干细胞衍生外泌体:再生医学的治疗新策略
Stem Cell-Derived Exosomes: A New Therapeutic Strategy in Regenerative Medicine
DOI: 10.12677/ACM.2022.12121633, PDF,    国家自然科学基金支持
作者: 张怡璇, 陆有群:北京大学第三医院,北京;北京大学医学部,北京;洪 晶, 彭荣梅*:北京大学第三医院,北京
关键词: 外泌体增殖干细胞再生医学Exosomes Proliferation Stem Cell Regenerative Medicine
摘要: 外泌体源自内吞膜,是纳米级的囊泡,含有核酸、蛋白质、脂质等生物分子,是原核生物和真核生物中细胞间通讯的有效载体,参与了多种病理生理过程的调节。当前研究发现,干细胞来源的外泌体具有促进细胞增殖、迁移、免疫调节等多种功能,可作为无细胞治疗剂应用于再生医学领域,包括急慢性肾损伤、缺血–再灌注损伤,肝脏、皮肤、角膜损伤等。本综述主要聚焦外泌体的促增殖作用,概述其未来可能的应用方向。
Abstract: Exosomes (EXOs), derived from endocytic membranes, are nanoscale vesicles containing biomol-ecules such as nucleic acids, proteins and lipids. They work as effective carriers of intercellular communication in prokaryotic and eukaryotic organisms, and play significant roles in the regulation of both physiological and pathological processes. Current studies suggest that stem cell-derived exosomes can promote cell proliferation, migration and immune regulation. They can be utilized as cell-free therapeutic agents in the field of regenerative medicine, including acute/chronic renal injury, ischemia reperfusion injury, liver regeneration, skin regeneration, corneal regeneration. This review focuses on the ability of exosomes in promoting cell proliferation and summarizes their possible future application directions.
文章引用:张怡璇, 陆有群, 洪晶, 彭荣梅. 干细胞衍生外泌体:再生医学的治疗新策略[J]. 临床医学进展, 2022, 12(12): 11329-11337. https://doi.org/10.12677/ACM.2022.12121633

参考文献

[1] Chargaff, E. and West, R. (1946) The Biological Significance of the Thromboplastic Protein of Blood. Journal of Bio-logical Chemistry, 166, 189-197. [Google Scholar] [CrossRef
[2] Szwedowicz, U., Łapińska, Z., GajewskaNaryniecka, A., et al. (2022) Exosomes and Other Extracellular Vesicles with High Therapeutic Potential: Their Applications in Oncology, Neurology, and Dermatology. Molecules, 27, Article No. 1303. [Google Scholar] [CrossRef] [PubMed]
[3] Ebrahimi, A., Ahmadi, H., et al. (2021) Therapeutic Effects of Stem Cells in Different Body Systems, a Novel Method That Is Yet to Gain Trust: A Comprehensive Review. Bosnian Journal of Basic Medical Sciences, 21, 672-701. [Google Scholar] [CrossRef] [PubMed]
[4] Alvites, R., Branquinho, M., et al. (2022) Mesenchymal Stem/Stromal Cells and Their Paracrine Activity-Immunomodulation Mechanisms and How to Influence the Therapeutic Potential. Pharmaceutics, 14, Article No. 381. [Google Scholar] [CrossRef] [PubMed]
[5] Baldini, N., et al. (2012) Mesenchymal Stem Cell Secreted Vesicles Provide Novel Opportunities in (Stem) Cell-Free Therapy. Frontiers in Physiology, 3, Article No. 359. [Google Scholar] [CrossRef] [PubMed]
[6] Han, C., Sun, X., Liu, L., et al. (2016) Exosomes and Their Therapeutic Potentials of Stem Cells. Stem Cells International, 2016, Article ID: 7653489. [Google Scholar] [CrossRef] [PubMed]
[7] Phinney, D.G. and Pittenger, M.F. (2017) Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells, 35, 851-858. [Google Scholar] [CrossRef] [PubMed]
[8] Lou, G., Chen, Z., Zheng, M., et al. (2017) Mesenchymal Stem Cell-Derived Exosomes as a New Therapeutic Strategy for Liver Diseases. Experimental & Molecular Medicine, 49, 346. [Google Scholar] [CrossRef] [PubMed]
[9] Mardpour, S., Yousefi, A.A., et al. (2018) The Extracellular Ves-icles-Derived from Mesenchymal Stromal Cells: A New Therapeutic Option in Regenerative Medicine. Journal of Cellular Biochemistry, 119, 8048-8073. [Google Scholar] [CrossRef] [PubMed]
