延缓间充质干细胞衰老的研究进展

doi:10.3969/j.issn.1674-8603.2020.02.014

摘要/Abstract

摘要： 间充质干细胞（MSCs）因其低免疫原性，强抗炎及免疫调节作用，成为细胞治疗及再生医学中重要的细胞来源之一。然而，体外培养的MSCs易衰老特性制约着其临床发展与应用。如何延缓MSCs的衰老成为国内外学者研究的热点领域。本文综述了MSCs衰老相关信号通路以及生物活性物质等在延缓MSCs衰老方面的研究进展，以期为MSCs的临床应用提供新的思路。

关键词: 间充质干细胞, 衰老, 延缓, 氧化应激

Abstract: Mesenchymal stem cells (MSCs) have been one of the most important cell sources in regenerative medicine on account of some outstanding advantages, e.g. low immunogenicity, strong anti - inflammatory and immune regulation. Nevertheless, the clinical development and application of MSCs are exceedingly restricted due to the characteristic of easy-aging in vitro culture. The issue on how to alleviate the senescence of MSCs is drawing much attention of both domestic and overseas researchers. This review summarizes MSCs aging signaling pathways and the process of related researches, to provide new insights to effective clinical applications of MSCs.

Key words: mesenchymal stem cells, senescence, alleviate, oxidative stress

沈昕吴国锋秦海燕. 延缓间充质干细胞衰老的研究进展[J]. 口腔生物医学, 2020, 11(2): 131-136.

