Effect of exosomes from adipose-derived stem cells on peripheral nerve regeneration_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

YIN Gang ^1,2 , LIU Caiyue ^3,4 , LIN Yaofa ² , XIE Zheng ² , HOU Chunlin ² ,  LIN Haodong ²

1. Department of Cell Biology, Naval Military Medical University (Second Military Medical University), Shanghai, 200433, P.R.China;
2. Department of Orthopaedic Surgery, Changzheng Hospital, Naval Military Medical University (Second Military Medical University), Shanghai, 200003, P.R.China;
3. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200011, P.R.China;
4. Department of Plastic Surgery, Changzheng Hospital, Naval Military Medical University (Second Military Medical University), Shanghai, 200003, P.R.China;

Corresponding author：

LIN Haodong, Email: linhaodong1978@smmu.edu.cn

Keywords：

Exosome; adipose-derived stem cells; peripheral nerve injury; nerve regeneration; rat

DOI：

10.7507/1002-1892.201707051

Video：

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ObjectiveTo investigate the effects of exosomes from adipose-derived stem cells (ADSCs) on peripheral nerve regeneration, and to find a new treatment for peripheral nerve injury. MethodsThirty-six adult Sprague Dawley (SD) rats (male or female, weighing 220-240 g) were randomly divided into 3 groups (n=12). Group A was the control group; group B was sciatic nerve injury group; group C was sciatic nerve injury combined with exosomes from ADSCs treatment group. The sciatic nerve was only exposed without injury in group A, and the sciatic nerve crush injury model was prepared in groups B and C. The SD rats in groups A and B were injected with PBS solution of 200 μL via tail veins; the SD rats in group C were injected with pure PBS solution of 200 μL containing 100 μg exosomes from ADSCs, once a week and injected for 12 weeks. At 1 week after the end of the injection, the rats were killed and the sciatic nerves were taken at the part of injury. The sciatic nerve fiber bundles were observed by HE staining; the SCs apoptosis of the sciatic nerve tissue were detected by TUNEL staining; the ultrastructure and SCs autophagy of the sciatic nerve were observed by transmission electron microscope. ResultsGross observation showed that there was no obvious abnormality in the injured limbs of group A, but there were the injured limbs paralysis and muscle atrophy in groups B and C, and the degree of paralysis and muscle atrophy in group C were lighter than those in group B. HE staining showed that the perineurium of group A was regular; the perineurium of group B was irregular, and there were a lot of cell-free structures and tissue fragments in group B; the perineurium of group C was more complete, and significantly well than that of group B. TUNEL staining showed that the SCs apoptosis was significantly increased in groups B and C than in group A, in group B than in group C (P<0.01). Transmission electron microscope observation showed that the SCs autophagosomes in groups B and C were significantly increased than those in group A, but the autophagosomes in group C were significantly lower than those in group B. ConclusionThe exosomes from ADSCs can promote the peripheral nerve regeneration. The mechanism may be related to reducing SCs apoptosis, inhibiting SCs autophagy, and reducing nerve Wallerian degeneration.

Citation： YIN Gang, LIU Caiyue, LIN Yaofa, XIE Zheng, HOU Chunlin, LIN Haodong. Effect of exosomes from adipose-derived stem cells on peripheral nerve regeneration. Chinese Journal of Reparative and Reconstructive Surgery, 2018, 32(12): 1592-1596. doi: 10.7507/1002-1892.201707051 Copy

