缺氧环境下BMSCs促进VECs增殖和血管形成
摘要
目的：
观察成人骨髓间充质干细胞在体外缺氧环境下对人脐静脉内皮细胞增殖和血管形成能力的影响并探讨其可能机制，为干细胞更好的应用于临床上缺血缺氧性疾病的治疗提供理论依据。
方法：
收集成人骨髓血，密度梯度离心法收集分离BMSCs并进行体外扩增培养，传至第4代用于实验；流式细胞技术鉴定BMSCs表面标志物。
收集BMSCs常氧环境(氧浓度为21%)下培养24h和缺氧环境下(含1%O2，5%CO2和94%N2的混合气体环境)培养24h后的细胞上清液即条件培养基。HUVECs传代培养后分成3组进行实验：对照组、 BMSCsCMN-HUVECs组和BMSCsCMH-HUVECs组，各实验组细胞于缺氧环境下用含不同条件培养基的培养液培养，体外血管形成实验分析3组HUVECs在Matrigel上管腔样结构形成情况，并进行量化比较；MTT检测3组HUVECs增殖能力。
BMSCs在缺氧环境下培养0h、12h、24h和48h后，RT-PCR检测细胞内SDF-1和VEGF的基因表达情况，0h为对照组，12h、24h和48h为实验组；ELISA法检测细胞上清液中SDF-1和VEGF的蛋白含量。
结果：
1.人BMSCs传至第4代呈漩涡状长梭形即纤维母细胞样生长；对数生长期的HUVECs多为多角形或短梭形，呈”铺路石”样排列生长
2.人BMSCs阳性表达CD29、CD44和CD90，而阴性表达CD34、CD45和CD106
3. BMSCsCMH-HUVECs组管腔样结构多于对照组和BMSCsCMN-HUVECs组。[14±2.3与3±0.59；14±2.3与5±1.1，P＜0.05]
4.不同缺氧时间点(12h，24h和48h)BMSCsCMH-HUVECs组细胞增殖能力均显著高于对照组和BMSCsCMN-HUVECs组。[0.54±0.053与0.33±0.041，0.68±0.091与0.42±0.048，0.72±0.106与0.49±0.074；0.54±0.053与0.31±0.041，0.68±0.091与0.43±0.071，0.72±0.106与0.51±0.086，P＜0.05]
5.不同缺氧时间点(12h，24h和48h)BMSCs的SDF-1和VEGF基因表达水平均显著高于对照组。[VEGF：0.718±0.048vs0.532±0.081，0.922±0.104vs0.532±0.081，0.843±0.092vs0.532±0.081；SDF-1：0.569±0.091vs0.361±0.035，0.701±0.046vs0.361±0.035，0.695±0.074vs0.361±0.035，P＜0.05]
6. BMSCsCMH中SDF-1和VEGF蛋白含量均明显高于BMSCsCMN。[SDF-1：(4.52±0.44)ng/106cells与(1.37±0.09) ng/106cells；VEGF：(7.94±0.89) ng/106cell与(2.75±0.23) ng/106cells，P＜0.05]。
结论：
1.缺氧环境下收集的条件培养基即BMSCsCMH显著提高HUVECs增殖和在Matrigel上管腔样结构形成能力；
2.缺氧显著上调BMSCs的SDF-1和VEGF基因表达，并促进二者大量分泌至细胞上清液中发挥作用；
3.成人BMSCs在缺氧环境下通过旁分泌SDF-1和VEGF提高血管内皮细胞增殖活性和管腔样结构形成能力，促进血管新生。
Objective:
To investigate the effects of human bone marrow msesenchymal stem cells(BMSCs) on proliferation and angiogenesis of human umbilical vein endothelial cells(HUVECs) and its possible mechanism in hypoxia; For the better used ofmesenchymal stem cells in the treatment of Ischemia-Hypoxia disease in clinicalprovided theortical basis.
Methods:
Collected human bone marrow, BMSCs separated by density gradient centrif-ugation were cultured, expanded in vitro and used at passage4; Their phenotypiccharacterizations were indentified by flow cytometry(FCM).
After BMSCs exposed to normoxic(oxygen concentration was21%) andhypoxia(an atmosphere containing1%O2,5%CO2and94%N2) for24h, then collectedcells supernatant(named as conditioned medium, CM). HUVECs were cultured,expanded, passaged and divided into three groups: the control group, BMCsCMN–HUVECs and BMSCsCMH-HUVECs. Cells in each experimental group werecultured with different CM in hypixia. Tube-like structures formation of HUVECs inMatrigel were analyzed as the assay of angiogenesis in vitro, and conductedquantitative comparison; Proliferation of HUVECs were detected by MTT.
