified MSCs promote angiogenesis and neurogenesis and attenuate apoptosis after spinal cord injury in rats., Neuroscience, 424, 133, 10.1016/j.neuroscience.2019.10.043

Huang, , Extracellular vesicles derived from epidural fat-mesenchymal stem cells attenuate NLRP3 inflammasome activation and improve functional recovery after spinal cord injury., Neurochem. Res., 45, 760, 10.1007/s11064-019-02950-x

Huang, 2017, Systemic administration of exosomes released from mesenchymal stromal cells attenuates apoptosis, inflammation, and promotes angiogenesis after spinal cord injury in rats., J. Neurotrauma, 34, 3388, 10.1089/neu.2017.5063

Imai, 2008, Delayed accumulation of activated macrophages and inhibition of remyelination after spinal cord injury in an adult rodent model., J. Neurosurg. Spine, 8, 58, 10.3171/SPI-08/01/058

Jackson, 2016, Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS., Stem Cells, 34, 2210, 10.1002/stem.2372

Kalluri, 2020, The biology, function, and biomedical applications of exosomes., Science, 367, 10.1126/science.aau6977

Khan, 2021, Native and bioengineered exosomes for ischemic stroke therapy., Front. Cell Dev. Biol., 9, 10.3389/fcell.2021.619565

Kim, 2011, Isolation and culture of neurons and astrocytes from the mouse brain cortex., Methods Mol. Biol., 793, 63, 10.1007/978-1-61779-328-8_4

Koganti, 2020, Invasion of microglia/macrophages and granulocytes into the Mauthner axon myelin sheath following spinal cord injury of the adult goldfish, Carassius auratus., J. Morphol., 281, 135, 10.1002/jmor.21086

Kopper, 2018, Myelin as an inflammatory mediator: myelin interactions with complement, macrophages, and microglia in spinal cord injury., J. Neurosci. Res., 96, 969, 10.1002/jnr.24114

Kucharova, 2017, Distinct NG2 proteoglycan-dependent roles of resident microglia and bone marrow-derived macrophages during myelin damage and repair., PLoS One, 12, 10.1371/journal.pone.0187530

Lankford, 2018, Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord., PLoS One, 13, 10.1371/journal.pone.0190358

Lee, 2021, Therapeutic features and updated clinical trials of mesenchymal stem cell (MSC)-derived exosomes., J. Clin. Med., 10, 10.3390/jcm10040711

Li, 2020, Glial metabolic rewiring promotes axon regeneration and functional recovery in the central nervous system., Cell Metab., 32, 767, 10.1016/j.cmet.2020.08.015

Li, 2020, Microglia-organized scar-free spinal cord repair in neonatal mice., Nature, 587, 613, 10.1038/s41586-020-2795-6

Liu, 2019, Exosomes derived from bone mesenchymal stem cells repair traumatic spinal cord injury by suppressing the activation of A1 neurotoxic reactive astrocytes., J. Neurotrauma, 36, 469, 10.1089/neu.2018.5835

Liu, 2021, Mesenchymal stem cell-derived exosomes: therapeutic opportunities and challenges for spinal cord injury., Stem Cell Res. Ther., 12, 10.1186/s13287-021-02153-8

Liu, 2021, Myelin debris stimulates NG2/CSPG4 expression in bone marrow-derived macrophages in the injured spinal cord., Front. Cell. Neurosci., 15, 10.3389/fncel.2021.651827

Lloyd, 2017, Microglia: origins, homeostasis, and roles in myelin repair., Curr. Opin. Neurobiol., 47, 113, 10.1016/j.conb.2017.10.001

Milich, 2019, The origin, fate, and contribution of macrophages to spinal cord injury pathology., Acta Neuropathol., 137, 785, 10.1007/s00401-019-01992-3

Nardone, 2015, Assessment of corticospinal excitability after traumatic spinal cord injury using MEP recruitment curves: a preliminary TMS study., Spinal Cord, 53, 534, 10.1038/sc.2015.12

