AMD3100联合G-CSF对糖尿病小鼠骨髓内皮祖细胞的动员作用
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摘要
目的:以糖尿病小鼠(db/db)为研究对象,比较单一使用AMD3100与AMD3100联合粒细胞集落刺激因子(granulocyte colony-stimulating,G-CSF)及两者不同使用顺序对骨髓内皮祖细胞(endothelial progenitor cells,EPCs)的动员效果,为临床获取糖尿病人EPCs进行细胞治疗提供思路。方法:采用AMD3100、重组人粒细胞集落刺激因子注射液(recombinant human granulocyte colony-stimulating,rh G-CSF)参考国内外文献所述剂量和方法进行骨髓EPCs的动员。选用5~6周雄性小鼠,随机将80只db/db小鼠分为A组(AMD3100+NS动员组),B组(AMD3100+G-CSF动员组),C组(G-CSF+AMD3100动员组)和D组(NS空白对照组);80只db/+小鼠为相应对照组,分组对应为A’组,B’组,C’组和D’组。每组在动员后第3、7、10、14天4个时间点于心脏部位取外周血,流式细胞仪检测CD34+/CD133+/Flk-1+细胞的比例。结果取平均值用均值±标准差(单位%)表示,统计学方法处理后进行比较和分析。结果:(1)D组和D’组在动员后第3、7、10、14天4个时间点,CD34+/CD133+/Flk-1+细胞比例无差异(P>0.05),但D’组中CD34+/CD133+/Flk-1+细胞比例高于D组(P=0.003)。(2)A组、B组和C组db/db小鼠在动员后第3、7、10、14天4个时间点,CD34+/CD133+/Flk-1+细胞比例逐渐上升,A组至第7天达到峰值,随后逐渐下降;B组和C组至第10天达到峰值,随后逐渐下降,且在达到峰值时CD34+/CD133+/Flk-1+细胞比例与其余3个时间点相比差异有意义(P=0.000)。在第10天,B组和C组db/db小鼠外周血中CD34+/CD133+/Flk-1+细胞比例较A组和D组高(P=0.000),但B组和C组db/db小鼠外周血中CD34+/CD133+/Flk-1+细胞比例之间的差异无统计学意义(P>0.05)。(3)A’组、B’组和C’组db/+小鼠在动员后第3、7、10、14天4个时间点,CD34+/CD133+/Flk-1+细胞比例逐渐上升,至第7天达到高峰,随后逐渐下降,且在第7天CD34+/CD133+/Flk-1+细胞比例与其余3个时间点相比差异有意义(P=0.000)。在达到峰值的第7天,C’组CD34+/CD133+/Flk-1+细胞比例较A’组、B’组和D’组高(P=0.000)。结论:AMD3100联合G-CSF动员骨髓EPCs的效果优于单一使用AMD3100的动员效果,在非糖尿病状态下,先使用G-CSF再联合AMD3100的动员作用更优,但在糖尿病状态下先使用AMD3100再联合G-CSF的动员作用更优。
Objective:To investigate the role of AMD3100 and granulocyte colony-stimulating(G-CSF)used alone or in different sequences in the mobilization of bone marrow endothelial progenitor cells(EPCs)in diabetic mice(db/db mice),and to provide thoughts for collecting EPCs from diabetic patients for clinical treatment. Methods:With reference to the dose and methods described in related articles in China and foreign countries,AMD3100 and recombinant human granulocyte colony-stimulating(rh G-CSF)injection were used for the mobilization of bone barrow EPCs. A total of 80 male db/db mice aged 5-6 weeks were randomly divided into group A(AMD3100+NS mobilization group),group B(AMD3100+G-CSF mobilization group),group C(G-CSF +AMD3100 mobilization group),and group D(NS blank control group). A total of 80 db/+male mice were selected as corresponding controls and were divided into groups A',B',C',and D'. Peripheral blood samples were collected from the heart on days 3,7,10,and 14 after mobilization,and flow cytometry was used to measure the proportion of CD34+/CD133+/Flk-1+cells. The results were expressed as mean±standard deviation(%),and comparison and analysis were performed after statistical analysis. Results:On days 3,7,10,and 14 after mobilization,there was no significant difference in the propor tion of CD34+/CD133+/Flk-1+cells between groups D and D'(P>0.05),but group D'had a higher proportion than group D(P=0.003).In group A,the proportion of CD34+/CD133+/Flk-1+ cells gradually increased and reached the highest value on day 7 and then gradually decreased;in groups B and C,the proportion of CD34+/CD133+/Flk-1+ cells gradually increased and reached the highest value on day10 and then gradually decreased;the proportion of CD34 +/CD133 +/Flk-1+ cells at the peak was significantly higher than that at the other three time points(P=0.000). On day 10,groups B and C had a significantly higher proportion of CD34+/CD133+/Flk-1+ cells in peripheral blood of db/db mice than groups A and D(P=0.000),but there was no significant difference between groups B and C(P>0.05). In groups A',B',and C'after mobilization,the proportion of CD34+/CD133+/Flk-1+ cells gradually increased and reached the peak on day 7 and then gradually decreased;the proportion of CD34+/CD133+/Flk-1+ cells on day 7 was significantly higher than that at the other three time points(P=0.000). On day 7,the C'group had a significantly higher proportion of CD34+/CD133+/Flk-1+ cells than groups A',B',and D'(P=0.000). Conclusion:AMD3100 combined with G-CSF has a better effect in the mobilization of bone marrow EPCs than AMD3100 alone. In non-diabetic conditions,G-CSF followed by the addition of AMD3100 has a better mobilization effect,but in diabetic conditions,AMD3100 followed by the addition of G-CSF has a better mobilization effect.
