{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T04:55:13Z","timestamp":1777524913060,"version":"3.51.4"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["31771128"],"award-info":[{"award-number":["31771128"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Science and Technology Development Fund, Macau SAR","award":["0127\/2019\/A3"],"award-info":[{"award-number":["0127\/2019\/A3"]}]},{"name":"The Science and Technology Development Fund, Macau SAR","award":["0113\/2018\/A3"],"award-info":[{"award-number":["0113\/2018\/A3"]}]},{"name":"The Science and Technology Development Fund, Macau SAR","award":["0044\/2019\/AGJ"],"award-info":[{"award-number":["0044\/2019\/AGJ"]}]},{"DOI":"10.13039\/501100004733","name":"Universidade de Macau","doi-asserted-by":"publisher","award":["MYRG2018-00134-FHS"],"award-info":[{"award-number":["MYRG2018-00134-FHS"]}],"id":[{"id":"10.13039\/501100004733","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Yunnan Provincial Innovation Team","award":["2018HC003"],"award-info":[{"award-number":["2018HC003"]}]},{"name":"Yunnan Provincial Innovation Team","award":["2017HC009"],"award-info":[{"award-number":["2017HC009"]}]},{"name":"Joint Special Fund of Applied Fundamental Research of Kunming Medical University granted by Science and Technology Office of Yunnan province","award":["2017FE468-129"],"award-info":[{"award-number":["2017FE468-129"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Res Ther"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Spinal cord injury (SCI) is a debilitating medical condition that can result in the irreversible loss of sensorimotor function. Current therapies fail to provide an effective recovery being crucial to develop more effective approaches. Mesenchymal stem cell (MSC) exosomes have been shown to be able to facilitate axonal growth and act as mediators to regulate neurogenesis and neuroprotection, holding great therapeutic potential in SCI conditions. This study aimed to assess the potential of human placental MSC (hpMSC)-derived exosomes on the functional recovery and reactivation of endogenous neurogenesis in an experimental animal model of SCI and to explore the possible mechanisms involved.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The hpMSC-derived exosomes were extracted and transplanted in an experimental animal model of SCI with complete transection of the thoracic segment. Functional recovery, the expression of neural stem\/progenitor cell markers and the occurrence of neurogenesis, was assessed 60\u2009days after the treatment. In vitro, neural stem cells (NSCs) were incubated with the isolated exosomes for 24\u2009h, and the phosphorylation levels of mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinases (ERK), and cAMP response element binding (CREB) proteins were assessed by western blot.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Exosomes were successfully isolated and purified from hpMSCs. Intravenous injections of these purified exosomes significantly improved the locomotor activity and bladder dysfunction of SCI animals. Further study of the exosomes\u2019 therapeutic action revealed that hpMSC-derived exosomes promoted the activation of proliferating endogenous neural stem\/progenitor cells as denoted by the significant increase of spinal SOX2<jats:sup>+<\/jats:sup>GFAP<jats:sup>+<\/jats:sup>, PAX6<jats:sup>+<\/jats:sup>Nestin<jats:sup>+<\/jats:sup>, and SOX1<jats:sup>+<\/jats:sup>KI67<jats:sup>+<\/jats:sup> cells. Moreover, animals treated with exosomes exhibited a significative higher neurogenesis, as indicated by the higher percentage of DCX<jats:sup>+<\/jats:sup>MAP 2<jats:sup>+<\/jats:sup> neurons. In vitro, hpMSC-derived exosomes promoted the proliferation of NSCs and the increase of the phosphorylated levels of MEK, ERK, and CREB.