Wnt/β-catenin信号通路调控间充质干细胞向肺泡上皮细胞分化及在慢性阻塞性肺病修复中的作用
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摘要
背景:研究发现Wnt/β-catenin信号通路在间充质干细胞增殖、分化过程中具有重要调控效应。因此,间充质干细胞移植过程中遇到的难题,如细胞存活时间短、分化比例低等,有望通过调控Wnt/β-catenin信号通路来找到解决方案,让干细胞移植为慢性阻塞性肺病提供治疗新希望。目的:对Wnt/β-catenin信号通路调控间充质干细胞向肺泡上皮细胞分化在慢性阻塞性肺病修复中的机制及研究进展进行综述。方法:由第一作者在Pub Med、Elsevier、Medline等外文数据库及中国知网、万方及中国生物医学文献数据库等中文数据库检索2007至2017年的相关文献。中文检索词:间充质干细胞、慢性阻塞性肺疾病、Wnt/β-catenin信号通路、肺泡上皮细胞分化;英文检索词:Chronic Obstructive Pulmonary Disease,Wnt/β-catenin signaling pathway,Mesenchymal Stem Cells(MSCs),pulmonary epithelial differentiation。经过筛选,保留50篇文献进行进一步分析。结果与结论:Wnt/β-catenin信号通路有望打破间充质干细胞移植向肺上皮细胞分化率低的局限。慢性阻塞性肺疾病患者的肺脏环境复杂,而Wnt/β-catenin信号通路极易受诱导条件等外界因素影响,不同诱导条件对Wnt/β-catenin信号通路的调控效应是不一样的。因此,Wnt/β-catenin信号通路调控间充质干细胞向肺上皮细胞分化与间充质干细胞移植修复慢性阻塞性肺病的研究仍任重道远。
BACKGROUND: Wnt/β-catenin signaling pathway plays an important role in the proliferation and differentiation of mesenchymal stem cells(MSCs). Therefore, the problems encountered during MSCs transplantation, such as low differentiation rate and short survival time, are expected to find a solution by regulating the Wnt/β-catenin signaling pathway, making MSCs transplantation become a new hope of the treatment of chronic obstructive pulmonary disease(COPD). OBJECTIVE: To summarize the progress in Wnt/β-catenin signaling pathway that regulates MSCs to differentiate into epithelial cells in the treatment of COPD and the relevant mechanisms. METHODS: Pub Med, Elsevier, Medline, CNKI, Wan Fang, and CBMdisc databases were retrieved for relevant articles published from 2007 to 2017. The keywords were "chronic obstructive pulmonary disease; Wnt/β-catenin signaling pathway; mesenchymal stem cells(MSCs); pulmonary epithelial differentiation" in Chinese and English, respectively. After literature screening, 50 eligible articles were further analyzed. RESULTS AND CONCLUSION: The Wnt/β-catenin signaling pathway is expected to reverse the low differentiation of MSCs into lung epithelial cells. COPD patients have a complex lung environment, and Wnt/β-catenin signaling pathway is extremely sensitive to the environmental factors. In addition, the regulation by Wnt/β-catenin signaling pathway is varied under different induction conditions. Therefore, enormous investigations are needed to clarify the regulation of the differentiation of MSCs into lung epithelial cells by the Wnt/β-catenin signaling pathway in the treatment of COPD.
BACKGROUND: Wnt/β-catenin signaling pathway plays an important role in the proliferation and differentiation of mesenchymal stem cells(MSCs). Therefore, the problems encountered during MSCs transplantation, such as low differentiation rate and short survival time, are expected to find a solution by regulating the Wnt/β-catenin signaling pathway, making MSCs transplantation become a new hope of the treatment of chronic obstructive pulmonary disease(COPD). OBJECTIVE: To summarize the progress in Wnt/β-catenin signaling pathway that regulates MSCs to differentiate into epithelial cells in the treatment of COPD and the relevant mechanisms. METHODS: Pub Med, Elsevier, Medline, CNKI, Wan Fang, and CBMdisc databases were retrieved for relevant articles published from 2007 to 2017. The keywords were "chronic obstructive pulmonary disease; Wnt/β-catenin signaling pathway; mesenchymal stem cells(MSCs); pulmonary epithelial differentiation" in Chinese and English, respectively. After literature screening, 50 eligible articles were further analyzed. RESULTS AND CONCLUSION: The Wnt/β-catenin signaling pathway is expected to reverse the low differentiation of MSCs into lung epithelial cells. COPD patients have a complex lung environment, and Wnt/β-catenin signaling pathway is extremely sensitive to the environmental factors. In addition, the regulation by Wnt/β-catenin signaling pathway is varied under different induction conditions. Therefore, enormous investigations are needed to clarify the regulation of the differentiation of MSCs into lung epithelial cells by the Wnt/β-catenin signaling pathway in the treatment of COPD.