Objective:To investigate the role of AMD3100 and granulocyte colony-stimulating(G-CSF)used alone or in different sequences in the mobilization of bone marrow endothelial progenitor cells(EPCs)in diabetic mice(db/db mice),and to provide thoughts for collecting EPCs from diabetic patients for clinical treatment. Methods:With reference to the dose and methods described in related articles in China and foreign countries,AMD3100 and recombinant human granulocyte colony-stimulating(rh G-CSF)injection were used for the mobilization of bone barrow EPCs. A total of 80 male db/db mice aged 5-6 weeks were randomly divided into group A(AMD3100+NS mobilization group),group B(AMD3100+G-CSF mobilization group),group C(G-CSF +AMD3100 mobilization group),and group D(NS blank control group). A total of 80 db/+male mice were selected as corresponding controls and were divided into groups A',B',C',and D'. Peripheral blood samples were collected from the heart on days 3,7,10,and 14 after mobilization,and flow cytometry was used to measure the proportion of CD34+/CD133+/Flk-1+cells. The results were expressed as mean±standard deviation(%),and comparison and analysis were performed after statistical analysis. Results:On days 3,7,10,and 14 after mobilization,there was no significant difference in the propor tion of CD34+/CD133+/Flk-1+cells between groups D and D'(P>0.05),but group D'had a higher proportion than group D(P=0.003).In group A,the proportion of CD34+/CD133+/Flk-1+ cells gradually increased and reached the highest value on day 7 and then gradually decreased;in groups B and C,the proportion of CD34+/CD133+/Flk-1+ cells gradually increased and reached the highest value on day10 and then gradually decreased;the proportion of CD34 +/CD133 +/Flk-1+ cells at the peak was significantly higher than that at the other three time points(P=0.000). On day 10,groups B and C had a significantly higher proportion of CD34+/CD133+/Flk-1+ cells in peripheral blood of db/db mice than groups A and D(P=0.000),but there was no significant difference between groups B and C(P>0.05). In groups A',B',and C'after mobilization,the proportion of CD34+/CD133+/Flk-1+ cells gradually increased and reached the peak on day 7 and then gradually decreased;the proportion of CD34+/CD133+/Flk-1+ cells on day 7 was significantly higher than that at the other three time points(P=0.000). On day 7,the C'group had a significantly higher proportion of CD34+/CD133+/Flk-1+ cells than groups A',B',and D'(P=0.000). Conclusion:AMD3100 combined with G-CSF has a better effect in the mobilization of bone marrow EPCs than AMD3100 alone. In non-diabetic conditions,G-CSF followed by the addition of AMD3100 has a better mobilization effect,but in diabetic conditions,AMD3100 followed by the addition of G-CSF has a better mobilization effect.
引文
[1]吉宗珊,刘思颖,权威,等.内皮祖细胞分离培养及应用技术新进展[J].现代生物医学进展,2016,16(8):1567-1572.
[2]Shen WC,Liang CJ,Wu VC,et al.Endothelial progenitor cells derived from Wharton’s jelly of the umbilical cord reduces ischemia-induced hind limb injury in diabetic mice by inducing HIF-1α/IL-8 expression[J].Stem Cells Dev,2013,22(9):1408-1418.
[3]Chen W,Wu Y,Li L,et al.Adenosine accelerates the healing of diabetic ischemic ulcers by improving autophagy of endothelial progenitor cells grown on a biomaterial[J].Sci Rep,2015,5:11594.
[4]Sukmawat D,Fujimura S,Jitsukawa S,et al.Oxidative stress tolerance of early stage diabetic endothelial progenitor cell[J].Regen Ther,2015,1:38-44.
[5]高彩艳,买超平,哈小琴.内皮祖细胞修复糖尿病患者血管并发症:可成为新治疗策略吗?[J].中国组织工程研究,2014,18(32):5214-5219.