BMSCs exposed to hypoxia for0h,12h,24h and48h, intracellular levels ofSDF-1and VEGF mRNA were assayed by RT-PCR, the group of0h as the controlgroup,12h,24h and48h as experimental groups. The secretion of SDF-1and VEGFquantitatively analyzed by ELISA.
Results：
1. Under inverted phase-contrast microscopy, Human BMSCs exhibited swirlinglong fusiform namely fibroblast-like morphology growth；HUVECs were polygon orshort spindle, exhibited “paving stone” like arrangement growth.
2. BMSCs expressed CD29，CD44and CD90，but CD34，CD45and CD106 were negative.
3. The number of tube-like structures of cells in BMSCsCMH-HUVECs group inMatrigel increased significantly compared with the control group and BMSCsCMN-HUVECs group.[14±2.3与3±0.59;14±2.3与5±1.1, P＜0.05]
4. The proliferation of cells in BMSCsCMH-HUVECs group at the different timepoints of hypoxia(12h,24h and48h) increased significantly compared with thecontrol group and BMSCsCMN-HUVECs group.[0.54±0.053vs0.33±0.041,0.68±0.091vs0.42±0.048,0.72±0.106vs0.49±0.074;0.54±0.053vs0.31±0.041,0.68±0.091vs0.43±0.071,0.72±0.106vs0.51±0.086, P＜0.05]
5. The expression of SDF-1and VEGF mRNA at the different time point ofhypoxia(12h,24h and48h) were higher than those of the control group.[VEGF:0.718±0.048vs0.532±0.081,0.922±0.104vs0.532±0.081,0.843±0.092vs0.532±0.081; SDF-1:0.569±0.091vs0.361±0.035,0.701±0.046vs0.361±0.035,0.695±0.074vs0.361±0.035, P＜0.05]
6. The expression of SDF-1and VEGF protein in BMSCsCMHobviously higherthan those of BMSCsCMN.[VEGF:(7.94±0.89) ng/106cell vs (2.75±0.23) ng/106cells; SDF-1:(4.52±0.44)ng/106cells vs (1.37±0.09) ng/106cells, P＜0.05].
Conclusion：
1. BMSCsCMHpromoted proliferation and tube-like structures formation inMatrigel of HUVECs.
2. Hypoxia significantlt up-regulated the gene expression of SDF-1and VEGF inBMSCs; and promoted the cytokine of SDF-1and VEGF secreted into cellsupernatant considerablely, then came into play.
3. Human BMSCs improved proliferation and tube-like structures formation ofVascular endothelial cells(VECs) and promote angiogenesis in hypoxia，throughparacrined SDF-1and VEGF.
观察成人骨髓间充质干细胞在体外缺氧环境下对人脐静脉内皮细胞增殖和血管形成能力的影响并探讨其可能机制，为干细胞更好的应用于临床上缺血缺氧性疾病的治疗提供理论依据。
方法：
收集成人骨髓血，密度梯度离心法收集分离BMSCs并进行体外扩增培养，传至第4代用于实验；流式细胞技术鉴定BMSCs表面标志物。
收集BMSCs常氧环境(氧浓度为21%)下培养24h和缺氧环境下(含1%O2，5%CO2和94%N2的混合气体环境)培养24h后的细胞上清液即条件培养基。HUVECs传代培养后分成3组进行实验：对照组、 BMSCsCMN-HUVECs组和BMSCsCMH-HUVECs组，各实验组细胞于缺氧环境下用含不同条件培养基的培养液培养，体外血管形成实验分析3组HUVECs在Matrigel上管腔样结构形成情况，并进行量化比较；MTT检测3组HUVECs增殖能力。
BMSCs在缺氧环境下培养0h、12h、24h和48h后，RT-PCR检测细胞内SDF-1和VEGF的基因表达情况，0h为对照组，12h、24h和48h为实验组；ELISA法检测细胞上清液中SDF-1和VEGF的蛋白含量。
结果：
1.人BMSCs传至第4代呈漩涡状长梭形即纤维母细胞样生长；对数生长期的HUVECs多为多角形或短梭形，呈”铺路石”样排列生长
2.人BMSCs阳性表达CD29、CD44和CD90，而阴性表达CD34、CD45和CD106
3. BMSCsCMH-HUVECs组管腔样结构多于对照组和BMSCsCMN-HUVECs组。[14±2.3与3±0.59；14±2.3与5±1.1，P＜0.05]
4.不同缺氧时间点(12h，24h和48h)BMSCsCMH-HUVECs组细胞增殖能力均显著高于对照组和BMSCsCMN-HUVECs组。[0.54±0.053与0.33±0.041，0.68±0.091与0.42±0.048，0.72±0.106与0.49±0.074；0.54±0.053与0.31±0.041，0.68±0.091与0.43±0.071，0.72±0.106与0.51±0.086，P＜0.05]
5.不同缺氧时间点(12h，24h和48h)BMSCs的SDF-1和VEGF基因表达水平均显著高于对照组。[VEGF：0.718±0.048vs0.532±0.081，0.922±0.104vs0.532±0.081，0.843±0.092vs0.532±0.081；SDF-1：0.569±0.091vs0.361±0.035，0.701±0.046vs0.361±0.035，0.695±0.074vs0.361±0.035，P＜0.05]