引文
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[14]Shang J,Zhao J,Wu X,et al.Interleukin-33 promotes inflammatory cytokine production in chronic airway inflammation.Biochem Cell Biol.2015;93(4):359-366.
[15]Martínez-González I,Cruz MJ,Moreno R,et al.Human mesenchymal stem cells resolve airway inflammation,hyperreactivity,and histopathology in a mouse model of occupational asthma.Stem Cells Dev.2014;23(19):2352-2363.
[16]Huang K,Kang X,Wang X,et al.Conversion of bone marrow mesenchymal stem cells into type II alveolar epithelial cells reduces pulmonary fibrosis by decreasing oxidative stress in rats.Mol Med Rep.2015;11(3):1685-1692.
[17]Fischer UM,Harting MT,Jimenez F,et al.Pulmonary passage is a major obstacle for intravenous stem cell delivery:the pulmonary first-pass effect.Stem Cells Dev.2009;18(5):683-692.
[18]Liang ZX,Sun JP,Wang P,et al.Bone marrow-derived mesenchymal stem cells protect rats from endotoxin-induced acute lung injury.Chin Med J(Engl).2011;124(17):2715-2722.
[19]Mari?as-Pardo L,Mirones I,Amor-Carro O,et al.Mesenchymal stem cells regulate airway contractile tissue remodeling in murine experimental asthma.Allergy.2014;69(6):730-740.
[20]Hansmann G,Fernandez-Gonzalez A,Aslam M,et al.Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension.Pulm Circ.2012;2(2):170-181.
[21]白冲,戈霞晖.间充质干细胞是否可用于哮喘的治疗[J].中国呼吸与危重监护杂志,2011,10(6):517-519.
[22]Mei SH,McC arter SD,Deng Y,et al.Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1.PLoS Med.2007 Sep;4(9):e269.
[23]Gupta N,Su X,Popov B,et al.Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice.J Immunol.2007;179(3):1855-1863.
[24]苏尚,吴畏.Wnt/β-catenin信号通路对靶基因转录的调控[J].中国科学:生命科学,2014,44(10):1029-1042.
[25]Willert K,Nusse R.Wnt proteins.Cold Spring Harb Perspect Biol.2012;4(9):a007864.
[26]Holstein TW.The evolution of the Wnt pathway.Cold Spring Harb Perspect Biol.2012;4(7):a007922.
[27]Niehrs C.The complex world of WNT receptor signalling.Nat Rev Mol Cell Biol.2012;13(12):767-779.
[28]郑群,徐立红.经典Wnt信号通路中β-连环蛋白的影响[J].细胞生物学杂志,2009,31(2):183-190.
[29]Bernard P,Fleming A,Lacombe A,et al.Wnt4 inhibits beta-catenin/TCF signalling by redirecting beta-catenin to the cell membrane.Biol Cell.2008;100(3):167-177.
[30]Mohammed MK,Shao C,Wang J,et al.Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal,tumorigenesis and cancer chemoresistance.Genes Dis.2016;3(1):11-40.
[31]Clevers H,Loh KM,Nusse R.Stem cell signaling.An integral program for tissue renewal and regeneration:Wnt signaling and stem cell control.Science.2014;346(6205):1248012.
[32]MacD onald BT,Tamai K,He X.Wnt/beta-catenin signaling:components,mechanisms,and diseases.Dev Cell.2009;17(1):9-26.
[33]Kikuchi K,Niikura Y,Kitagawa K,et al.Dishevelled,a Wnt signalling component,is involved in mitotic progression in cooperation with Plk1.EMBO J.2010;29(20):3470-3483.