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study provides evidence that the use of hpMSC-derived exosomes may constitute a promising therapeutic strategy for the treatment of SCI.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13287-021-02248-2","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T06:03:14Z","timestamp":1615528994000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["Exosomes derived from human placental mesenchymal stem cells enhanced the recovery of spinal cord injury by activating endogenous neurogenesis"],"prefix":"10.1186","volume":"12","author":[{"given":"Wenshu","family":"Zhou","sequence":"first","affiliation":[]},{"given":"Marta","family":"Silva","sequence":"additional","affiliation":[]},{"given":"Chun","family":"Feng","sequence":"additional","affiliation":[]},{"given":"Shumei","family":"Zhao","sequence":"additional","affiliation":[]},{"given":"Linlin","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Shuai","family":"Li","sequence":"additional","affiliation":[]},{"given":"Jingmei","family":"Zhong","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9014-0055","authenticated-orcid":false,"given":"Wenhua","family":"Zheng","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"issue":"9304","key":"2248_CR1","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/S0140-6736(02)07603-1","volume":"359","author":"JW McDonald","year":"2002","unstructured":"McDonald JW, Sadowsky C. Spinal-cord injury. Lancet. 2002;359(9304):417\u201325.","journal-title":"Lancet"},{"issue":"1","key":"2248_CR2","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1186\/s12974-016-0736-y","volume":"13","author":"X Sun","year":"2016","unstructured":"Sun X, et al. Multiple organ dysfunction and systemic inflammation after spinal cord injury: a complex relationship. J Neuroinflammation. 2016;13(1):260.","journal-title":"J Neuroinflammation"},{"key":"2248_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2147\/JN.S143236","volume":"6","author":"Y Kang","year":"2017","unstructured":"Kang Y, et al. Epidemiology of worldwide spinal cord injury: a literature review. J Neurorestoratol. 2017;6:1\u20139.","journal-title":"J Neurorestoratol"},{"issue":"6","key":"2248_CR4","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1177\/0963689718755778","volume":"27","author":"B Fan","year":"2018","unstructured":"Fan B, et al. Microenvironment imbalance of spinal cord injury. Cell Transplant. 2018;27(6):853\u201366.","journal-title":"Cell Transplant"},{"issue":"3s","key":"2248_CR5","doi-asserted-by":"publisher","first-page":"S9","DOI":"10.1093\/neuros\/nyw080","volume":"80","author":"CS Ahuja","year":"2017","unstructured":"Ahuja CS, et al. Traumatic spinal cord injury-repair and regeneration. Neurosurgery. 2017;80(3s):S9\u2013s22.","journal-title":"Neurosurgery"},{"issue":"8","key":"2248_CR6","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.4103\/1673-5374.274332","volume":"15","author":"Y Zheng","year":"2020","unstructured":"Zheng Y, et al. Multimodal treatment for spinal cord injury: a sword of neuroregeneration upon neuromodulation. Neural Regen Res. 2020;15(8):1437\u201350.","journal-title":"Neural Regen Res"},{"issue":"1","key":"2248_CR7","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1186\/s13287-019-1357-z","volume":"10","author":"A Shao","year":"2019","unstructured":"Shao A, et al. Crosstalk between stem cell and spinal cord injury: pathophysiology and treatment strategies. Stem Cell Res Ther. 2019;10(1):238.","journal-title":"Stem Cell Res Ther"},{"issue":"5411","key":"2248_CR8","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1126\/science.284.5411.143","volume":"284","author":"MF Pittenger","year":"1999","unstructured":"Pittenger MF, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143\u20137.","journal-title":"Science"},{"issue":"6","key":"2248_CR9","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1089\/scd.2007.0154","volume":"17","author":"S Barlow","year":"2008","unstructured":"Barlow S, et al. Comparison of human placenta- and bone marrow-derived multipotent mesenchymal stem cells. Stem Cells Dev. 2008;17(6):1095\u2013107.","journal-title":"Stem Cells Dev"},{"issue":"7448","key":"2248_CR10","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/nature12143","volume":"497","author":"G Zhang","year":"2013","unstructured":"Zhang G, et al. Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. Nature. 2013;497(7448):211\u20136.","journal-title":"Nature"},{"issue":"10","key":"2248_CR11","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1038\/ncb2562","volume":"14","author":"J Li","year":"2012","unstructured":"Li J, Tang Y, Cai D. IKKbeta\/NF-kappaB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat Cell Biol. 2012;14(10):999\u20131012.","journal-title":"Nat Cell Biol"},{"issue":"5","key":"2248_CR12","doi-asserted-by":"publisher","first-page":"eaav5086","DOI":"10.1126\/sciadv.aav5086","volume":"5","author":"K Kobayakawa","year":"2019","unstructured":"Kobayakawa K, et al. Macrophage centripetal migration drives spontaneous healing process after spinal cord injury. Sci Adv. 2019;5(5):eaav5086.","journal-title":"Sci Adv"},{"issue":"3","key":"2248_CR13","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1089\/neu.2019.6540","volume":"37","author":"JG Cooper","year":"2020","unstructured":"Cooper JG, et al. Spinal cord injury results in chronic mechanical stiffening. J Neurotrauma. 2020;37(3):494\u2013506.","journal-title":"J Neurotrauma"},{"issue":"1","key":"2248_CR14","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.cell.2018.02.004","volume":"173","author":"DO Dias","year":"2018","unstructured":"Dias DO, et al. Reducing pericyte-derived scarring promotes recovery after spinal cord injury. Cell. 2018;173(1):153\u2013165.e22.","journal-title":"Cell"},{"issue":"2","key":"2248_CR15","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.molmed.2018.12.006","volume":"25","author":"G Moll","year":"2019","unstructured":"Moll G, et al. Intravascular mesenchymal stromal\/stem cell therapy product diversification: time for new clinical guidelines. Trends Mol Med. 2019;25(2):149\u201363.","journal-title":"Trends Mol Med"},{"issue":"6","key":"2248_CR16","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1016\/j.stem.2011.05.012","volume":"8","author":"CE Goldring","year":"2011","unstructured":"Goldring CE, et al. Assessing the safety of stem cell therapeutics. Cell Stem Cell. 2011;8(6):618\u201328.","journal-title":"Cell Stem Cell"},{"issue":"23","key":"2248_CR17","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1089\/scd.2020.0133","volume":"29","author":"Z Ren","year":"2020","unstructured":"Ren Z, et al. Mesenchymal stem cell-derived exosomes: Hope for spinal cord injury repair. Stem Cells Dev. 2020;29(23):1467\u201378.","journal-title":"Stem Cells Dev"},{"issue":"3","key":"2248_CR18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033115","volume":"7","author":"S Bruno","year":"2012","unstructured":"Bruno S, et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One. 2012;7(3):e33115.","journal-title":"PLoS One"},{"issue":"3","key":"2248_CR19","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.scr.2009.12.003","volume":"4","author":"RC Lai","year":"2010","unstructured":"Lai RC, et al. Exosome secreted by MSC reduces myocardial ischemia\/reperfusion injury. Stem Cell Res. 2010;4(3):214\u201322.","journal-title":"Stem Cell Res"},{"issue":"1","key":"2248_CR20","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1089\/ten.teb.2014.0300","volume":"21","author":"TN Lamichhane","year":"2015","unstructured":"Lamichhane TN, et al. Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine. Tissue Eng Part B Rev. 2015;21(1):45\u201354.","journal-title":"Tissue Eng Part B Rev"},{"key":"2248_CR21","doi-asserted-by":"publisher","unstructured":"Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977. https:\/\/doi.org\/10.1126\/science.aau6977.","DOI":"10.1126\/science.aau6977"},{"key":"2248_CR22","first-page":"Unit 3.22","volume":"Chapter 3","author":"C Th\u00e9ry","year":"2006","unstructured":"Th\u00e9ry C, et al. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3:Unit 3.22.","journal-title":"Curr Protoc Cell Biol"},{"key":"2248_CR23","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1101\/sqb.2016.81.030932","volume":"81","author":"R Kalluri","year":"2016","unstructured":"Kalluri R, LeBleu VS. Discovery of double-stranded genomic DNA in circulating exosomes. Cold Spring Harb Symp Quant Biol. 2016;81:275\u201380.","journal-title":"Cold Spring Harb Symp Quant Biol"},{"issue":"1","key":"2248_CR24","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1186\/s13195-020-00670-x","volume":"12","author":"M Guo","year":"2020","unstructured":"Guo M, et al. Mesenchymal stem cell-derived exosome: a promising alternative in the therapy of Alzheimer\u2019s disease. Alzheimers Res Ther. 2020;12(1):109.","journal-title":"Alzheimers Res Ther"},{"key":"2248_CR25","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/5584_2018_219","volume":"1089","author":"CR Harrell","year":"2018","unstructured":"Harrell CR, et al. Therapeutic potential of mesenchymal stem cell-derived exosomes in the treatment of eye diseases. Adv Exp Med Biol. 2018;1089:47\u201357.","journal-title":"Adv Exp Med Biol"},{"issue":"4","key":"2248_CR26","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1172\/JCI81129","volume":"126","author":"R Xu","year":"2016","unstructured":"Xu R, et al. Extracellular vesicle isolation and characterization: toward clinical application. J Clin Invest. 2016;126(4):1152\u201362.","journal-title":"J Clin Invest"},{"issue":"9","key":"2248_CR27","doi-asserted-by":"publisher","first-page":"1606","DOI":"10.1038\/mt.2010.105","volume":"18","author":"D Sun","year":"2010","unstructured":"Sun D, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18(9):1606\u201314.","journal-title":"Mol Ther"},{"issue":"4","key":"2248_CR28","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/nbt.1807","volume":"29","author":"L Alvarez-Erviti","year":"2011","unstructured":"Alvarez-Erviti L, et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341\u20135.","journal-title":"Nat Biotechnol"},{"key":"2248_CR29","doi-asserted-by":"publisher","first-page":"119675","DOI":"10.1016\/j.biomaterials.2019.119675","volume":"231","author":"S Le Saux","year":"2020","unstructured":"Le Saux S, et al. Post-production modifications of murine mesenchymal stem cell (mMSC) derived extracellular vesicles (EVs) and impact on their cellular interaction. Biomaterials. 2020;231:119675.","journal-title":"Biomaterials"},{"issue":"3","key":"2248_CR30","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1089\/neu.2018.5835","volume":"36","author":"W Liu","year":"2019","unstructured":"Liu W, et al. Exosomes derived from bone mesenchymal stem cells repair traumatic spinal cord injury by suppressing the activation of A1 neurotoxic reactive astrocytes. J Neurotrauma. 2019;36(3):469\u201384.","journal-title":"J Neurotrauma"},{"issue":"1","key":"2248_CR31","doi-asserted-by":"publisher","first-page":"19604","DOI":"10.1038\/s41598-020-76290-0","volume":"10","author":"K Menezes","year":"2020","unstructured":"Menezes K, et al. Human mesenchymal stromal\/stem cells recruit resident pericytes and induce blood vessels maturation to repair experimental spinal cord injury in rats. Sci Rep. 2020;10(1):19604.","journal-title":"Sci Rep"},{"key":"2248_CR32","doi-asserted-by":"publisher","unstructured":"Pelekanos RA, et al. Isolation and expansion of mesenchymal stem\/stromal cells derived from human placenta tissue. J Vis Exp. 2016;(112):54204. https:\/\/doi.org\/10.3791\/54204.","DOI":"10.3791\/54204"},{"issue":"15","key":"2248_CR33","doi-asserted-by":"publisher","first-page":"4640","DOI":"10.1039\/C6AN00892E","volume":"141","author":"Y Weng","year":"2016","unstructured":"Weng Y, et al. Effective isolation of exosomes with polyethylene glycol from cell culture supernatant for in-depth proteome profiling. Analyst. 