[6]Yttkihlde N,Masaaki I,Gangjian Q,et al.CXCR4 antagonist AMD3100 accelerates impaired wound healing in diabetic mice[J].J Invest Dermatol,2012,132(3 Pt 1):711-720.
[7]刘峰,刘志达,武楠,等.粒细胞集落刺激因子动员对大鼠内皮祖细胞体外扩增的影响[J].中国组织工程研究与临床康复,2008,12(51):10033-10036.
[8]Ma XL,Sun XL,Wan CY,et al.Significance of circulating endothelial progenitor cells in patients with fracture healing process[J].J Orthop Res,2012,30(11):1860-1866.
[9]Berezin AE,Kremzer AA,Berezina TA,et al.Data regarding association between serum osteoprotegerin level,numerous of circulating endothelial-derived and mononuclear-derived progenitor cells in patients with metabolic syndrome[J].Data In Brief,2016,8:717-722.
[10]Berezin AE,Kremzer AA.Circulating endothelial progenitor cells as markers for severity of ischemic chronic heart failure[J].J Card Fail,2014,20(6):438-447.
[11]Im JY,Min WK,Park MH,et al.AMD3100 improves ovariectomy-induced osteoporosis in mice by facilitating mobilization of hematopoietic stem/progenitor cells[J].BMB Rep,2014,47(8):439–444.
[12]Dar A,Schajnovitz A,Lapid K,et al.Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells[J].Leukemia,2011,25(8):1286-1296.
[13]Otsuka S,Bebb G.The CXCR4/SDF-1 chemokine receptor axis:a new target therapeutic for non-small cell lung cancer[J].J Thor Oncol,2008,3(12):1379-1383.
[14]Perez LE,Alpdogan O,Shieh J H,et al.Increased plasma levels of stromal-derived factor-1(SDF-1/CXCL12)enhance human thrombopoiesis and mobilize human colony-forming cells(CFC)in NOD/SCID mice[J].Exp Hematol,2004,32(3):300-307.
[15]Jujo K,Hamada H,Iwakura A,et al.CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction[J].Proc Natl Acad Sci USA,2010,107(24):11008-11013.
[16]Mehta HM,Malandra M,Corey SJ.G-CSF and GM-CSF in neutropenia[J].J Immunol,2015,195(4):1341-1349.
[17]Hsu YM,Cushing MM.Autologous stem cell mobilization and collection[J].Hematol Oncol Clin North Am,2016,30(3):573-589.
[18]Herrmann M,Zeiter S,Eberli U,et al.Five days granulocyte colony-stimulating factor treatment increases bone formation and reduces gap size of a rat segmental bone defect:a pilot study[J].Front Bioeng Biotechnol,2018,6:5.
[19]Deng MW,Wei SJ,Yew TL,et al.Cell therapy with G-CSF-mobilized stem cells in a rat osteoarthritis model[J].Cell Transplant,2015,24(6):1085-1096.
[20]Fruehauf S,Seeger T,Maier P,et al.The CXCR4 antagonist AMD3100 releases a subset of G-CSF-primed peripheral blood progenitor cells with specific gene expression characteristics[J].Exp Hematol,2006,34(8):1052-1059.
[21]Jantunen E.Novel strategies for blood stem cell mobilization:special focus on plerixafor[J].Expert Opin Biol Ther,2011,11(9):1241-1248.
[22]Fadini GP,Avogaro A.Potential manipulation of endothelial progenitor cells in diabetes and its complications[J].Diabetes Obes Metab,2010,12(7):570-583.
[23]Winkler IG,Pettit AR,Raggatt LJ,et al.Hematopoietic stem cell mobilizing agents G-CSF,cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation[J].Leukemia,2012,26(7):1594-1601.
[24]Broxmeyer HE,Hoggatt J,O’Leary HA,et al.Dipeptidylpeptidase4 negatively regulates colony-stimulating factor activity and stress hematopoiesis[J].Nat Med,2012,18(12):1786-1796.
[25]Albiero M,Poncina N,Tjwa M,et al.Diabetes causes bone marrow autonomic neuropathy and impairs stem cell mobilization via dysregulated p66Shc and Sirt1[J].Diabetes,2014,63(4):1353-1365.
[26]Spinetti G,Cordella D,Fortunato O,et al.Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients:implication of the micro RNA-155/FOXO3a signaling pathway[J].Circ Res,2013,112(3):510-522.
[27]Di Persio JF.Diabetic stem-cell“mobilopathy”[J].N Engl J Med,2011,365(26):2536-2538.
[28]Fadini GP,Fiala M,Cappellari R,et al.Diabetes limits stem cell mobilization following G-CSF but not plerixafor[J].Diabetes,2015,64(8):2969-2977.
[29]Bendall LJ,Bradstock KF.G-CSF:from granulopoietic stimulant to bone marrow stem cell mobilizing agent[J].Cytokine Growth Factor Rev,2014,25(4):355-367.