[34]Osolodkin DI,Palyulin VA,Zefirov NS.Glycogen synthase kinase 3 as an anticancer drug target:novel experimental findings and trends in the design of inhibitors.Curr Pharm Des.2013;19(4):665-679.
[35]Wisniewska MB,Nagalski A,Dabrowski M,et al.Novelβ-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability.BMC Genomics.2012;13:635.
[36]Holland JD,Klaus A,Garratt AN,et al.Wnt signaling in stem and cancer stem cells.Curr Opin Cell Biol.2013;25(2):254-264.
[37]Neth P,Ciccarella M,Egea V,et al.Wnt signaling regulates the invasion capacity of human mesenchymal stem cells.Stem Cells.2006;24(8):1892-1903.
[38]Zhang WG,He L,Shi XM,et al.Regulation of transplanted mesenchymal stem cells by the lung progenitor niche in rats with chronic obstructive pulmonary disease.Respir Res.2014;15:33.
[39]Popov BV,Serikov VB,Petrov NS,et al.Lung epithelial cells induce endodermal differentiation in mouse mesenchymal bone marrow stem cells by paracrine mechanism.Tissue Eng.2007;13(10):2441-2450.
[40]Wang C,Zhu H,Sun Z,et al.Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury.Am J Physiol Cell Physiol.2014;307(3):C234-244.
[41]Sun Z,Gong X,Zhu H,et al.Inhibition of Wnt/β-catenin signaling promotes engraftment of mesenchymal stem cells to repair lung injury.J Cell Physiol.2014;229(2):213-224.
[42]Cai SX,Liu AE,Chen S,et al.Activation of Wnt/β-catenin signalling promotes mesenchymal stem cells to repair injured alveolar epithelium induced by lipopolysaccharide in mice.Stem Cell Research&Therapy.2015;6:65.
[43]Okamura M,Kudo H,Wakabayashi K,et al.COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis.Proc Natl Acad Sci U S A.2009;106(14):5819-5824.
[44]Hoverter NP,Waterman ML.A Wnt-fall for gene regulation:repression.Sci Signal.2008;1(39):pe43.
[45]Falconi G,Fabiani E,Fianchi L,et al.Impairment of PI3K/AKT and WNT/β-catenin pathways in bone marrow mesenchymal stem cells isolated from patients with myelodysplastic syndromes.Exp Hematol.2016;44(1):75-83.e1-4.
[46]Wang R,Ahmed J,Wang G,et al.Down-regulation of the canonical Wntβ-catenin pathway in the airway epithelium of healthy smokers and smokers with COPD.PLo S One.2011;6(4):e14793.
[47]Osiris Therapeutics reports interim data for COPD stem cell study.http://investor.osiris.com/release.cfm?Year=&Release Type=&DisplayP age=2
[48]48 Grigoryan T,Wend P,Klaus A,et al.Deciphering the function of canonical Wnt signals in development and disease:conditional lossand gain-of-function mutations of beta-catenin in mice.Genes Dev.2008;22(17):2308-2341.
[49]李春艳,张莹,卢瑶,等.β-连环素/TCF-4复合体在非小细胞肺癌的研究[J].中国现代医学杂志,2008,18(19):2809-2812.
[50]Baarsma HA,Spanjer AI,Haitsma G,et al.Activation of WNT/β-catenin signaling in pulmonary fibroblasts by TGF-β?is increased in chronic obstructive pulmonary disease.PLo S One.2011;6(9):e2545
[2]Gupta D,Agarwal R,Aggarwal AN,et al.Guidelines for diagnosis and management of chronic obstructive pulmonary disease:Joint ICS/NCCP(I)recommendations.Lung India.2013;30(3):228-267.
[3]Mar??a R,Rodrigues DM,Dias M,et al.Classification of Chronic Obstructive Pulmonary Disease(COPD)according to the new Global Initiative for Chronic Obstructive Lung Disease(GOLD)2017:Comparison with GOLD 2011.COPD.2018;15(1):21-26.
[4]Forey BA,Thornton AJ,Lee PN.Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD,chronic bronchitis and emphysema.BMC Pulm Med.2011;11:36.
[5]Angelis N,Porpodis K,Zarogoulidis P,et al.Airway inflammation in chronic obstructive pulmonary disease.J Thorac Dis.2014;6 Suppl1:S167-172.