[10] Mendt, M., Rezvani, K. and Shpall, E. (2019) Mesenchymal Stem Cell-Derived Exosomes for Clinical Use. Bone Marrow Transplantation, 54, 789-792. [Google Scholar] [CrossRef] [PubMed]
[11] Lee, J., et al. (2020) Mesenchymal Stem/Stromal Cell-Derived Exosomes for Immunomodulatory Therapeutics and Skin Regeneration. Cells, 9, Article No. 1157. [Google Scholar] [CrossRef] [PubMed]
[12] Kalluri, R. and LeBleu, V.S. (2020) The Biology, Function, and Bio-medical Applications of Exosomes. Science, 367, eaau6977. [Google Scholar] [CrossRef] [PubMed]
[13] He, C., Zheng, S., Luo, Y., et al. (2018) Exosome Theranostics: Biology and Translational Medicine. Theranostics, 8, 237-255. [Google Scholar] [CrossRef] [PubMed]
[14] Cha, H., Hong, S., et al. (2020) Stem Cell-Derived Exosomes and Nanovesicles: Promotion of Cell Proliferation, Migration, and Anti-Senescence for Treatment of Wound Damage and Skin Ageing. Pharmaceutics, 12, Article No. 1135. [Google Scholar] [CrossRef] [PubMed]
[15] An, Y., Lin, S., Tan, X., et al. (2021) Exosomes from Adi-pose-Derived Stem Cells and Application to Skin Wound Healing. Cell Proliferation, 54, Article No. 12993. [Google Scholar] [CrossRef] [PubMed]
[16] Pelchen, M.A., et al. (2016) The Intracellular Plasma Membrane-Connected Compartment in the Assembly of HIV-1 in Human Macrophages. BMC Biology, 14, Article No. 50. [Google Scholar] [CrossRef] [PubMed]
[17] Teng, F. and Fussenegger, M. (2020) Shedding Light on Extra-cellular Vesicle Biogenesis and Bioengineering. Advanced Science (Weinh), 8, Article ID: 2003505. [Google Scholar] [CrossRef] [PubMed]
[18] Sinha, S., Hoshino, D., et al. (2016) Cortactin Promotes Exosome Secretion by Controlling Branched Actin Dynamics. Journal of Cell Biology, 214, 197-213. [Google Scholar] [CrossRef] [PubMed]
[19] Raposo, G., Nijman, H.W., Stoorvogel, W., et al. (1996) B Lympho-cytes Secrete Antigen-Presenting Vesicles. The Journal of Experimental Medicine, 183, 1161-1172. [Google Scholar] [CrossRef] [PubMed]
[20] Peters, P.J., Geuze, H.J., et al. (1989) Molecules Relevant for T Cell-Target Cell Interaction Are Present in Cytolytic Granules of Human T Lymphocytes. European Journal of Immu-nology, 19, 1469-1475. [Google Scholar] [CrossRef] [PubMed]
[21] Zitvogel, L., Regnault, A., Lozier, A., et al. (1998) Eradication of Established Murine Tumors Using a Novel Cell-Free Vaccine: Dendritic Cell-Derived Exosomes. Nature Medicine, 4, 594-600. [Google Scholar] [CrossRef] [PubMed]
[22] Heijnen, H.F.G., Schiel, A.E., Fijnheer, R., et al. (1999) Ac-tivated Platelets Release Two Types of Membrane Vesicles: Microvesicles by Surface Shedding and Exosomes Derived from Exocytosis of Multivesicular Bodies and Alpha-Granules. Blood, 94, 3791-3799. [Google Scholar] [CrossRef
[23] Fevrier, B., Vilette, D., Archer, F., et al. (2004) Cells Release Prions in Association with Exosomes. Proceedings of the National Academy of Sciences of the United States of America, 101, 9683-9688. [Google Scholar] [CrossRef] [PubMed]
[24] Wolfers, J., Lozier, A., Raposo, G., et al. (2001) Tumor-Derived Exosomes Are a Source of Shared Tumor Rejection Antigens for CTL Cross-Priming. Nature Medicine, 7, 297-303. [Google Scholar] [CrossRef] [PubMed]
