Abstract
Mesenchymal stem cells (MSCs)-based therapy has been reported to be a potential approach to treat various diseases and the paracrine role might be the underlying mechanism. Exosomes were considered an important part of this paracrine role. It was reported that maintenance of MSCs in hypoxia conditions for a short time has shown to be beneficial for the therapeutic effect of MSCs and MSCs-derived exosomes. In this review, we summarized the recent developments on exosomes derived from hypoxia-preconditioned mesenchymal stem cells (hypoMSCs-Exo), including the characteristics of hypoMSCs-Exo in morphology and contents, diseases in which hypoMSCs-Exo showed more effective, and the cellular and molecular mechanisms that hypoMSCs-Exo showed more effective in disease treatment. Besides, we also discussed the limitations of current studies and the issues that needed to be improved in the application of hypoMSCs-Exo. This review aimed to promote a comprehensive and systematic understanding of this type of exosome with great therapeutic potential.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Available underlying data will be provided upon reasonable request.
References
Abdollahi H, Harris L, Zhang P, McIlhenny S, Srinivas V, Tulenko T, DiMuzio P (2011) The role of hypoxia in stem cell differentiation and therapeutics. J Surg Res 165(1):112–117. https://doi.org/10.1016/j.jss.2009.09.057
Asgari Taei A, Khodabakhsh P, Nasoohi S, Farahmandfar M, Dargahi L (2022) Paracrine effects of mesenchymal stem cells in ischemic stroke: opportunities and challenges. Mol Neurobiol. https://doi.org/10.1007/s12035-022-02967-4
Bister N, Pistono C, Huremagic B, Jolkkonen J, Giugno R, Malm T (2020) Hypoxia and extracellular vesicles: a review on methods, vesicular cargo and functions. J Extracell Vesicles 10(1):e12002
Cao S, Huang Y, Dai Z, Liao Y, Zhang J, Wang L, Liu L (2022) Circular RNA mmu_circ_0001295 from hypoxia pretreated adipose-derived mesenchymal stem cells (ADSCs) exosomes improves outcomes and inhibits sepsis-induced renal injury in a mouse model of sepsis. Bioengineered 13(3):6323–6331. https://doi.org/10.1080/21655979.2022.2044720
Cheng H, Chang S, Xu R, Chen L, Song X, Wu J, Ma J (2020) Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis. Stem Cell Res Ther 11(1):224. https://doi.org/10.1186/s13287-020-01737-0
Cui GH, Wu J, Mou FF, Xie WH, Wang FB, Wang QL, Guo HD (2018) Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. Faseb J 32(2):654–668. https://doi.org/10.1096/fj.201700600R
Eiro N, Fraile M, González-Jubete A, González LO, Vizoso FJ (2022) Mesenchymal (stem) stromal cells based as new therapeutic alternative in inflammatory bowel disease: basic mechanisms, experimental and clinical evidence, and challenges. Int J Mol Sci 23(16). https://doi.org/10.3390/ijms23168905
Fu Y, Sui B, Xiang L, Yan X, Wu D, Shi S, Hu X (2021) Emerging understanding of apoptosis in mediating mesenchymal stem cell therapy. Cell Death Dis 12(6):596. https://doi.org/10.1038/s41419-021-03883-6
Gao S, Zhang Y, Liang K, Bi R, Du Y (2022) Mesenchymal stem cells (MSCs): a novel therapy for type 2 diabetes. Stem Cells Int 2022:8637493. https://doi.org/10.1155/2022/8637493
Gao W, He R, Ren J, Zhang W, Wang K, Zhu L, Liang T (2021) Exosomal HMGB1 derived from hypoxia-conditioned bone marrow mesenchymal stem cells increases angiogenesis via the JNK/HIF-1α pathway. FEBS Open Bio 11(5):1364–1373. https://doi.org/10.1002/2211-5463.13142
Ge L, Xun C, Li W, Jin S, Liu Z, Zhuo Y, Lu M (2021) Extracellular vesicles derived from hypoxia-preconditioned olfactory mucosa mesenchymal stem cells enhance angiogenesis via miR-612. J Nanobiotechnology 19(1):380. https://doi.org/10.1186/s12951-021-01126-6
