Tail-vein injection of MSC-derived small extracellular vesicles facilitates the restoration of hippocampal neuronal morphology and function in APP / PS1 mice

Cell Death Discovery - Tập 7 Số 1
Han Wang1, Yuqi Liu1, Junchen Li1, Tian Wang2, Yue Hei1, Huiming Li1, Handong Wang2, Lina Wang2, Ruijing Zhao2, Weiping Liu1, Qianfa Long3
1Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No. 127 Changle West Road, 710032, Xi’an, P.R. China
2Mini-invasive Neurosurgery and Translational Medical Center, Xi’an Central Hospital, Xi’an Jiaotong University, No. 161, West 5th Road, Xincheng District, 710003, Xi’an, P.R. China
3Affiliated Hospital of Yan’an University, Yongxiang Road, Baota District, 716000, Yan’an, China

Tóm tắt

AbstractMesenchymal stem-cell-derived small extracellular vesicles (MSC-EVs), as a therapeutic agent, have shown great promise in the treatment of neurological diseases. To date, the neurorestorative effects and underlying mechanism of MSC-EVs in Alzheimer’s disease (AD) are not well known. Herein, we aimed to investigate the action of MSC-EVs on the neuronal deficits in β-amyloid protein (Aβ)-stimulated hippocampal neurons, or AD cell (SHSY5Y cell lines) and animal (APPswe / PS1dE9 mice) models. In the present study, the cell and AD models received a single-dose of MSC-EVs, and were then assessed for behavioral deficits, pathological changes, intracellular calcium transients, neuronal morphology alterations, or electrophysiological variations. Additionally, the nuclear factor E2-related factor 2 (Nrf2, a key mediator of neuronal injury in AD) signaling pathway was probed by western blotting in vitro and in vivo models of AD. Our results showed that MSC-EVs therapy improved the cognitive impairments and reduced the hippocampal Aβ aggregation and neuronal loss in AD mice. Markedly, EV treatment restored the calcium oscillations, dendritic spine alterations, action potential abnormalities, or mitochondrial changes in the hippocampus of AD models. Also, we found that the Nrf2 signaling pathway participated in the actions of MSC-EVs in the cell and animal models. Together, these data indicate that MS-EVs as promising nanotherapeutics for restoration of hippocampal neuronal morphology and function in APP / PS1 mice, further highlighting the clinical values of MSC-EVs in the treatment of AD.

Từ khóa


Tài liệu tham khảo

Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol. 2018;25:59–70.

Galvin JE, Howard DH, Denny SS, Dickinson S, Tatton N. The social and economic burden of frontotemporal degeneration. Neurology. 2017;89:2049–2056.

Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci. 2011;14:285–293.

Richetin K, et al. Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer’s disease. Nat Neurosci. 2020;23:1567–1579.

Zott B, et al. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science. 2019;365:559–565.

Cummings JL, Tong G, Ballard C. Treatment combinations for Alzheimer’s disease: current and future pharmacotherapy options. J Alzheimers Dis. 2019;67:779–794.

Cossu G, et al. Lancet Commission: stem cells and regenerative medicine. Lancet. 2018;391:883–910.

Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal stem cells for neurological disorders. Adv Sci. 2021;8:2002944.

Zhang ZG, Buller B, Chopp M. Exosomes—beyond stem cells for restorative therapy in stroke and neurological injury. Nat Rev Neurol. 2019;15:193–203.

van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–228.

Perets N, et al. Golden exosomes selectively target brain pathologies in neurodegenerative and neurodevelopmental disorders. Nano Lett. 2019;19:3422–3431.

Long Q, et al. Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus. Proc Natl Acad Sci USA. 2017;114:E3536–E3545.

Wegierski T, Kuznicki J. Neuronal calcium signaling via store-operated channels in health and disease. Cell Calcium. 2018;74:102–111.

Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci. 2019;20:148–160.

Kamat PK, et al. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: understanding the therapeutics strategies. Mol Neurobiol. 2016;53:648–661.

Osama A, Zhang J, Yao J, Yao X, Fang J. Nrf2: a dark horse in Alzheimer’s disease treatment. Ageing Res Rev. 2020;64:101206.