[25] Vrijsen, K.R., Sluijter, J.P.G., Schuchardt, M.W.L., et al. (2010) Cardiomyocyte Progenitor Cell-Derived Exosomes Stimulate Migration of Endothelial Cells. Journal of Cellular and Molecular Medicine, 14, 1064-1070. [Google Scholar] [CrossRef] [PubMed]
[26] Dignat-George, F. and Boulanger, C.M. (2011) The Many Faces of Endothelial Microparticles. Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 27-33. [Google Scholar] [CrossRef
[27] Lai, R.C., Arslan, F., Lee, M.M., et al. (2010) Exosome Secreted by MSC Reduces Myocardial Ischemia/Reperfusion Injury. Stem Cell Research, 4, 214-222. [Google Scholar] [CrossRef] [PubMed]
[28] Edelmann, M.J. and Kima, P.E. (2022) Current Understanding of Extracellular Vesicle Homing/Tropism. Zoonoses, 2, 14. [Google Scholar] [CrossRef
[29] Tkach, M. and Théry, C. (2016) Communication by Ex-tracellular Vesicles: Where We Are and Where We Need to Go. Cell, 164, 1226-1232. [Google Scholar] [CrossRef] [PubMed]
[30] Batagov, A.O. and Kurochkin, I.V. (2013) Exosomes Secreted by Human Cells Transport Largely mRNA Fragments That Are Enriched in the 3’-Untranslated Regions. Biology Direct, 8, Article No. 12. [Google Scholar] [CrossRef] [PubMed]
[31] Bruno, S., Grange, C., et al. (2009) Mesenchymal Stem Cell-Derived Microvesicles Protect against Acute Tubular Injury. Journal of the American Society of Nephrology, 20, 1053-1067. [Google Scholar] [CrossRef
[32] Kosanović, M., Milutinovic, B., Glamočlija, S., et al. (2022) Extracellular Vesicles and Acute Kidney Injury: Potential Therapeutic Avenue for Renal Repair and Regeneration. International Journal of Molecular Sciences, 23, Article No. 3792. [Google Scholar] [CrossRef] [PubMed]
[33] Zhang, B., Wang, M., Gong, A., et al. (2015) HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing. Stem Cells, 33, 2158-2168. [Google Scholar] [CrossRef] [PubMed]
[34] Katsuda, T., Tsuchiya, R., Kosaka, N., et al. (2013) Human Adipose Tis-sue-Derived Mesenchymal Stem Cells Secrete Functional Neprilysin-Bound Exosomes. Scientific Reports, 3, Article No. 1197. [Google Scholar] [CrossRef] [PubMed]
[35] Amarnath, S., et al. (2015) Bone Marrow-Derived Mesenchymal Stromal Cells Harness Purinergenic Signaling to Tolerize Human Th1 Cells in Vivo. Stem Cells, 33, 1200-1212. [Google Scholar] [CrossRef] [PubMed]
[36] Cheng, X., Zhang, G., Zhang, L., et al. (2018) Mesenchymal Stem Cells Deliver Exogenous miR-21 via Exosomes to Inhibit Nucleus Pulposus Cell Apoptosis and Reduce Intervertebral Disc Degeneration. Journal of Cellular and Molecular Medicine, 22, 261-276. [Google Scholar] [CrossRef] [PubMed]
[37] Xin, H., Wang, F., Li, Y., et al. (2017) Secondary Release of Exosomes from Astrocytes Contributes to the Increase in Neural Plasticity and Improvement of Functional Recovery after Stroke in Rats Treated with Exosomes Harvested from MicroRNA 133b-Overexpressing Multipotent Mesenchymal Stromal Cells. Cell Transplantation, 26, 243-257. [Google Scholar] [CrossRef
[38] Negahdari, B., et al. (2018) Stem Cell Therapy: A New Thera-peutic Option for Cardiovascular Diseases. Journal of Cellular Biochemistry, 119, 95-104. [Google Scholar] [CrossRef] [PubMed]
[39] YanezMo, M., Andreu, Z., et al. (2015) Biological Properties of Extracel-lular Vesicles and Their Physiological Functions. Journal of Extracellular Vesicles, 4, Article No. 27066.