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2.	Sadeghian H, Wolfe GI. Therapy update in nerve, neuromuscular junction and myopathic disorders. Curr Opin Neurol, 2010, 23(5): 496-501.
3.	Cooney DS, Wimmers EG, Ibrahim Z, et al. Mesenchymal stem cells enhance nerve regeneration in a rat sciatic nerve repair and hindlimb transplant model. Sci Rep, 2016, 6: 31306.
4.	Chaput N, Taïeb J, Schartz NE, et al. Exosome-based immunotherapy. Cancer Immunol Immunother, 2004, 53(3): 234-239.
5.	Yue Y, Yang X, Zhang L, et al. Low-intensity pulsed ultrasound upregulates pro-myelination indicators of Schwann cells enhanced by co-culture with adipose-derived stem cells. Cell Prolif, 2016, 49(6): 720-728.
6.	李超然, 黄桂林, 王帅. 间充质干细胞来源外泌体促进损伤组织修复与再生的应用与进展. 中国组织工程研究, 2018, 22(1): 133-139.
7.	Hervera A, Virgiliis De F, Palmisano I, et al. Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nat Cell Biol, 2018, 20(3): 307-319.
8.	Xu B, Zhang Y, Du XF, et al. Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Cell Res, 2017, 27(7): 882-897.
9.	Nielsen EØ, Chen L, Hansen JO, et al. Optimizing osteogenic differentiation of ovine adipose-derived stem cells by osteogenic induction medium and FGFb, BMP2, or NELL1 in vitro. Stem Cells Int, 2018, 2018: 9781393.
10.	张静, 易阳艳, 阳水发, 等. 脂肪干细胞来源外泌体对人脐静脉血管内皮细胞增殖、迁移及管样分化的影响. 中国修复重建外科杂志, 2018, 32(10): 1351-1357.
11.	林耀发, 宗海洋, 胡显腾, 等. 大鼠坐骨神经损伤后 Spastin 表达变化的实验研究. 中国修复重建外科杂志, 2017, 31(1): 80-84.
12.	Mor D, Kendig MD, Kang JWM, et al. Peripheral nerve injury impairs the ability to maintain behavioural flexibility following acute stress in the rat. Behav Brain Res, 2017, 328: 123-129.
13.	Cobianchi S, Jaramillo J, Luvisetto S, et al. Botulinum neurotoxin A promotes functional recovery after peripheral nerve injury by increasing regeneration of myelinated fibers. Neuroscience, 2017, 359: 82-91.
14.	Wang JT, Medress ZA, Barres BA. Axon degeneration: molecular mechanisms of a self-destruction pathway. J Cell Biol, 2012, 196(1): 7-18.
15.	Kikuchi S, Ninomiya T, Kohno T, et al. Cobalt inhibits motility of axonal mitochondria and induces axonal degeneration in cultured dorsal root ganglion cells of rat. Cell Biol Toxicol, 2018, 34(2): 93-107.
16.	Zhang Y, Chopp M, Liu XS, et al. Exosomes derived from mesenchymal stromal cells promote axonal growth of cortical neurons. Mol Neurobiol, 2017, 54(4): 2659-2673.
17.	周敏, 洪莉, 胡鸣, 等. 外泌体在周围神经损伤中的研究进展. 医学综述, 2017, 23(13): 2497-2500.
18.	Tassew NG, Charish J, Shabanzadeh AP, et al. Exosomes mediate mobilization of autocrine Wnt10b to promote axonal regeneration in the injured CNS. Cell Rep, 2017, 20(1): 99-111.
19.	Gomez-Sanchez JA, Pilch KS, van der Lans M, et al. After nerve injury, lineage tracing shows that myelin and remak Schwann cells elongate extensively and branch to form repair Schwann cells, which shorten radically on remyelination. J Neurosci, 2017, 37(37): 9086-9099.
20.	Clements MP, Byrne E, Camarillo Guerrero LF, et al. The wound microenvironment reprograms Schwann cells to invasive mesenchymal-like cells to drive peripheral nerve regeneration. Neuron, 2017, 96(1): 98-114.
21.	Takamatsu H, Takegahara N, Nakagawa Y, et al. Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nat Immunol, 2010, 11(7): 594-600.