参考文献 61

[1]	Rodriguez A M, Elabd C, Amri E Z, et al.The human adipose tissue is a source of multipotent stem cells[J].Biochimie, 2005, 87(1):125-8
[2]	Chen F H, Rousche K T, Tuan R S.Technology Insight: adult stem cells in cartilage regeneration and tissue engineering[J].Nat Clin Pract Rheumatol, 2006, 2(7):373-82
[3]	Le Blanc K, Davies L C.MSCs-cells with many sides[J].Cytotherapy, 2018, 20(3):273-278
[4]	Gorgoulis V, Adams P D, Alimonti A, et al.Cellular senescence: defining a path forward[J], 2019, 179(4): 813-827.
[5]	Charif N, Li Y Y, Targa L, et al.Aging of bone marrow mesenchymal stromalstem cells: Implications on autologous regenerative medicine[J].Biomed Mater Eng, 2017, 28(s1):S57-s63
[6]	Fehrer C, Lepperdinger G.Mesenchymal stem cell aging[J].Exp Gerontol, 2005, 40(12):926-30
[7]	Stolzing A, Jones E, Mcgonagle D, et al.Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies[J].Mech Ageing Dev, 2008, 129(3):163-73
[8]	Zhou S, Greenberger J S, Epperly M W, et al.Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts[J].Aging Cell, 2008, 7(3):335-43
[9]	Hernandez-Segura A, Nehme J, Demaria M.Hallmarks of Cellular Senescence[J].Trends in Cell Biology, 2018, 28(6):436-453
[10]	Harman D.Aging: a theory based on free radical and radiation chemistry[J].J Gerontol, 1956, 11(3):298-300
[11]	Siomek A, Gackowski D, Szpila A, et al.Epigenetic modifications and NF-kappaB pathway activity in Cu,Zn-SOD-deficient mice[J].Mol Cell Biochem, 2014, 397(1-2):187-94
[12]	Calderwood S K, Murshid A, Prince T.The shock of aging: molecular chaperones and the heat shock response in longevity and aging--a mini-review[J].Gerontology, 2009, 55(5):550-558
[13]	verbye A, Fengsrud M, Seglen P O.Proteomic analysis of membrane-associated proteins from rat liver autophagosomes[J].Autophagy, 2007, 3(4):300-322
[14]	Hou Y, Wei H, Luo Y, et al.Modulating expression of brain heat shock proteins by estrogen in ovariectomized mice model of aging[J], 45(5): 323-330.
[15]	Jeong S G, Cho G W.Endogenous ROS levels are increased in replicative senescence in human bone marrow mesenchymal stromal cells[J].Biochem Biophys Res Commun, 2015, 460(4):971-6
[16]	Niture S K, Khatri R, Jaiswal A K.Regulation of Nrf2-an update[J]. Free radical biology & medicine, 2014, 66: 36-44.
[17]	Milani P, Ambrosi G, Gammoh O, et al.SOD1 and DJ-1 converge at Nrf2 pathway: a clue for antioxidant therapeutic potential in neurodegeneration[J]. Oxid Med Cell Longev, 2013, 2013: 1-12.
[18]	Youle R J, Van Der Bliek A M.Mitochondrial fission,fusion,and stress[J].Science, 2012, 337(6098):1062-5
[19]	Sharpless N E, Depinho R A.Telomeres,stem cells,senescence,and cancer[J].J Clin Invest, 2004, 113(2):160-8
[20]	Baxter M A, Wynn R F, Jowitt S N, et al.Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion[J].Stem Cells, 2004, 22(5):675-82
[21]	Wu L, Multani A S, He H, et al.Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres[J].Cell, 2006, 126(1):49-62
[22]	Von Zglinicki T, Saretzki G, Ladhoff J, et al.Human cell senescence as a DNA damage response[J].Mech Ageing Dev, 2005, 126(1):111-7
[23]	Morgan M J, Liu Z G.Crosstalk of reactive oxygen species and NF-kappaB signaling[J].Cell Res, 2011, 21(1):103-15
[24]	Guo Z, Kozlov S, Lavin M F, et al.ATM activation by oxidative stress[J].Science (New York, N.Y.), 2010, 330(6003):517-521
[25]	Westerheide S D, Anckar J, Stevens S M, Jr.et alStress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1[J].Science (New York, N.Y.), 2009, 323(5917):1063-1066
[26]	Liu T, Ma X, Ouyang T, et al.SIRT1 reverses senescence via enhancing autophagy and attenuates oxidative stress-induced apoptosis through promoting p53 degradation[J]. International journal of biological macromolecules, 2018, 117: 225-234.
[27]	刘斐, 宋词, 彭玲, et al.低氧通过激活PI3K/Akt途径抑制活性氧产生调节人牙髓细胞氧化应激状态[C]. 中华口腔医学会第十一次全国牙体牙髓病学学术大会论文汇编, 2018.
[28]	Nan L-P, Wang F, Ran D, et al.Naringin alleviates H(2)O(2)-induced apoptosis via the PI3K/Akt pathway in rat nucleus pulposus-derived mesenchymal stem cells[J]. Connective tissue research, 2019: 1-14.
[29]	谢荣辉.N-乙酰半胱氨酸对过氧化氢诱导的骨髓间充质干细胞凋亡的保护及作用机制研究[J]. 中国药理学通报(1): 54-59.
[30]	Matheu A, Maraver A, Klatt P, et al.Delayed ageing through damage protection by the Arfp53 pathway[J].Nature, 2007, 448(7151):375-9
[31]	Demidenko Z N, Korotchkina L G, Gudkov A V, et al.Paradoxical suppression of cellular senescence by p53[J].Proc Natl Acad Sci U S A, 2010, 107(21):9660-4