[40] Grange, C., Skovronova, R., Marabese, F., et al. (2019) Stem Cell-Derived Extracellular Vesicles and Kidney Regeneration. Cells, 8, Article No. 1240. [Google Scholar] [CrossRef] [PubMed]
[41] Gregorini, M., Corradetti, V., et al. (2017) Perfusion of Isolated Rat Kidney with Mesenchymal Stromal Cells/Extracellular Vesicles Prevents Ischaemic Injury. Journal of Cellular and Molecular Medicine, 21, 3381-3393. [Google Scholar] [CrossRef] [PubMed]
[42] Grange, C., Tritta, S., Tapparo, M., et al. (2019) Stem Cell-Derived Ex-tracellular Vesicles Inhibit and Revert Fibrosis Progression in a Mouse Model of Diabetic Nephropathy. Scientific Re-ports, 9, Article No. 4468. [Google Scholar] [CrossRef] [PubMed]
[43] Li, T., Yan, Y., Wang, B., et al. (2013) Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis. Stem Cells and Development, 22, 845-854. [Google Scholar] [CrossRef] [PubMed]
[44] Aldawsari, H. and Amiji, M. (2016) Pancreatic Cancer Cell Exosome-Mediated Macrophage Reprogramming and the Role of MicroRNAs 155 and 125b2 Transfection Using Na-noparticle Delivery Systems. Scientific Reports, 6, Article No. 30110. [Google Scholar] [CrossRef] [PubMed]
[45] Alhomrani, M., Correia, J., Zavou, M., et al. (2017) The Human Amnion Epithelial Cell Secretome Decreases Hepatic Fibrosis in Mice with Chronic Liver Fibrosis. Frontiers in Pharmacology, 8, Article No. 748. [Google Scholar] [CrossRef] [PubMed]
[46] Nojima, H., et al. (2016) Hepatocyte Exosomes Mediate Liver Repair and Regeneration via Sphingosine-1-Phosphate. Journal of Hepatology, 64, 60-68. [Google Scholar] [CrossRef] [PubMed]
[47] Liu, Y., Lou, G., Li, A., et al. (2018) AMSC-Derived Exosomes Alleviate Lipopolysaccharide/d-Galactosamine-Induced Acute Liver Failure by miR-17-Mediated Reduction of TXNIP/NLRP3 Inflammasome Activation in Macrophages. EBioMedicine, 36, 140-150. [Google Scholar] [CrossRef] [PubMed]
[48] Zhang, S., Jiang, L., Hu, H., et al. (2020) Pretreatment of Exosomes Derived from hUCMSCs with TNF-α Ameliorates Acute Liver Failure by Inhibiting the Activation of NLRP3 in Macrophage. Life Sciences, 246, Article ID: 117401. [Google Scholar] [CrossRef] [PubMed]
[49] Shao, M., Xu, Q., Wu, Z., et al. (2020) Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Ameliorate IL-6-Induced Acute Liver Injury through miR-455-3p. Stem Cell Research & Therapy, 11, Article No. 37. [Google Scholar] [CrossRef] [PubMed]
[50] Huang, L., Ma, W., Ma, Y., et al. (2015) Exosomes in Mesenchymal Stem Cells, a New Therapeutic Strategy for Cardiovascular Diseases? International Journal of Biological Sciences, 11, 238-245. [Google Scholar] [CrossRef] [PubMed]
[51] Feng, Y., Huang, W., Wani, M., et al. (2014) Ischemic Preconditioning Potentiates the Protective Effect of Stem Cells through Secretion of Exosomes by Targeting Mecp2 via miR-22. PLOS ONE, 9, e88685. [Google Scholar] [CrossRef] [PubMed]