Nguyen, 2011, Quantitative assessment of immune cells in the injured spinal cord tissue by flow cytometry: a novel use for a cell purification method., J. Vis. Exp., 50, 10.3791/2698

Nikfarjam, 2020, Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine., J. Transl. Med., 18, 10.1186/s12967-020-02622-3

Ohno, 2013, Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells., Mol. Ther., 21, 185, 10.1038/mt.2012.180

Rolfe, 2017, In vitro phagocytosis of myelin debris by bone marrow-derived macrophages., J. Vis. Exp., 130

Samal, 2021, Drug delivery to the bone microenvironment mediated by exosomes: an axiom or enigma., Int. J. Nanomedicine, 16, 3509, 10.2147/ijn.s307843

Savino, 2021, Macrophage receptor with collagenous structure polymorphism and recurrent respiratory infections and wheezing during infancy: a 5-years follow-up study., Front. Pediatr., 9, 10.3389/fped.2021.666423

Sefiani, 2021, The potential role of inflammation in modulating endogenous hippocampal neurogenesis after spinal cord injury., Front. Neurosci., 15, 10.3389/fnins.2021.682259

Van Broeckhoven, 2021, Macrophage phagocytosis after spinal cord injury: when friends become foes., Brain, 10.1093/brain/awab250

Vargas, 2010, Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury., Proc. Natl. Acad. Sci. U.S.A., 107, 11993, 10.1073/pnas.1001948107

Wan, 2021, GIT1 protects traumatically injured spinal cord by prompting microvascular endothelial cells to clear myelin debris., Aging (Albany N. Y.), 13, 7067, 10.18632/aging.202560

Wang, 2020, Astrocytes directly clear myelin debris through endocytosis pathways and followed by excessive gliosis after spinal cord injury., Biochem. Biophys. Res. Commun., 525, 20, 10.1016/j.bbrc.2020.02.069

Wang, 2015, Macrophages in spinal cord injury: phenotypic and functional change from exposure to myelin debris., Glia, 63, 635, 10.1002/glia.22774

Wang, 2012, MIF produced by bone marrow-derived macrophages contributes to teratoma progression after embryonic stem cell transplantation., Cancer Res., 72, 2867, 10.1158/0008-5472.CAN-11-3247

Wu, 2021, Metformin promotes microglial cells to facilitate myelin debris clearance and accelerate nerve repairment after spinal cord injury., Acta Pharmacol. Sin., 10.1038/s41401-021-00759-5

Yuan, 2019, Exosomes derived from pericytes improve microcirculation and protect blood-spinal cord barrier after spinal cord injury in mice., Front. Neurosci., 13, 10.3389/fnins.2019.00319

Zeng, 2020, Exosomes secreted from bone marrow mesenchymal stem cells attenuate oxygen-glucose deprivation/reoxygenation-induced pyroptosis in PC12 cells by promoting AMPK-dependent autophagic flux., Front. Cell. Neurosci., 14, 10.3389/fncel.2020.00182

Zhang, 2019, Exosomes–beyond stem cells for restorative therapy in stroke and neurological injury., Nat. Rev. Neurol., 15, 193, 10.1038/s41582-018-0126-4

Zhou, 2019, Activating adiponectin signaling with exogenous adiporon reduces myelin lipid accumulation and suppresses macrophage recruitment after spinal cord injury., J. Neurotrauma, 36, 903, 10.1089/neu.2018.5783

Zhou, 2019, Microvascular endothelial cells engulf myelin debris and promote macrophage recruitment and fibrosis after neural injury., Nat. Neurosci., 22, 421, 10.1038/s41593-018-0324-9

Zrzavy, 2021, Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury., Brain, 144, 144, 10.1093/brain/awaa360

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Frontiers in Cell and Developmental Biology

Tập 9

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