Gupta S, Rawat S, Krishnakumar V, Rao EP, Mohanty S (2022) Hypoxia preconditioning elicit differential response in tissue-specific MSCs via immunomodulation and exosomal secretion. Cell Tissue Res 388(3):535–548. https://doi.org/10.1007/s00441-022-03615-y
Han YD, Bai Y, Yan XL, Ren J, Zeng Q, Li XD, Han Y (2018) Co-transplantation of exosomes derived from hypoxia-preconditioned adipose mesenchymal stem cells promotes neovascularization and graft survival in fat grafting. Biochem Biophys Res Commun 497(1):305–312. https://doi.org/10.1016/j.bbrc.2018.02.076
Hodson L (2014) Adipose tissue oxygenation: effects on metabolic function. Adipocyte 3(1):75–80. https://doi.org/10.4161/adip.27114
Hu MS, Borrelli MR, Lorenz HP, Longaker MT, Wan DC (2018) Mesenchymal stromal cells and cutaneous wound healing: a comprehensive review of the background, role, and therapeutic potential. Stem Cells Int 2018:6901983. https://doi.org/10.1155/2018/6901983
Kang X, Jiang L, Chen X, Wang X, Gu S, Wang J, Zhang J (2021) Exosomes derived from hypoxic bone marrow mesenchymal stem cells rescue OGD-induced injury in neural cells by suppressing NLRP3 inflammasome-mediated pyroptosis. Exp Cell Res 405(1):112635. https://doi.org/10.1016/j.bbrc.2018.02.076
Karami Fath M, Anjomrooz M, Taha SR, Shariat Zadeh M, Sahraei M, Atbaei R, Barati G (2022) The therapeutic effect of exosomes from mesenchymal stem cells on colorectal cancer: toward cell-free therapy. Pathol Res Pract 237:154024. https://doi.org/10.1016/j.prp.2022.154024
Li B, Xian X, Lin X, Huang L, Liang A, Jiang H, Gong Q (2022) Hypoxia alters the proteome profile and enhances the angiogenic potential of dental pulp stem cell-derived exosomes. Biomolecules 12(4). https://doi.org/10.3390/biom12040575
Liang Y, Wu JH, Zhu JH, Yang H (2022) Exosomes secreted by hypoxia-pre-conditioned adipose-derived mesenchymal stem cells reduce neuronal apoptosis in rats with spinal cord injury. J Neurotrauma 39(9–10):701–714. https://doi.org/10.1089/neu.2021.0290
Lin X, Wang H, Wu T, Zhu Y, Jiang L (2022) Exosomes derived from stem cells from apical papilla promote angiogenesis via miR-126 under hypoxia. Oral Dis. https://doi.org/10.1111/odi.14285
Liu H, Jin M, Ji M, Zhang W, Liu A, Wang T (2022a) Hypoxic pretreatment of adipose-derived stem cell exosomes improved cognition by delivery of circ-Epc1 and shifting microglial M1/M2 polarization in an Alzheimer’s disease mice model. Aging (albany NY) 14(7):3070–3083. https://doi.org/10.18632/aging.203989
Liu P, Qin L, Liu C, Mi J, Zhang Q, Wang S, Wu X (2022b) Exosomes derived from hypoxia-conditioned stem cells of human deciduous exfoliated teeth enhance angiogenesis via the transfer of let-7f-5p and miR-210–3p. Front Cell Dev Biol 10:879877. https://doi.org/10.3389/fcell.2022.879877
Liu W, Li L, Rong Y, Qian D, Chen J, Zhou Z, Cai W (2020a) Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126. Acta Biomater 103:196–212. https://doi.org/10.1016/j.actbio.2019.12.020
Liu W, Rong Y, Wang J, Zhou Z, Ge X, Ji C, Cai W (2020b) Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization. J Neuroinflammation 17(1):47. https://doi.org/10.1186/s12974-020-1726-7
Liu X, Wang J, Wang P, Zhong L, Wang S, Feng Q, Zhou L (2022c) Hypoxia-pretreated mesenchymal stem cell-derived exosomes-loaded low-temperature extrusion 3D-printed implants for neural regeneration after traumatic brain injury in canines. Front Bioeng Biotechnol 10:1025138. https://doi.org/10.3389/fbioe.2022.1025138
Mu J, Li L, Wu J, Huang T, Zhang Y, Cao J, Gao J (2022) Hypoxia-stimulated mesenchymal stem cell-derived exosomes loaded by adhesive hydrogel for effective angiogenic treatment of spinal cord injury. Biomater Sci 10(7):1803–1811. https://doi.org/10.1039/d1bm01722e