[52] Follis, A.V., et al. (2013) PUMA Binding Induces Partial Un-folding within BCL-xL to Disrupt p53 Binding and Promote Apoptosis. Nature Chemical Biology, 9, 163-168. [Google Scholar] [CrossRef] [PubMed]
[53] Shao, L., Zhang, Y., Lan, B., et al. (2017) MiRNA-Sequence Indicates That Mesenchymal Stem Cells and Exosomes Have Similar Mechanism to Enhance Cardiac Repair. BioMed Research International, 2017, Article ID: 4150705. [Google Scholar] [CrossRef] [PubMed]
[54] Maegdefessel, L., Raaz, U., et al. (2014) miR-24 Limits Aortic Vas-cular Inflammation and Murine Abdominal Aneurysm Development. Nature Communications, 5, Article No. 5214. [Google Scholar] [CrossRef] [PubMed]
[55] Sabin, K., Kikyo, N. (2014) Microvesicles as Mediators of Tissue Re-generation. Translational Research, 163, 286-295. [Google Scholar] [CrossRef] [PubMed]
[56] Zhang, S., Liu, X., et al. (2020) Mesenchymal Stromal Cell-Derived Exosomes Improve Pulmonary Hypertension through Inhibition of Pulmonary Vascular Remodeling. Respiratory Research, 21, Article No. 71. [Google Scholar] [CrossRef] [PubMed]
[57] Liang, X., Zhang, L., Wang, S., et al. (2016) Exosomes Secreted by Mesenchymal Stem Cells Promote Endothelial Cell Angiogenesis by Transferring miR-125a. Journal of Cell Science, 129, 2182-2189. [Google Scholar] [CrossRef] [PubMed]
[58] Kang, T., Naddell, C., et al. (2016) Adipose-Derived Stem Cells Induce Angiogenesis via Microvesicle Transport of miRNA-31. Stem Cells Translational Medicine, 5, 440-450. [Google Scholar] [CrossRef] [PubMed]
[59] Choi, E.W., et al. (2018) Exosomes from Human Adipose-Derived Stem Cells Promote Proliferation and Migration of Skin Fibroblasts. Experimental Dermatology, 27, 1170-1172. [Google Scholar] [CrossRef] [PubMed]
[60] Wang, L., Hu, L., Zhou, X., et al. (2017) Exosomes Secreted by Human Adipose Mesenchymal Stem Cells Promote Scarless Cutaneous Repair by Regulating Extracellular Matrix Remodelling. Scientific Reports, 7, Article No. 13321. [Google Scholar] [CrossRef] [PubMed]
[61] Tiwari, A., Singh, A., Verma, S., et al. (2021) Mini Review: Current Trends and Understanding of Exosome Therapeutic Potential in Corneal Diseases. Frontiers in Pharmacology, 12, Article ID: 684712. [Google Scholar] [CrossRef] [PubMed]
[62] Buono, L., Scalabrin, S., et al. (2021) Mesenchymal Stem Cell-Derived Extracellular Vesicles Protect Human Corneal Endothelial Cells from Endoplasmic Reticulum Stress-Mediated Apoptosis. International Journal of Molecular Sciences, 22, Article No. 4930. [Google Scholar] [CrossRef] [PubMed]
[63] Shang, Q., Chu, Y., Li, Y., et al. (2020) Adipose-Derived Mesenchymal Stromal Cells Promote Corneal Wound Healing by Accelerating the Clearance of Neutrophils in Cornea. Cell Death & Disease, 11, Article No. 707. [Google Scholar] [CrossRef] [PubMed]