Calkins MJ, et al. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2009;11:497–508.

Witwer KW, et al. Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles. 2019;8:1609206.

Pannaccione A, et al. The Na(+)/Ca(2+)exchanger in Alzheimer’s disease. Cell Calcium. 2020;87:102190.

Liu Y, et al. Muscone ameliorates synaptic dysfunction and cognitive deficits in APP/PS1 mice. J Alzheimers Dis. 2020;76:491–504.

Ginsberg SD, et al. Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer’s disease progression. Biol Psychiatry. 2010;68:885–893.

Flannery PJ, Trushina E. Mitochondrial dynamics and transport in Alzheimer’s disease. Mol Cell Neurosci. 2019;98:109–120.

Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36.

Padurariu M, Ciobica A, Mavroudis I, Fotiou D, Baloyannis S. Hippocampal neuronal loss in the CA1 and CA3 areas of Alzheimer’s disease patients. Psychiatr Danub. 2012;24:152–158.

Pozueta J, Lefort R, Shelanski ML. Synaptic changes in Alzheimer’s disease and its models. Neuroscience. 2013;251:51–65.

Ingelsson M, et al. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004;62:925–931.

Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4:517–529.

Zhang H, Liu J, Sun S, Pchitskaya E, Popugaeva E, Bezprozvanny I. Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 2015;45:561–580.

Kurudenkandy FR, et al. Amyloid-β-induced action potential desynchronization and degradation of hippocampal gamma oscillations is prevented by interference with peptide conformation change and aggregation. J Neurosci. 2014;34:11416–11425.

Kaczorowski CC, Sametsky E, Shah S, Vassar R, Disterhoft JF. Mechanisms underlying basal and learning-related intrinsic excitability in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2011;32:1452–1465.

Cadonic C, Sabbir MG, Albensi BC. Mechanisms of mitochondrial dysfunction in Alzheimer’s disease. Mol Neurobiol. 2016;53:6078–6090.

Wang T, et al. MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system. Biomaterials. 2020;257:120264.

Griñán-Ferré C, et al. The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer’s disease pathology: From antioxidant to epigenetic therapy. Ageing Res Rev. 2021;67:101271.

Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47:1304–1309.

Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73:3221–3247.

Ren P, et al. Nrf2 ablation promotes Alzheimer’s disease-like pathology in APP/PS1 transgenic mice: the role of neuroinflammation and oxidative stress. Oxid Med Cell Longev. 2020;2020:3050971.

Lastres-Becker I, et al. Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis. Brain. 2014;137:78–91.

Rojo de la Vega M, Dodson M, Chapman E, Zhang DD. NRF2-targeted therapeutics: new targets and modes of NRF2 regulation. Curr Opin Toxicol. 2016;1:62–70.

Schäfer M, et al. Nrf2 links epidermal barrier function with antioxidant defense. EMBO Mol Med. 2012;4:364–379.

Cuddy LK, Seah C, Pasternak SH, Rylett RJ. Differential regulation of the high-affinity choline transporter by wild-type and Swedish mutant amyloid precursor protein. J Neurochem. 2015;134:769–782.

Xian P, et al. Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice. Theranostics. 2019;9:5956–5975.

Roberts-Dalton HD, et al. Fluorescence labelling of extracellular vesicles using a novel thiol-based strategy for quantitative analysis of cellular delivery and intracellular traffic. Nanoscale. 2017;9:13693–13706.

Cap KC, et al. Distinct dual roles of p-Tyr42 RhoA GTPase in tau phosphorylation and ATP citrate lyase activation upon different Aβ concentrations. Redox Biol. 2020;32:101446.

Long Q, et al. Functional recovery and neuronal regeneration of a rat model of epilepsy by transplantation of Hes1-down regulated bone marrow stromal cells. Neuroscience. 2012;212:214–224.

Zhang Y, Xiao Z, He Z, Chen J, Wang X, Jiang L. Dendritic complexity change in the triple transgenic mouse model of Alzheimer’s disease. PeerJ. 2020;8:e8178.

Thông tin
Thông tin xuất bản

Cell Death Discovery

Tập 7 Số 1

Thông tin tác giả