The application progress of exosomes derived from mesenchymal stem cells in tissue regeneration of orthopedics_West China Medical Journal

Authors：

XING Fei , CHEN Ran , DUAN Xin , CHEN Jialei ,  XIANG Zhou

Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

XIANG Zhou, Email: xiangzhou15@hotmail.com

Keywords：

Mesenchymal stem cells; Exosomes; Tissue engineering; Repair; Tissue regeneration

DOI：

10.7507/1002-0179.201810072

Video：

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Exosomes derived from mesenchymal stem cells are a class of discoid extracellular vesicles with a diameter of 40—100 nm discovered in recent years. They contain abundant nucleic acids, proteins and lipids, and have abundant biological information. Exosomes derived from mesenchymal stem cells regulate cell activities by acting on receptor cells, and promote regeneration of many tissues, such as bone, cartilage, skin, intervertebral disc, and spinal nerves. Studies have shown that exosomes derived from mesenchymal stem cells have similar biological functions as mesenchymal stem cells, and are more stable and easier to be preserved. Therefore, they have been increasingly applied in the field of orthopedic tissue repair in recent years. This paper reviews the application of exosomes derived from mesenchymal stem cells in orthopedics.

Citation： XING Fei, CHEN Ran, DUAN Xin, CHEN Jialei, XIANG Zhou. The application progress of exosomes derived from mesenchymal stem cells in tissue regeneration of orthopedics. West China Medical Journal, 2018, 33(12): 1558-1562. doi: 10.7507/1002-0179.201810072 Copy

1.	Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol, 2007, 213(2): 341-347.
2.	Meirelles LD, Fontes AM, Covas DT, et al. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev, 2009, 20(5/6): 419-427.
3.	Cordonnier M, Chanteloup G, Isambert NA, et al. Exosomes in cancer theranostic: diamonds in the rough. Cell Adh Migr, 2017, 11(2): 151-163.
4.	Fang T, Lv H, Lv G, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun, 2018, 9(1): 191.
5.	Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature, 2015, 523(7559): 177-182.
6.	Dougherty JA, Mergaye M, Kumar N, et al. Potential role of exosomes in mending a broken heart: nanoshuttles propelling future clinical therapeutics forward. Stem Cells, 2017: 5785436.
7.	Simons M, Raposo G. Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol, 2009, 21(4): 575-581.
8.	Kharaziha P, Ceder S, Li Q, et al. Tumor cell-derived exosomes: a message in a bottle. Biochim Biophys Acta, 2012, 1826(1): 103-111.
9.	Blanchard N, Lankar D, Faure F, et al. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol, 2002, 168(7): 3235-3241.
10.	Chen TS, Lai RC, Lee MM, et al. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res, 2010, 38(1): 215-224.
11.	Record M, Silvente-Poirot S, Poirot MA. Extracellular vesicles: lipids as key components of their biogenesis and functions. J Lipid Res, 2018, 59(8): 1316-1324.
12.	Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol, 2002, 2(8): 569-579.
13.	Alvarez ML, Khosroheidari M, Ravi RK, et al. Comparison of protein, microRNA, and mRNA yields using different methods of urinary exosome isolation for the discovery of kidney disease biomarkers. Kidney Int, 2012, 82(9): 1024-1032.
14.	Cheruvanky A, Zhou H, Pisitkun T, et al. Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. Am J Physiol Renal Physiol, 2007, 292(5): F1657-F1661.
15.	Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res, 2010, 4(3): 214-222.
16.	Clayton A, Court J, Navabi H, et al. Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. J Immunol Methods, 2001, 247(1/2): 163-174.
17.	Wunsch BH, Smith JT, Gifford SM, et al. Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. Nat Nanotechnol, 2016, 11(11): 936-940.
18.	Salomon C, Yee S, Scholz-Romero K, et al. Extravillous trophoblast cells-derived exosomes promote vascular smooth muscle cell migration. Front Pharmacol, 2014, 5: 175.
19.	Lässer C, Eldh M, Lötvall J. Isolation and characterization of RNA-containing exosomes. J Vis Exp, 2012(59): e3037.