[64] Han, K.Y., et al. (2017) Potential Role of Corneal Epithelial Cell-Derived Exosomes in Corneal Wound Healing and Neovascularization. Scientific Reports, 7, Article No. 40548. [Google Scholar] [CrossRef] [PubMed]
[65] Leszczynska, A., Kulkarni, M., et al. (2018) Exosomes from Normal and Diabetic Human Corneolimbal Keratocytes Differentially Regulate Migration, Proliferation and Marker Expression of Limbal Epithelial Cells. Scientific Reports, 8, Article No. 15173. [Google Scholar] [CrossRef] [PubMed]
[66] Shojaati, G., Khandaker, I., et al. (2019) Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA. Stem Cells Translational Medicine, 8, 1192-1201. [Google Scholar] [CrossRef] [PubMed]
[67] Samaeekia, R., Rabiee, B., Putra, I., et al. (2018) Effect of Human Corneal Mesenchymal Stromal Cell-Derived Exosomes on Corneal Epithelial Wound Healing. Investigative Ophthal-mology & Visual Science, 59, 5194-5200. [Google Scholar] [CrossRef] [PubMed]
[68] Yao, L., et al. (2012) Role of Mesenchymal Stem Cells on Cornea Wound Healing Induced by Acute Alkali Burn. PLOS ONE, 7, Article No. 30842. [Google Scholar] [CrossRef] [PubMed]
[69] Xin, H., Li, Y., Cui, Y., et al. (2013) Systemic Administration of Exosomes Released from Mesenchymal Stromal Cells Promote Functional Recovery and Neurovascular Plasticity after Stroke in Rats. Journal of Cerebral Blood Flow & Metabolism, 33, 1711-1715. [Google Scholar] [CrossRef] [PubMed]
[70] Pei, X., Li, Y.., Zhu, L., et al. (2020) Astrocyte-Derived Exosomes Transfer miR-190b to Inhibit Oxygen and Glucose Deprivation-Induced Autophagy and Neuronal Apoptosis. Cell Cycle, 19, 906-917. [Google Scholar] [CrossRef] [PubMed]
[71] Xin, H., Katakowski, M., Wang, F., et al. (2017) MicroRNA Cluster miR-17-92 Cluster in Exosomes Enhance Neuroplasticity and Functional Recovery after Stroke in Rats. Stroke, 48, 747-753. [Google Scholar] [CrossRef
[72] Chiarini, A., Armato, U., Gardenal, E., et al. (2017) Amyloid β-Exposed Human Astrocytes Overproduce Phospho-Tau and Overrelease It within Exosomes, Effects Sup-pressed by Calcilytic NPS 2143-Further Implications for Alzheimer’s Therapy. Frontiers in Neuroscience, 11, Article No. 217. [Google Scholar] [CrossRef] [PubMed]
[73] Rosas Hernandez, H., Cuevas, E., et al. (2019) Characterization of Serum Exosomes from a Transgenic Mouse Model of Alzheimer’s Disease. Current Alzheimer Research, 16, 388-395. [Google Scholar] [CrossRef] [PubMed]
[74] Mahairaki, V. and Delgado Peraza, F. (2020) Astro-cyte- and Neuron-Derived Extracellular Vesicles from Alzheimer’s Disease Patients Effect Complement-Mediated Neurotoxicity. Cells, 9, Article No. 1618. [Google Scholar] [CrossRef] [PubMed]