2016;141(15):4640\u20136.","journal-title":"Analyst"},{"issue":"10","key":"2248_CR34","doi-asserted-by":"publisher","DOI":"10.1590\/1414-431x20187076","volume":"51","author":"D Kou","year":"2018","unstructured":"Kou D, et al. Transplantation of rat-derived microglial cells promotes functional recovery in a rat model of spinal cord injury. Braz J Med Biol Res. 2018;51(10):e7076.","journal-title":"Braz J Med Biol Res"},{"key":"2248_CR35","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/978-1-4939-7253-1_18","volume":"1660","author":"P Cizmar","year":"2017","unstructured":"Cizmar P, Yuana Y. Detection and characterization of extracellular vesicles by transmission and cryo-transmission electron microscopy. Methods Mol Biol. 2017;1660:221\u201332.","journal-title":"Methods Mol Biol"},{"key":"2248_CR36","doi-asserted-by":"publisher","first-page":"231","DOI":"10.3389\/fphar.2016.00231","volume":"7","author":"A Marote","year":"2016","unstructured":"Marote A, et al. MSCs-derived exosomes: cell-secreted nanovesicles with regenerative potential. Front Pharmacol. 2016;7:231.","journal-title":"Front Pharmacol"},{"issue":"2","key":"2248_CR37","doi-asserted-by":"publisher","first-page":"164","DOI":"10.3171\/2013.10.SPINE13113","volume":"20","author":"A Brown","year":"2014","unstructured":"Brown A, et al. Perfusion imaging of spinal cord contusion: injury-induced blockade and partial reversal by \u03b22-agonist treatment in rats. J Neurosurg Spine. 2014;20(2):164\u201371.","journal-title":"J Neurosurg Spine"},{"issue":"4","key":"2248_CR38","doi-asserted-by":"publisher","first-page":"856","DOI":"10.3171\/2014.11.JNS14770","volume":"122","author":"Y Zhang","year":"2015","unstructured":"Zhang Y, et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015;122(4):856\u201367.","journal-title":"J Neurosurg"},{"issue":"11","key":"2248_CR39","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1038\/jcbfm.2013.152","volume":"33","author":"H Xin","year":"2013","unstructured":"Xin H, et al. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33(11):1711\u20135.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"1","key":"2248_CR40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0190358","volume":"13","author":"KL Lankford","year":"2018","unstructured":"Lankford KL, et al. Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS One. 2018;13(1):e0190358.","journal-title":"PLoS One"},{"issue":"43","key":"2248_CR41","doi-asserted-by":"publisher","first-page":"13354","DOI":"10.1073\/pnas.1510194112","volume":"112","author":"Z Yang","year":"2015","unstructured":"Yang Z, et al. NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury. Proc Natl Acad Sci U S A. 2015;112(43):13354\u20139.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"2248_CR42","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2019.e01324","volume":"5","author":"RU Ahmed","year":"2019","unstructured":"Ahmed RU, Alam M, Zheng YP. Experimental spinal cord injury and behavioral tests in laboratory rats. Heliyon. 2019;5(3):e01324.","journal-title":"Heliyon"},{"issue":"4","key":"2248_CR43","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1016\/j.stem.2016.08.020","volume":"19","author":"TM Fandel","year":"2016","unstructured":"Fandel TM, et al. Transplanted human stem cell-derived interneuron precursors mitigate mouse bladder dysfunction and central neuropathic pain after spinal cord injury. Cell Stem Cell. 2016;19(4):544\u201357.","journal-title":"Cell Stem Cell"},{"issue":"11","key":"2248_CR44","doi-asserted-by":"publisher","first-page":"F1296","DOI":"10.1152\/ajprenal.00074.2014","volume":"306","author":"W Yu","year":"2014","unstructured":"Yu W, et al. Spontaneous voiding by mice reveals strain-specific lower urinary tract function to be a quantitative genetic trait. Am J Physiol Renal Physiol. 