6. BMSCsCMH中SDF-1和VEGF蛋白含量均明显高于BMSCsCMN。[SDF-1：(4.52±0.44)ng/106cells与(1.37±0.09) ng/106cells；VEGF：(7.94±0.89) ng/106cell与(2.75±0.23) ng/106cells，P＜0.05]。
结论：
1.缺氧环境下收集的条件培养基即BMSCsCMH显著提高HUVECs增殖和在Matrigel上管腔样结构形成能力；
2.缺氧显著上调BMSCs的SDF-1和VEGF基因表达，并促进二者大量分泌至细胞上清液中发挥作用；
3.成人BMSCs在缺氧环境下通过旁分泌SDF-1和VEGF提高血管内皮细胞增殖活性和管腔样结构形成能力，促进血管新生。
Objective:
To investigate the effects of human bone marrow msesenchymal stem cells(BMSCs) on proliferation and angiogenesis of human umbilical vein endothelial cells(HUVECs) and its possible mechanism in hypoxia; For the better used ofmesenchymal stem cells in the treatment of Ischemia-Hypoxia disease in clinicalprovided theortical basis.
Methods:
Collected human bone marrow, BMSCs separated by density gradient centrif-ugation were cultured, expanded in vitro and used at passage4; Their phenotypiccharacterizations were indentified by flow cytometry(FCM).
After BMSCs exposed to normoxic(oxygen concentration was21%) andhypoxia(an atmosphere containing1%O2,5%CO2and94%N2) for24h, then collectedcells supernatant(named as conditioned medium, CM). HUVECs were cultured,expanded, passaged and divided into three groups: the control group, BMCsCMN–HUVECs and BMSCsCMH-HUVECs. Cells in each experimental group werecultured with different CM in hypixia. Tube-like structures formation of HUVECs inMatrigel were analyzed as the assay of angiogenesis in vitro, and conductedquantitative comparison; Proliferation of HUVECs were detected by MTT.
BMSCs exposed to hypoxia for0h,12h,24h and48h, intracellular levels ofSDF-1and VEGF mRNA were assayed by RT-PCR, the group of0h as the controlgroup,12h,24h and48h as experimental groups. The secretion of SDF-1and VEGFquantitatively analyzed by ELISA.
Results：
1. Under inverted phase-contrast microscopy, Human BMSCs exhibited swirlinglong fusiform namely fibroblast-like morphology growth；HUVECs were polygon orshort spindle, exhibited “paving stone” like arrangement growth.
2. BMSCs expressed CD29，CD44and CD90，but CD34，CD45and CD106 were negative.
3. The number of tube-like structures of cells in BMSCsCMH-HUVECs group inMatrigel increased significantly compared with the control group and BMSCsCMN-HUVECs group.[14±2.3与3±0.59;14±2.3与5±1.1, P＜0.05]
4. The proliferation of cells in BMSCsCMH-HUVECs group at the different timepoints of hypoxia(12h,24h and48h) increased significantly compared with thecontrol group and BMSCsCMN-HUVECs group.[0.54±0.053vs0.33±0.041,0.68±0.091vs0.42±0.048,0.72±0.106vs0.49±0.074;0.54±0.053vs0.31±0.041,0.68±0.091vs0.43±0.071,0.72±0.106vs0.51±0.086, P＜0.05]
5. The expression of SDF-1and VEGF mRNA at the different time point ofhypoxia(12h,24h and48h) were higher than those of the control group.[VEGF:0.718±0.048vs0.532±0.081,0.922±0.104vs0.532±0.081,0.843±0.092vs0.532±0.081; SDF-1:0.569±0.091vs0.361±0.035,0.701±0.046vs0.361±0.035,0.695±0.074vs0.361±0.035, P＜0.05]
6. The expression of SDF-1and VEGF protein in BMSCsCMHobviously higherthan those of BMSCsCMN.[VEGF:(7.94±0.89) ng/106cell vs (2.75±0.23) ng/106cells; SDF-1:(4.52±0.44)ng/106cells vs (1.37±0.09) ng/106cells, P＜0.05].