[6]Dang-Tan T,Ismaila A,Zhang S,et al.Clinical,humanistic,and economic burden of chronic obstructive pulmonary disease(COPD)in Canada:a systematic review.BMC Res Notes.2015;8:464.
[7]Ho TW,Tsai YJ,Ruan SY,et al.In-hospital and one-year mortality and their predictors in patients hospitalized for first-ever chronic obstructive pulmonary disease exacerbations:a nationwide population-based study.PLoS One.2014;9(12):e114866.
[8]Ogura-Tomomatsu H,Asano K,Tomomatsu K,et al.Predictors of osteoporosis and vertebral fractures in patients presenting with moderate-to-severe chronic obstructive lung disease.COPD.2012;9(4):332-337.
[9]Feary JR,Rodrigues LC,Smith CJ,et al.Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke:a comprehensive analysis using data from primary care.Thorax.2010;65(11):956-962.
[10]Wen F,Shen Y.Differential Features of COPD in China.BRN Rev.2017;3:74-85.
[11]Zhong N,Wang C,Yao W,et al.Prevalence of chronic obstructive pulmonary disease in China:a large,population-based survey.Am J Respir Crit Care Med.2007;176(8):753-760.
[12]Kearley J,Silver JS,Sanden C,et al.Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.Immunity.2015;42(3):566-579.
[13]Zong DD,Ouyang RY,Chen P.Epigenetic mechanisms in chronic obstructive pulmonary disease.Eur Rev Med Pharmacol Sci.2015;19(5):844-856.
[14]Shang J,Zhao J,Wu X,et al.Interleukin-33 promotes inflammatory cytokine production in chronic airway inflammation.Biochem Cell Biol.2015;93(4):359-366.
[15]Martínez-González I,Cruz MJ,Moreno R,et al.Human mesenchymal stem cells resolve airway inflammation,hyperreactivity,and histopathology in a mouse model of occupational asthma.Stem Cells Dev.2014;23(19):2352-2363.
[16]Huang K,Kang X,Wang X,et al.Conversion of bone marrow mesenchymal stem cells into type II alveolar epithelial cells reduces pulmonary fibrosis by decreasing oxidative stress in rats.Mol Med Rep.2015;11(3):1685-1692.
[17]Fischer UM,Harting MT,Jimenez F,et al.Pulmonary passage is a major obstacle for intravenous stem cell delivery:the pulmonary first-pass effect.Stem Cells Dev.2009;18(5):683-692.
[18]Liang ZX,Sun JP,Wang P,et al.Bone marrow-derived mesenchymal stem cells protect rats from endotoxin-induced acute lung injury.Chin Med J(Engl).2011;124(17):2715-2722.
[19]Mari?as-Pardo L,Mirones I,Amor-Carro O,et al.Mesenchymal stem cells regulate airway contractile tissue remodeling in murine experimental asthma.Allergy.2014;69(6):730-740.
[20]Hansmann G,Fernandez-Gonzalez A,Aslam M,et al.Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension.Pulm Circ.2012;2(2):170-181.
[21]白冲,戈霞晖.间充质干细胞是否可用于哮喘的治疗[J].中国呼吸与危重监护杂志,2011,10(6):517-519.
[22]Mei SH,McC arter SD,Deng Y,et al.Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1.PLoS Med.2007 Sep;4(9):e269.
[23]Gupta N,Su X,Popov B,et al.Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice.J Immunol.2007;179(3):1855-1863.
[24]苏尚,吴畏.Wnt/β-catenin信号通路对靶基因转录的调控[J].中国科学:生命科学,2014,44(10):1029-1042.
[25]Willert K,Nusse R.Wnt proteins.Cold Spring Harb Perspect Biol.2012;4(9):a007864.
[26]Holstein TW.The evolution of the Wnt pathway.Cold Spring Harb Perspect Biol.2012;4(7):a007922.
[27]Niehrs C.The complex world of WNT receptor signalling.Nat Rev Mol Cell Biol.2012;13(12):767-779.
[28]郑群,徐立红.经典Wnt信号通路中β-连环蛋白的影响[J].细胞生物学杂志,2009,31(2):183-190.
[29]Bernard P,Fleming A,Lacombe A,et al.Wnt4 inhibits beta-catenin/TCF signalling by redirecting beta-catenin to the cell membrane.Biol Cell.2008;100(3):167-177.