2014;306(11):F1296\u2013307.","journal-title":"Am J Physiol Renal Physiol"},{"issue":"2","key":"2248_CR45","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.stemcr.2015.10.007","volume":"6","author":"X Zhu","year":"2016","unstructured":"Zhu X, et al. A robust single primate neuroepithelial cell clonal expansion system for neural tube development and disease studies. Stem Cell Rep. 2016;6(2):228\u201342.","journal-title":"Stem Cell Rep"},{"issue":"14","key":"2248_CR46","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1089\/scd.2014.0316","volume":"24","author":"A Shabbir","year":"2015","unstructured":"Shabbir A, 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\u201347.","journal-title":"Stem Cells Dev"},{"issue":"5","key":"2248_CR47","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1111\/cpr.12279","volume":"49","author":"X Wu","year":"2016","unstructured":"Wu X, et al. Serum and xeno-free, chemically defined, no-plate-coating-based culture system for mesenchymal stromal cells from the umbilical cord. Cell Prolif. 2016;49(5):579\u201388.","journal-title":"Cell Prolif"},{"key":"2248_CR48","doi-asserted-by":"publisher","unstructured":"Welk B, et al. A pilot randomized-controlled trial of the urodynamic efficacy of mirabegron for patients with neurogenic lower urinary tract dysfunction. Neurourol Urodyn. 2018;37(8):2810-7. https:\/\/doi.org\/10.1002\/nau.23774.","DOI":"10.1002\/nau.23774"},{"issue":"1","key":"2248_CR49","first-page":"327","volume":"5","author":"WC de Groat","year":"2015","unstructured":"de Groat WC, Griffiths D, Yoshimura N. Neural control of the lower urinary tract. Compr Physiol. 2015;5(1):327\u201396.","journal-title":"Compr Physiol"},{"key":"2248_CR50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.autneu.2017.09.015","volume":"209","author":"JA Taylor","year":"2018","unstructured":"Taylor JA. Autonomic consequences of spinal cord injury. Auton Neurosci. 2018;209:1\u20133.","journal-title":"Auton Neurosci"},{"key":"2248_CR51","doi-asserted-by":"publisher","unstructured":"Bucan V, et al. Effect of exosomes from rat adipose-derived mesenchymal stem cells on neurite outgrowth and sciatic nerve regeneration after crush injury. Mol Neurobiol. 2019;56(3):1812-24. https:\/\/doi.org\/10.1007\/s12035-018-1172-z.","DOI":"10.1007\/s12035-018-1172-z"},{"issue":"9","key":"2248_CR52","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1177\/1545968318798955","volume":"32","author":"L Qing","year":"2018","unstructured":"Qing L, et al. Exosomes and their microRNA cargo: new players in peripheral nerve regeneration. Neurorehabil Neural Repair. 2018;32(9):765\u201376.","journal-title":"Neurorehabil Neural Repair"},{"key":"2248_CR53","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.neuropharm.2018.09.020","volume":"143","author":"MG Sabbir","year":"2018","unstructured":"Sabbir MG, Fernyhough P. Muscarinic receptor antagonists activate ERK-CREB signaling to augment neurite outgrowth of adult sensory neurons. Neuropharmacology. 2018;143:268\u201381.","journal-title":"Neuropharmacology"},{"issue":"2","key":"2248_CR54","doi-asserted-by":"publisher","first-page":"116","DOI":"10.5213\/inj.1938103.052","volume":"23","author":"MS Shin","year":"2019","unstructured":"Shin MS, et al. Long-term surgical and chemical castration deteriorates memory function through downregulation of PKA\/CREB\/BDNF and c-Raf\/MEK\/ERK pathways in hippocampus. Int Neurourol J. 2019;23(2):116\u201324.","journal-title":"Int Neurourol J"},{"issue":"6","key":"2248_CR55","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s00406-015-0588-y","volume":"265","author":"P Jiang","year":"2015","unstructured":"Jiang P, et al. Inhibition of MAPK\/ERK signaling blocks hippocampal neurogenesis and impairs cognitive performance in prenatally infected neonatal rats. Eur Arch Psychiatry Clin Neurosci. 