Conclusion：
1. BMSCsCMHpromoted proliferation and tube-like structures formation inMatrigel of HUVECs.
2. Hypoxia significantlt up-regulated the gene expression of SDF-1and VEGF inBMSCs; and promoted the cytokine of SDF-1and VEGF secreted into cellsupernatant considerablely, then came into play.
3. Human BMSCs improved proliferation and tube-like structures formation ofVascular endothelial cells(VECs) and promote angiogenesis in hypoxia，throughparacrined SDF-1and VEGF.
引文
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[65] Li Z, Guo J, Chang Q, et al. Paracrine role for mesenchymal stem cells in acute myocardialinfarction. Biol Pharm Bull.2009;32(8): p1343-6.
[66] Kagiwada H, Yashikit T, Ohshima A, et al. Human mesenchymal stem cells as a stablesource of VEGF-producing cells. J Tissue Eng Regen Med.2008;2(4): p184-9.
[67] Tang JM, Wang JN, Zhang L, et al. VEGF/SDF-1Promotes Cardiac Stem CellMobilization and Myocardial Repair in the Infarcted Heart. Cardiovasc Res.2011;91(3):402-11.
[68] Tang J, Wang J, Guo L, et al. Mesenchymal stem cells modified with stromal cell-derivedfactor1alpha improve cardiac remodeling via paracrine activation of hepatocyte growthfactor in a rat model of myocardial infarction. Mol Cells.2010;29(1): p9-19.
[69] Loh SA, Chang EI,Galvez MG, et al. SDF-1alpha expression during wound healing in theaged is HIF dependent. Plast Reconstr Surg.2009;123(2Suppl): p65S-75S.
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[72] Nakanishi C, Yamagishi M, Yamahara K, et al. Activation of cardiac progenitor cellsthrough paracrine effects of mesenchymal stem cells. Biochem Biophys Res Commun2008;374(1):11—6.
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[75] Nomura R, Yoshida D, and Teramoto A. Stromal cell-derived factor-1expression inpituitary adenoma tissues and upregulation in hypoxia. J Neurooncol,2009;94(2): p173-81.
[76] Lee EY, Xia Y, Kim WS, et al. Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell roliferation and up-regulation of VEGF and bFGF.Wound Repair Regen.2009;17(4): p.540-7.
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[1] Ota K, Nagai H, and Sheng G. Expression and hypoxic regulation of hif1alpha and hif2alphaduring early blood and endothelial cell differention in chick[J]. Gene Expr Patterns.2007;(7):761-766.
[2] Ben-Shoshan J, Schwartz S, Luboshits G, et al. Constitutive expression of HIF-1alpha andHIF-1alpha in bone marrow stromal cells differentially promotes their proangiogenicproperties[J]. Stem cells.2008;26(10):2634-2643.
[3] Patel SA, and Simon MC. Biology of hypoxia-inducible factor-2alpha in development anddisease[J]. Cell Death Differ.2008;15(4):628-634.
[4] Chen L, Endler A, and Shibasaki F. Hypoxia and angiogenesis:regulation of hypoxia-inducible factors via novel bingding factors[J]. Exp Mol Med.2009;41(12):849-857.
[5] Fong GH, and Takeda K. Role and regulation of proyl hydroxylase domain proteins[J].CellDeath Differ.2008;15(4):635-641.
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[11]Jones EA, Le Noble F, Eichmann A. What determines blood vessel structure? Geneticprespecification vs.Hemodynamics[J]. Physiology(Bethesda).2006;21:388-395.
[12]Huanf LE. Carrot and stick:HIF-alpha engages c-Myc in hypoxic adaptation [J]. Cell DeathDiffer.2008;15(4):672-677.
[13]Mizukami Y, Fujki K, Duerr EM, et al. Hypoxic regulation of vascular endothelial growthfactor through the induction of phosphatidylinositol3-kinase/Rho/ROCK and c-Myc[J]. JBiol Chem.2006;281(20):13957-1363.