Műzes G, Sipos F (2022) Mesenchymal stem cell-derived secretome: a potential therapeutic option for autoimmune and immune-mediated inflammatory diseases. Cells 11(15). https://doi.org/10.3390/cells11152300
Niazi V, Ghafouri-Fard S, Verdi J, Jeibouei S, Karami F, Pourhadi M, Zomorrod MS (2022) Hypoxia preconditioned mesenchymal stem cell-derived exosomes induce ex vivo expansion of umbilical cord blood hematopoietic stem cells CD133+ by stimulation of Notch signaling pathway. Biotechnol Prog 38(1):e3222. https://doi.org/10.1002/btpr.3222
Ren J (2022) Intermittent hypoxia BMSCs-derived exosomal miR-31-5p promotes lung adenocarcinoma development via WDR5-induced epithelial mesenchymal transition. Sleep Breath. https://doi.org/10.1007/s11325-022-02737-5
Rodríguez-Pallares J, García-Garrote M, Parga JA, Labandeira-García JL (2023) Combined cell-based therapy strategies for the treatment of Parkinson’s disease: focus on mesenchymal stromal cells. Neural Regen Res 18(3):478–484. https://doi.org/10.4103/1673-5374.350193
Sahoo S, Losordo D (2014) Exosomes and cardiac repair after myocardial infarction. Circ Res 114(2):333–344. https://doi.org/10.1161/circresaha.114.300639
Sang L, Guo X, Fan H, Shi J, Hou S, Lv Q (2022) Mesenchymal stem cell-derived extracellular vesicles as idiopathic pulmonary fibrosis microenvironment targeted delivery. Cells 11(15). https://doi.org/10.3390/cells11152322
Severino P, D’Amato A, Pucci M, Infusino F, Adamo F, Birtolo LI, Fedele F (2020) Ischemic heart disease pathophysiology paradigms overview: from plaque activation to microvascular dysfunction. Int J Mol Sci 21(21). https://doi.org/10.3390/ijms21218118
Sjöstedt S, Rooth G, Caligara F (1960) The oxygen tension of the blood in the umbilical cord and the intervillous space. Arch Dis Child 35(184):529–533. https://doi.org/10.1136/adc.35.184.529
Spencer J, Ferraro F, Roussakis E, Klein A, Wu J, Runnels J, Lin C (2014) Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508(7495):269–273. https://doi.org/10.1038/nature13034
Sun L, Zhu W, Zhao P, Wang Q, Fan B, Zhu Y, Zhang F (2020) Long noncoding RNA UCA1 from hypoxia-conditioned hMSC-derived exosomes: a novel molecular target for cardioprotection through miR-873–5p/XIAP axis. Cell Death Dis 11(8):696. https://doi.org/10.1038/s41419-020-02783-5
Taheem D, Foyt D, Loaiza S, Ferreira S, Ilic D, Auner H, Gentleman E (2018) Differential regulation of human bone marrow mesenchymal stromal cell chondrogenesis by hypoxia inducible factor-1α hydroxylase inhibitors. Stem Cells (Dayton, Ohio) 36(9):1380–1392. https://doi.org/10.1002/stem.2844
Thankam FG, Chandra I, Diaz C, Dilisio MF, Fleegel J, Gross RM, Agrawal DK (2020) Matrix regeneration proteins in the hypoxia-triggered exosomes of shoulder tenocytes and adipose-derived mesenchymal stem cells. Mol Cell Biochem 465(1–2):75–87. https://doi.org/10.1007/s11010-019-03669-7
Théry C, Witwer K, Aikawa E, Alcaraz M, Anderson J, Andriantsitohaina R, Zuba-Surma E (2018) Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 7(1):1535750. https://doi.org/10.1080/20013078.2018.1535750
Xu J, Chen P, Yu C, Shi Q, Wei S, Li Y, Di G (2022) Hypoxic bone marrow mesenchymal stromal cells-derived exosomal miR-182–5p promotes liver regeneration via FOXO1-mediated macrophage polarization. Faseb J 36(10):e22553. https://doi.org/10.1096/fj.202101868RRR
Xue C, Shen Y, Li X, Li B, Zhao S, Gu J, Zhao RC (2018) Exosomes derived from hypoxia-treated human adipose mesenchymal stem cells enhance angiogenesis through the PKA signaling pathway. Stem Cells Dev 27(7):456–465. https://doi.org/10.1089/scd.2017.0296