20.	Wu YE, Deng WT, Klinke ID. Exosomes: improved methods to characterize their morphology, RNA content, and surface protein biomarkers. Analyst, 2015, 140(19): 6631-6642.
21.	Lai RC, Tan SS, Teh BJ, et al. Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics, 2012: 971907.
22.	Gonzalez-King H, García NA, Ontoria-Oviedo I, et al. Hypoxia inducible factor-1α potentiates jagged 1-mediated angiogenesis by mesenchymal stem cell-derived exosomes. Stem Cells, 2017, 35(7): 1747-1759.
23.	Zhang B, Wu X, Zhang X, et al. Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway. Stem Cells Transl Med, 2015, 4(5): 513-522.
24.	Ma J, Zhao YY, Sun L, et al. Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D. Stem Cells Transl Med, 2017, 6(1): 51-59.
25.	Zhou JY, Tan XH, Tan YH, et al. Mesenchymal stem cell derived exosomes in cancer progression, metastasis and drug delivery: a comprehensive review. J Cancer, 2018, 9(17): 3129-3137.
26.	Zhang B, Yin Y, Lai RC, et al. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev, 2014, 23(11): 1233-1244.
27.	Zhao Y, Sun X, Cao W, et al. Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem Cells Int, 2015: 761643.
28.	Yu B, Kim HW, Gong M, et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol, 2015, 182: 349-360.
29.	Feng Y, Huang W, Wani M, et al. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One, 2014, 9(2): e88685.
30.	Wang Y, Zhang L, Li Y, et al. Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol, 2015, 192: 61-69.
31.	Narayanan R, Huang CC, Ravindran S. Hijacking the cellular mail: exosome mediated differentiation of mesenchymal stem cells. Stem Cells Int, 2016: 3808674.
32.	Hu GW, Li Q, Niu X, et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Res Ther, 2015, 6: 10.
33.	Furuta T, Miyaki S, Ishitobi H, et al. Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model. Stem Cells Transl Med, 2016, 5(12): 1620-1630.
34.	Zhang J, Liu X, Li H, et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther, 2016, 7(1): 136.
35.	Zhang S, Chu WC, Lai RC, et al. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis Cartilage, 2016, 24(12): 2135-2140.
36.	Chen Z, Wang H, Xia Y, et al. Therapeutic potential of mesenchymal cell-derived miRNA-150-5p-expressing exosomes in rheumatoid arthritis mediated by the modulation of MMP14 and VEGF. J Immunol, 2018, 201(8): 2472-2482.
37.	Zhu Y, Wang Y, Zhao B, et al. Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Ther, 2017, 8(1): 64.
38.	Huang S, Leung VY, Long D, et al. Coupling of small leucine-rich proteoglycans to hypoxic survival of a progenitor cell-like subpopulation in rhesus macaque intervertebral disc. Biomaterials, 2013, 34(28): 6548-6558.
39.	Lu K, Li HY, Yang K, et al. Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells. Stem Cell Res Ther, 2017, 8(1): 108.
40.	Cheng X, Zhang G, Zhang L, et al. Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration. J Cell Mol Med, 2018, 22(1): 261-276.
41.	Xin H, Katakowski M, Wang F, et al. MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke, 2017, 48(3): 747-753.
42.	Xin HQ, Li Y, Liu ZW, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells, 2013, 31(12): 2737-2746.
43.	Lankford KL, Arroyo EJ, Nazimek K, et al. Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS One, 2018, 13(1): e0190358.
44.	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, 2018, 89: 194-204.
45.	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, 2017, 34(24): 3388-3396.
46.	Shabbir A, Cox A, Rodriguez-Menocal LA, et al. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev, 2015, 24(14): 1635-1647.
47.	Zhang J, Guan J, Niu X, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med, 2015, 13: 49.
48.	Liang XL, Zhang LA, Wang SH, et al. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci, 2016, 129(11): 2182-2189.
49.	Hu L, Wang J, Zhou X, et al. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep, 2016, 6: 32993.
50.	Zhang B, Wang M, Gong A, et al. HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells, 2015, 33(7): 2158-2168.
51.	Fang S, Xu C, Zhang Y, et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-β/SMAD2 pathway during wound healing. Stem Cells Transl Med, 2016, 5(10): 1425-1439.

1. Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol, 2007, 213(2): 341-347.
2. Meirelles LD, Fontes AM, Covas DT, et al. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev, 2009, 20(5/6): 419-427.
3. Cordonnier M, Chanteloup G, Isambert NA, et al. Exosomes in cancer theranostic: diamonds in the rough. Cell Adh Migr, 2017, 11(2): 151-163.
4. Fang T, Lv H, Lv G, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun, 2018, 9(1): 191.
5. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature, 2015, 523(7559): 177-182.
6. Dougherty JA, Mergaye M, Kumar N, et al. Potential role of exosomes in mending a broken heart: nanoshuttles propelling future clinical therapeutics forward. Stem Cells, 2017: 5785436.
7. Simons M, Raposo G. Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol, 2009, 21(4): 575-581.
8. Kharaziha P, Ceder S, Li Q, et al. Tumor cell-derived exosomes: a message in a bottle. Biochim Biophys Acta, 2012, 1826(1): 103-111.
9. Blanchard N, Lankar D, Faure F, et al. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol, 2002, 168(7): 3235-3241.
10. Chen TS, Lai RC, Lee MM, et al. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res, 2010, 38(1): 215-224.
11. Record M, Silvente-Poirot S, Poirot MA. Extracellular vesicles: lipids as key components of their biogenesis and functions. J Lipid Res, 2018, 59(8): 1316-1324.
12. Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol, 2002, 2(8): 569-579.
13. Alvarez ML, Khosroheidari M, Ravi RK, et al. Comparison of protein, microRNA, and mRNA yields using different methods of urinary exosome isolation for the discovery of kidney disease biomarkers. Kidney Int, 2012, 82(9): 1024-1032.
14. Cheruvanky A, Zhou H, Pisitkun T, et al. Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. Am J Physiol Renal Physiol, 2007, 292(5): F1657-F1661.
15. Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res, 2010, 4(3): 214-222.
16. Clayton A, Court J, Navabi H, et al. Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. J Immunol Methods, 2001, 247(1/2): 163-174.
17. Wunsch BH, Smith JT, Gifford SM, et al. Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. Nat Nanotechnol, 2016, 11(11): 936-940.
18. Salomon C, Yee S, Scholz-Romero K, et al. Extravillous trophoblast cells-derived exosomes promote vascular smooth muscle cell migration. Front Pharmacol, 2014, 5: 175.
19. Lässer C, Eldh M, Lötvall J. Isolation and characterization of RNA-containing exosomes. J Vis Exp, 2012(59): e3037.
20. Wu YE, Deng WT, Klinke ID. Exosomes: improved methods to characterize their morphology, RNA content, and surface protein biomarkers. Analyst, 2015, 140(19): 6631-6642.
21. Lai RC, Tan SS, Teh BJ, et al. Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics, 2012: 971907.
22. Gonzalez-King H, García NA, Ontoria-Oviedo I, et al. Hypoxia inducible factor-1α potentiates jagged 1-mediated angiogenesis by mesenchymal stem cell-derived exosomes. Stem Cells, 2017, 35(7): 1747-1759.
23. Zhang B, Wu X, Zhang X, et al. Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway. Stem Cells Transl Med, 2015, 4(5): 513-522.
24. Ma J, Zhao YY, Sun L, et al. Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D. Stem Cells Transl Med, 2017, 6(1): 51-59.
25. Zhou JY, Tan XH, Tan YH, et al. Mesenchymal stem cell derived exosomes in cancer progression, metastasis and drug delivery: a comprehensive review. J Cancer, 2018, 9(17): 3129-3137.
26. Zhang B, Yin Y, Lai RC, et al. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev, 2014, 23(11): 1233-1244.
27. Zhao Y, Sun X, Cao W, et al. Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem Cells Int, 2015: 761643.
28. Yu B, Kim HW, Gong M, et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol, 2015, 182: 349-360.
29. Feng Y, Huang W, Wani M, et al. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One, 2014, 9(2): e88685.
30. Wang Y, Zhang L, Li Y, et al. Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol, 2015, 192: 61-69.
31. Narayanan R, Huang CC, Ravindran S. Hijacking the cellular mail: exosome mediated differentiation of mesenchymal stem cells. Stem Cells Int, 2016: 3808674.
32. Hu GW, Li Q, Niu X, et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Res Ther, 2015, 6: 10.
33. Furuta T, Miyaki S, Ishitobi H, et al. Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model. Stem Cells Transl Med, 2016, 5(12): 1620-1630.
34. Zhang J, Liu X, Li H, et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther, 2016, 7(1): 136.
35. Zhang S, Chu WC, Lai RC, et al. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis Cartilage, 2016, 24(12): 2135-2140.
36. Chen Z, Wang H, Xia Y, et al. Therapeutic potential of mesenchymal cell-derived miRNA-150-5p-expressing exosomes in rheumatoid arthritis mediated by the modulation of MMP14 and VEGF. J Immunol, 2018, 201(8): 2472-2482.
37. Zhu Y, Wang Y, Zhao B, et al. Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Ther, 2017, 8(1): 64.
38. Huang S, Leung VY, Long D, et al. Coupling of small leucine-rich proteoglycans to hypoxic survival of a progenitor cell-like subpopulation in rhesus macaque intervertebral disc. Biomaterials, 2013, 34(28): 6548-6558.
39. Lu K, Li HY, Yang K, et al. Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells. Stem Cell Res Ther, 2017, 8(1): 108.
40. Cheng X, Zhang G, Zhang L, et al. Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration. J Cell Mol Med, 2018, 22(1): 261-276.
41. Xin H, Katakowski M, Wang F, et al. MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke, 2017, 48(3): 747-753.
42. Xin HQ, Li Y, Liu ZW, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells, 2013, 31(12): 2737-2746.
43. Lankford KL, Arroyo EJ, Nazimek K, et al. Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS One, 2018, 13(1): e0190358.
44. 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, 2018, 89: 194-204.
45. 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, 2017, 34(24): 3388-3396.
46. Shabbir A, Cox A, Rodriguez-Menocal LA, et al. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev, 2015, 24(14): 1635-1647.
47. Zhang J, Guan J, Niu X, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med, 2015, 13: 49.
48. Liang XL, Zhang LA, Wang SH, et al. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci, 2016, 129(11): 2182-2189.
49. Hu L, Wang J, Zhou X, et al. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep, 2016, 6: 32993.
50. Zhang B, Wang M, Gong A, et al. HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells, 2015, 33(7): 2158-2168.
51. Fang S, Xu C, Zhang Y, et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-β/SMAD2 pathway during wound healing. Stem Cells Transl Med, 2016, 5(10): 1425-1439.

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