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[17]Dutta D, Ray S, Vivian JL, et al. Activation of the VEGFR1chromatin domain:an angiogenicsignal-ETS1/HIF-1alpha regulatory axis[J]. J Biol Chem.2008;283(37):25404-25413.
[18]Das R, Jahr H, Farrell E, et al. The role of hypoxia in bone marrow-derived mesenchymalstem cell:considerations for regenerative medicine approaches[J]. Tissue Eng Part B Rev.2010;16(2):159-168.
[19]Rosova I, Dao M, Nolta JA, et al. Hypoxic preconditioning results in increased motility andimproved therapeutic potential of human mesenchymal stem cell[J]. Stem Cell.2008;26(8):2173-2182.
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[1] Ota K, Nagai H, and Sheng G. Expression and hypoxic regulation of hif1alpha and hif2alphaduring early blood and endothelial cell differention in chick[J]. Gene Expr Patterns.2007;(7):761-766.
[2] Ben-Shoshan J, Schwartz S, Luboshits G, et al. Constitutive expression of HIF-1alpha andHIF-1alpha in bone marrow stromal cells differentially promotes their proangiogenicproperties[J]. Stem cells.2008;26(10):2634-2643.
[3] Patel SA, and Simon MC. Biology of hypoxia-inducible factor-2alpha in development anddisease[J]. Cell Death Differ.2008;15(4):628-634.
[4] Chen L, Endler A, and Shibasaki F. Hypoxia and angiogenesis:regulation of hypoxia-inducible factors via novel bingding factors[J]. Exp Mol Med.2009;41(12):849-857.
[5] Fong GH, and Takeda K. Role and regulation of proyl hydroxylase domain proteins[J].CellDeath Differ.2008;15(4):635-641.
[6] Van Hagen M, Overmeer RM, Abolvardi SS, et al. RNF-4and VHL regulate the proteasomaldegradation of SUMO-conjugated hypoxia-inducible-2alpha[J]. Nucleic Acids Res.2010;38(6):1822-1931.
[7] Sun H, Leverson D, Hunter T. Conserved function of RNF4family proteins in eukaryotes:targeting a ubiquitin ligase to SUMOylated proteins[J].EMBO J.2007;26(18):4102-4112.
[8] Aprelikova O, Wood M, Tackett S, et al. Role of ETS transcription factors in the hypoxia-inducible factor-2target gene selection[J]. Cancer Res.2006;66(11):5641-5647.
[9] Huc J, Sataur A, Wang L, et al. The N-terminal transactivation domain confers target genespecificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha[J]. Mol Biol Cell.2007;18(11):4528-4542.
[10]Zwezdaryk KJ, Coffelt SB, Figueroa YG, et al. Erythropoietin,a hypoxia-regulated factor,elicits a pro-angiogenic prohram in human mesenchymal stem cell[J]. Exp Hematol.2007;35(4):640-652.
[11]Jones EA, Le Noble F, Eichmann A. What determines blood vessel structure? Geneticprespecification vs.Hemodynamics[J]. Physiology(Bethesda).2006;21:388-395.
[12]Huanf LE. Carrot and stick:HIF-alpha engages c-Myc in hypoxic adaptation [J]. Cell DeathDiffer.2008;15(4):672-677.
[13]Mizukami Y, Fujki K, Duerr EM, et al. Hypoxic regulation of vascular endothelial growthfactor through the induction of phosphatidylinositol3-kinase/Rho/ROCK and c-Myc[J]. JBiol Chem.2006;281(20):13957-1363.
[14]Li Q, Kluz T, Sun H, et al. Mechanisms of c-Myc degradatiob by nickel compounds andhypoxia[J]. PLoS One.2009;4(12):e8531.
[15]Takeda N, Maemura K, Imai Y, et al. Endothelial PAS domain protein1gene promotesangiogenesis through the transactivation of both vascular endothelial growth factor and itsreceptor,Flt-1[J]. Circ Res.2004;95(2):146-153.
[16]Autiero M, Waltenberger J, Communi D, et al. Role of PIGE in the intra-and intermolecularcross talk between the VEGF receptors Flt1and Flk1[J]. Nat Med.2003;9(7):936-943.
[17]Dutta D, Ray S, Vivian JL, et al. Activation of the VEGFR1chromatin domain:an angiogenicsignal-ETS1/HIF-1alpha regulatory axis[J]. J Biol Chem.2008;283(37):25404-25413.
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