Yang T, Li W, Peng A, Liu J, Wang Q (2022a) Exosomes derived from bone marrow-mesenchymal stem cells attenuates cisplatin-induced ototoxicity in a mouse model. J Clin Med 11(16). https://doi.org/10.3390/jcm11164743
Yang Y, Li XB, Li Y, Li TX, Li P, Deng GM, Chen XH (2022b) Extracellular Vesicles derived from hypoxia-conditioned adipose-derived mesenchymal stem cells enhance lymphangiogenesis. Cell Transplant 31:9636897221107536. https://doi.org/10.1177/09636897221107536
Yu C, Boyd N, Cringle S, Alder V, Yu D (2002) Oxygen distribution and consumption in rat lower incisor pulp. Arch Oral Biol 47(7):529–536. https://doi.org/10.1016/s0003-9969(02)00036-5
Yuan N, Ge Z, Ji W, Li J (2021) Exosomes secreted from hypoxia-preconditioned mesenchymal stem cells prevent steroid-induced osteonecrosis of the femoral head by promoting angiogenesis in rats. Biomed Res Int 2021:6655225. https://doi.org/10.1155/2021/6655225
Zhang B, Tian X, Qu Z, Hao J, Zhang W (2022a) Hypoxia-preconditioned extracellular vesicles from mesenchymal stem cells improve cartilage repair in osteoarthritis. Membranes (Basel) 12(2). https://doi.org/10.3390/membranes12020225
Zhang HM, Yuan S, Meng H, Hou XT, Li J, Xue JC, Zhang QG (2022b) Stem cell-based therapies for inflammatory bowel disease. Int J Mol Sci 23(15). https://doi.org/10.3390/ijms23158494
Zhang L, Wei Q, Liu X, Zhang T, Wang S, Zhou L, Wang D (2021a) Exosomal microRNA-98–5p from hypoxic bone marrow mesenchymal stem cells inhibits myocardial ischemia-reperfusion injury by reducing TLR4 and activating the PI3K/Akt signaling pathway. Int Immunopharmacol 101(Pt B):107592. https://doi.org/10.1016/j.intimp.2021.107592
Zhang T, Yan S, Song Y, Chen C, Xu D, Lu B, Xu Y (2022c) Exosomes secreted by hypoxia-stimulated bone-marrow mesenchymal stem cells promote grafted tendon-bone tunnel healing in rat anterior cruciate ligament reconstruction model. J Orthop Translat 36:152–163. https://doi.org/10.1016/j.jot.2022.08.001
Zhang X, Sai B, Wang F, Wang L, Wang Y, Zheng L, Xiang J (2019) Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol Cancer 18(1):40. https://doi.org/10.1186/s12943-019-0959-5
Zhang XF, Wang T, Wang ZX, Huang KP, Zhang YW, Wang GL, Wang H (2021b) Hypoxic ucMSC-secreted exosomal miR-125b promotes endothelial cell survival and migration during wound healing by targeting TP53INP1. Mol Ther Nucleic Acids 26:347–359. https://doi.org/10.1016/j.omtn.2021.07.014
Zhu C, Yu J, Pan Q, Yang J, Hao G, Wang Y, Cao H (2016) Hypoxia-inducible factor-2 alpha promotes the proliferation of human placenta-derived mesenchymal stem cells through the MAPK/ERK signaling pathway. Sci Rep 6:35489. https://doi.org/10.1038/srep35489
Zhu J, Lu K, Zhang N, Zhao Y, Ma Q, Shen J, Yu H (2018a) Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artif Cells Nanomed Biotechnol 46(8):1659–1670. https://doi.org/10.1080/21691401.2017.1388249
Zhu LP, Tian T, Wang JY, He JN, Chen T, Pan M, Bai YP (2018b) Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics 8(22):6163–6177. https://doi.org/10.7150/thno.28021
Funding
This study was funded by China Postdoctoral Science Foundation (2022M722257) and National Natural Science Foundation of China (U21A20369).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Ethical approval
Not applicable.
Informed consent
Not applicable.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Dong, J., Wu, B. & Tian, W. Exosomes derived from hypoxia-preconditioned mesenchymal stem cells (hypoMSCs-Exo): advantages in disease treatment. Cell Tissue Res 392, 621–629 (2023). https://doi.org/10.1007/s00441-023-03758-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-023-03758-6