1. Castillo-Galván ML, Martínez-Ruiz FM, de la Garza-Castro O, et al. Study of peripheral nerve injury in trauma patients. Gac Med Mex, 2014, 150(6): 527-532.
2. Sadeghian H, Wolfe GI. Therapy update in nerve, neuromuscular junction and myopathic disorders. Curr Opin Neurol, 2010, 23(5): 496-501.
3. Cooney DS, Wimmers EG, Ibrahim Z, et al. Mesenchymal stem cells enhance nerve regeneration in a rat sciatic nerve repair and hindlimb transplant model. Sci Rep, 2016, 6: 31306.
4. Chaput N, Taïeb J, Schartz NE, et al. Exosome-based immunotherapy. Cancer Immunol Immunother, 2004, 53(3): 234-239.
5. Yue Y, Yang X, Zhang L, et al. Low-intensity pulsed ultrasound upregulates pro-myelination indicators of Schwann cells enhanced by co-culture with adipose-derived stem cells. Cell Prolif, 2016, 49(6): 720-728.
6. 李超然, 黄桂林, 王帅. 间充质干细胞来源外泌体促进损伤组织修复与再生的应用与进展. 中国组织工程研究, 2018, 22(1): 133-139.
7. Hervera A, Virgiliis De F, Palmisano I, et al. Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nat Cell Biol, 2018, 20(3): 307-319.
8. Xu B, Zhang Y, Du XF, et al. Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Cell Res, 2017, 27(7): 882-897.
9. Nielsen EØ, Chen L, Hansen JO, et al. Optimizing osteogenic differentiation of ovine adipose-derived stem cells by osteogenic induction medium and FGFb, BMP2, or NELL1 in vitro. Stem Cells Int, 2018, 2018: 9781393.
10. 张静, 易阳艳, 阳水发, 等. 脂肪干细胞来源外泌体对人脐静脉血管内皮细胞增殖、迁移及管样分化的影响. 中国修复重建外科杂志, 2018, 32(10): 1351-1357.
11. 林耀发, 宗海洋, 胡显腾, 等. 大鼠坐骨神经损伤后 Spastin 表达变化的实验研究. 中国修复重建外科杂志, 2017, 31(1): 80-84.
12. Mor D, Kendig MD, Kang JWM, et al. Peripheral nerve injury impairs the ability to maintain behavioural flexibility following acute stress in the rat. Behav Brain Res, 2017, 328: 123-129.
13. Cobianchi S, Jaramillo J, Luvisetto S, et al. Botulinum neurotoxin A promotes functional recovery after peripheral nerve injury by increasing regeneration of myelinated fibers. Neuroscience, 2017, 359: 82-91.
14. Wang JT, Medress ZA, Barres BA. Axon degeneration: molecular mechanisms of a self-destruction pathway. J Cell Biol, 2012, 196(1): 7-18.
15. Kikuchi S, Ninomiya T, Kohno T, et al. Cobalt inhibits motility of axonal mitochondria and induces axonal degeneration in cultured dorsal root ganglion cells of rat. Cell Biol Toxicol, 2018, 34(2): 93-107.
16. Zhang Y, Chopp M, Liu XS, et al. Exosomes derived from mesenchymal stromal cells promote axonal growth of cortical neurons. Mol Neurobiol, 2017, 54(4): 2659-2673.
17. 周敏, 洪莉, 胡鸣, 等. 外泌体在周围神经损伤中的研究进展. 医学综述, 2017, 23(13): 2497-2500.
18. Tassew NG, Charish J, Shabanzadeh AP, et al. Exosomes mediate mobilization of autocrine Wnt10b to promote axonal regeneration in the injured CNS. Cell Rep, 2017, 20(1): 99-111.
19. Gomez-Sanchez JA, Pilch KS, van der Lans M, et al. After nerve injury, lineage tracing shows that myelin and remak Schwann cells elongate extensively and branch to form repair Schwann cells, which shorten radically on remyelination. J Neurosci, 2017, 37(37): 9086-9099.
20. Clements MP, Byrne E, Camarillo Guerrero LF, et al. The wound microenvironment reprograms Schwann cells to invasive mesenchymal-like cells to drive peripheral nerve regeneration. Neuron, 2017, 96(1): 98-114.
21. Takamatsu H, Takegahara N, Nakagawa Y, et al. Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nat Immunol, 2010, 11(7): 594-600.

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