[30]Mohammed MK,Shao C,Wang J,et al.Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal,tumorigenesis and cancer chemoresistance.Genes Dis.2016;3(1):11-40.
[31]Clevers H,Loh KM,Nusse R.Stem cell signaling.An integral program for tissue renewal and regeneration:Wnt signaling and stem cell control.Science.2014;346(6205):1248012.
[32]MacD onald BT,Tamai K,He X.Wnt/beta-catenin signaling:components,mechanisms,and diseases.Dev Cell.2009;17(1):9-26.
[33]Kikuchi K,Niikura Y,Kitagawa K,et al.Dishevelled,a Wnt signalling component,is involved in mitotic progression in cooperation with Plk1.EMBO J.2010;29(20):3470-3483.
[34]Osolodkin DI,Palyulin VA,Zefirov NS.Glycogen synthase kinase 3 as an anticancer drug target:novel experimental findings and trends in the design of inhibitors.Curr Pharm Des.2013;19(4):665-679.
[35]Wisniewska MB,Nagalski A,Dabrowski M,et al.Novelβ-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability.BMC Genomics.2012;13:635.
[36]Holland JD,Klaus A,Garratt AN,et al.Wnt signaling in stem and cancer stem cells.Curr Opin Cell Biol.2013;25(2):254-264.
[37]Neth P,Ciccarella M,Egea V,et al.Wnt signaling regulates the invasion capacity of human mesenchymal stem cells.Stem Cells.2006;24(8):1892-1903.
[38]Zhang WG,He L,Shi XM,et al.Regulation of transplanted mesenchymal stem cells by the lung progenitor niche in rats with chronic obstructive pulmonary disease.Respir Res.2014;15:33.
[39]Popov BV,Serikov VB,Petrov NS,et al.Lung epithelial cells induce endodermal differentiation in mouse mesenchymal bone marrow stem cells by paracrine mechanism.Tissue Eng.2007;13(10):2441-2450.
[40]Wang C,Zhu H,Sun Z,et al.Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury.Am J Physiol Cell Physiol.2014;307(3):C234-244.
[41]Sun Z,Gong X,Zhu H,et al.Inhibition of Wnt/β-catenin signaling promotes engraftment of mesenchymal stem cells to repair lung injury.J Cell Physiol.2014;229(2):213-224.
[42]Cai SX,Liu AE,Chen S,et al.Activation of Wnt/β-catenin signalling promotes mesenchymal stem cells to repair injured alveolar epithelium induced by lipopolysaccharide in mice.Stem Cell Research&Therapy.2015;6:65.
[43]Okamura M,Kudo H,Wakabayashi K,et al.COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis.Proc Natl Acad Sci U S A.2009;106(14):5819-5824.
[44]Hoverter NP,Waterman ML.A Wnt-fall for gene regulation:repression.Sci Signal.2008;1(39):pe43.
[45]Falconi G,Fabiani E,Fianchi L,et al.Impairment of PI3K/AKT and WNT/β-catenin pathways in bone marrow mesenchymal stem cells isolated from patients with myelodysplastic syndromes.Exp Hematol.2016;44(1):75-83.e1-4.
[46]Wang R,Ahmed J,Wang G,et al.Down-regulation of the canonical Wntβ-catenin pathway in the airway epithelium of healthy smokers and smokers with COPD.PLo S One.2011;6(4):e14793.
[47]Osiris Therapeutics reports interim data for COPD stem cell study.http://investor.osiris.com/release.cfm?Year=&Release Type=&DisplayP age=2
[48]48 Grigoryan T,Wend P,Klaus A,et al.Deciphering the function of canonical Wnt signals in development and disease:conditional lossand gain-of-function mutations of beta-catenin in mice.Genes Dev.2008;22(17):2308-2341.
[49]李春艳,张莹,卢瑶,等.β-连环素/TCF-4复合体在非小细胞肺癌的研究[J].中国现代医学杂志,2008,18(19):2809-2812.
[50]Baarsma HA,Spanjer AI,Haitsma G,et al.Activation of WNT/β-catenin signaling in pulmonary fibroblasts by TGF-β?is increased in chronic obstructive pulmonary disease.PLo S One.2011;6(9):e2545