2015;265(6):497\u2013509.","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"issue":"1","key":"2248_CR56","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s10616-008-9162-z","volume":"58","author":"M Evangelista","year":"2008","unstructured":"Evangelista M, Soncini M, Parolini O. Placenta-derived stem cells: new hope for cell therapy? Cytotechnology. 2008;58(1):33\u201342.","journal-title":"Cytotechnology"},{"key":"2248_CR57","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.neuroscience.2019.10.043","volume":"424","author":"JH Huang","year":"2020","unstructured":"Huang JH, et al. Exosomes derived from miR-126-modified MSCs promote angiogenesis and neurogenesis and attenuate apoptosis after spinal cord injury in rats. Neuroscience. 2020;424:133\u201345.","journal-title":"Neuroscience"},{"issue":"1","key":"2248_CR58","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.cell.2019.08.001","volume":"179","author":"Y Zhu","year":"2019","unstructured":"Zhu Y, et al. Migratory neural crest cells phagocytose dead cells in the developing nervous system. Cell. 2019;179(1):74\u201389.e10.","journal-title":"Cell"},{"key":"2248_CR59","doi-asserted-by":"publisher","first-page":"135399","DOI":"10.1016\/j.neulet.2020.135399","volume":"739","author":"C Zhang","year":"2020","unstructured":"Zhang C, et al. Exosomes derived from human placenta-derived mesenchymal stem cells improve neurologic function by promoting angiogenesis after spinal cord injury. Neurosci Lett. 2020;739:135399.","journal-title":"Neurosci Lett"},{"key":"2248_CR60","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.nbd.2018.12.003","volume":"124","author":"Y Ma","year":"2019","unstructured":"Ma Y, et al. Induced neural progenitor cells abundantly secrete extracellular vesicles and promote the proliferation of neural progenitors via extracellular signal-regulated kinase pathways. Neurobiol Dis. 2019;124:322\u201334.","journal-title":"Neurobiol Dis"},{"key":"2248_CR61","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3389\/fnmol.2013.00023","volume":"6","author":"WS Chan","year":"2013","unstructured":"Chan WS, et al. Differential regulation of proliferation and neuronal differentiation in adult rat spinal cord neural stem\/progenitors by ERK1\/2, Akt, and PLC\u03b3. Front Mol Neurosci. 2013;6:23.","journal-title":"Front Mol Neurosci"},{"issue":"8","key":"2248_CR62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0135111","volume":"10","author":"YS Takeda","year":"2015","unstructured":"Takeda YS, Xu Q. Neuronal differentiation of human mesenchymal stem cells using exosomes derived from differentiating neuronal cells. PLoS One. 2015;10(8):e0135111.","journal-title":"PLoS One"}],"container-title":["Stem Cell Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-021-02248-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13287-021-02248-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-021-02248-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T06:08:21Z","timestamp":1615529301000},"score":1,"resource":{"primary":{"URL":"https:\/\/stemcellres.biomedcentral.com\/articles\/10.1186\/s13287-021-02248-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":62,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2248"],"URL":"https:\/\/doi.org\/10.1186\/s13287-021-02248-2","relation":{},"ISSN":["1757-6512"],"issn-type":[{"value":"1757-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]},"assertion":[{"value":"15 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The use of human placenta samples was approved by the ethics committee of Kunming University of Science and Technology, and the written informed consent was obtained before clinical sampling.The animal care procedures were reviewed and approved by an Institutional Animal Care and Use Committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"174"}}