	[32].
	[47]
[33]	Alimonti A, Nardella C, Chen Z, et al.A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis[J].J Clin Invest, 2010, 120(3):681-93
[34]	Feng Z, Levine A J.The regulation of energy metabolism and the IGF-1mTOR pathways by the p53 protein[J].Trends Cell Biol, 2010, 20(7):427-34
[35]	Kim J Y, Lee J-S, Han Y-S, et al.Pretreatment with Lycopene Attenuates Oxidative Stress-Induced Apoptosis in Human Mesenchymal Stem Cells[J].Biomolecules & therapeutics, 2015, 23(6):517-524
[36]	Jin H J, Lee H J, Heo J, et al.Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells[J].Antioxidants & redox signaling, 2016, 24(9):471-485
[37]	Romanov S R, Kozakiewicz B K, Holst C R, et al.Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes[J].Nature, 2001, 409(6820):633-7
[38]	Ito T, Sawada R, Fujiwara Y, et al.FGF-2 suppresses cellular senescence of human mesenchymal stem cells by down-regulation of TGF-beta2[J].Biochemical and biophysical research communications, 2007, 359(1):108-114
[39]	Lee H J, Choi B, Kim Y, et al.The Upregulation of Toll-Like Receptor 3 via Autocrine IFN-β Signaling Drives the Senescence of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Through JAK1[J]. Frontiers in immunology, 2019, 10: 1659-1659.
[40]	Xia W, Hou M.Macrophage migration inhibitory factor rescues mesenchymal stem cells from doxorubicin-induced senescence though the PI3K-Akt signaling pathway[J].International journal of molecular medicine, 2018, 41(2):1127-1137
[41]	Severino V, Alessio N, Farina A, et al.Insulin-like growth factor binding proteins 4 and 7 released by senescent cells promote premature senescence in mesenchymal stem cells[J].Cell Death Dis, 2013, 4(11):e911-
[42]	Raposo G, Stoorvogel W.Extracellular vesicles: exosomes,microvesicles,and friends[J].J Cell Biol, 2013, 200(4):373-83
[43]	雷倩.脐带间充质干细胞来源微泡逆转间充质干细胞衰老及其机制研究[D]. 华中科技大学, 2017.
[44]	张宁.脐带MSCs来源exosomes改善老年MSCs衰老及心梗疗效[D]. 浙江大学, 2018.
[45]	Griffiths S, Baraniak P R, Copland I B, et al.Human platelet lysate stimulates high-passage and senescent human multipotent mesenchymal stromal cell growth and rejuvenation in vitro[J].Cytotherapy, 2013, 15(12):1469-83
[46]	Reiter R J, Acuna-Castroviejo D, Tan D X, et al.Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system[J]. Ann N Y Acad Sci, 2001, 939: 200-215.
[47]	方佳.褪黑素介导内质网应激延缓犬脂肪间充质干细胞衰老作用的机制[D]. 西北农林科技大学, 2018.
[48]	Liu B, Ghosh S, Yang X, et al.Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria[J].Cell Metab, 2012, 16(6):738-50
[49]	Yang M, Teng S, Ma C, et al.Ascorbic acid inhibits senescence in mesenchymal stem cells through ROS and AKTmTOR signaling[J].Cytotechnology, 2018, 70(5):1301-1313
[50]	Zanichelli F, Capasso S, Di Bernardo G, et al.Low concentrations of isothiocyanates protect mesenchymal stem cells from oxidative injuries,while high concentrations exacerbate DNA damage[J].Apoptosis, 2012, 17(9):964-74
[51]	Kanehira M, Kikuchi T, Ohkouchi S, et al.Targeting lysophosphatidic acid signaling retards culture-associated senescence of human marrow stromal cells[J].PLoS One, 2012, 7(2):e32185-
[52]	杨蕾.姜黄素修饰的丝素蛋白生物材料对细胞衰老的调控[D]. 苏州大学, 2016.
[53]	Gharibi B, Farzadi S, Ghuman M, et al.Inhibition of AktmTOR attenuates age-related changes in mesenchymal stem cells[J].Stem Cells, 2014, 32(8):2256-66
[54]	曹玉林.雷帕霉素逆转衰老脐带间充质干细胞促血管新生功能的研究[D]. 华中科技大学, 2018.
[55]	曾毅, 葛颂, 金岩.Ku0063794、雷帕霉素延缓大鼠骨髓间充质干细胞的复制性衰老[C]. 2016国际口腔及颅颌前沿研究研讨会暨全国口腔生物医学年会, 2016: 2.
[56]	Gu Z, Tan W, Ji J, et al.Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRLlpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway[J].Aging (Albany NY), 2016, 8(5):1102-14
[57]	Song X, Dai J, Li H, et al.Anti-aging effects exerted by Tetramethylpyrazine enhances self-renewal and neuronal differentiation of rat bMSCs by suppressing NF-kB signaling[J]. Biosci Rep, 2019, 39(6).
[58]	Frobel J, Hemeda H, Lenz M, et al.Epigenetic rejuvenation of mesenchymal stromal cells derived from induced pluripotent stem cells[J].Stem Cell Reports, 2014, 3(3):414-22
[59]	张涛, 王攀, 马珊珊.慢病毒介导的过表达对人脐带间充质干细胞衰老的影响[J].郑州大学学报: 医学版, 2017, 52(3):259-263
[60]	Liang X, Ding Y, Lin F, et al.Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3KAKT and MAPKERK pathways[J].Faseb j, 2019, 33(3):4559-4570
[61]	Chen G, Zhang Y, Yu S, et al.Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress[J]. Stem Cells, 2019, 37(9):