[30]Tanaka R,Masuda H,Kato S,et al.Autologous G-CSF-mobilized peripheral blood CD34+cell therapy for diabetic patients with chronic nonhealing ulcer[J].Cell Transplant,2014,23(2):167-179.
[31]王钰,龙爽,谭力,等.粒细胞集落刺激因子激活β-catenin促进创面修复[J].第三军医大学学报,2015,37(16):1648-1651.
[32]Zou SB,Yoon WY,Han SK,et al.Cytotoxicity of silver dressings on diabetic fibroblasts[J].Int Wound J,2013,10(3):306-312.
[33]Dulchavsky D,Gao X,Liu YB,et al.Bone marrow-derived stromal cells(BMSCs)interact with fibroblasts in accelerating wound healing[J].J Invest Surg,2008,21(5):270-279.
[34]彭颖,赵阳,解英,等.异体皮肤成纤维细胞在糖尿病小鼠创面愈合中的作用及其机制[J].中华烧伤杂志,2018,34(8):532-541
[35]Lin Q,Wesson RN,Maeda H,et al.Pharmacological mobilization of endogenous stem cells significantly promotes skin regeneration after full thickness excision:the synergistic activity of AMD3100 and tacrolimus[J].J Invest Dermatol,2014,134(9):2458-2468.
[36]张培岩,陈丁丁.内皮祖细胞的迁移及对血管修复作用的研究进展[J].海峡药学,2017,29(3):10-15.
[37]Newey SE,Tsaknakis G,Khoo CP,et al.The hematopoietic chemokine CXCL12 promotes integration of human endothelial colony forming cell-derived cells into immature vessel networks[J].Stem Cells Dev,2014,23(22):2730-2743.
[38]Tanaka R,Masuda H,Fujimura S,et al.Quality-quantity control culture enhances vasculogenesis and wound healingefficacy of human diabetic peripheral blood CD34+cells[J].Stem Cells Transl Med,2018,7(5):428-438.
[39]Sukmawati D,Tanaka R,Ito-Hirano R,et al.The role of Notch signaling in diabetic endothelial progenitor cells dysfunction[J].J Diabetes Complications,2016,30(1):12-20.
[40]Liu J,Deutsch U,Jeong J,et al.Constitutive notch signaling in adult transgenic mice inhibits b FGF-induced angiogenesis and blocks ovarian follicle development[J].Genesis,2014,52(9):809-816.
[41]Hasan SS,Tsaryk R,Lange M,et al.Endothelial Notch signalling limits angiogenesis via control of artery formation[J].Nat Cell Biol,2017,19(8):928-940.
[2]Shen WC,Liang CJ,Wu VC,et al.Endothelial progenitor cells derived from Wharton’s jelly of the umbilical cord reduces ischemia-induced hind limb injury in diabetic mice by inducing HIF-1α/IL-8 expression[J].Stem Cells Dev,2013,22(9):1408-1418.
[3]Chen W,Wu Y,Li L,et al.Adenosine accelerates the healing of diabetic ischemic ulcers by improving autophagy of endothelial progenitor cells grown on a biomaterial[J].Sci Rep,2015,5:11594.
[4]Sukmawat D,Fujimura S,Jitsukawa S,et al.Oxidative stress tolerance of early stage diabetic endothelial progenitor cell[J].Regen Ther,2015,1:38-44.
[5]高彩艳,买超平,哈小琴.内皮祖细胞修复糖尿病患者血管并发症:可成为新治疗策略吗?[J].中国组织工程研究,2014,18(32):5214-5219.
[6]Yttkihlde N,Masaaki I,Gangjian Q,et al.CXCR4 antagonist AMD3100 accelerates impaired wound healing in diabetic mice[J].J Invest Dermatol,2012,132(3 Pt 1):711-720.
[7]刘峰,刘志达,武楠,等.粒细胞集落刺激因子动员对大鼠内皮祖细胞体外扩增的影响[J].中国组织工程研究与临床康复,2008,12(51):10033-10036.
[8]Ma XL,Sun XL,Wan CY,et al.Significance of circulating endothelial progenitor cells in patients with fracture healing process[J].J Orthop Res,2012,30(11):1860-1866.
[9]Berezin AE,Kremzer AA,Berezina TA,et al.Data regarding association between serum osteoprotegerin level,numerous of circulating endothelial-derived and mononuclear-derived progenitor cells in patients with metabolic syndrome[J].Data In Brief,2016,8:717-722.
[10]Berezin AE,Kremzer AA.Circulating endothelial progenitor cells as markers for severity of ischemic chronic heart failure[J].J Card Fail,2014,20(6):438-447.
[11]Im JY,Min WK,Park MH,et al.AMD3100 improves ovariectomy-induced osteoporosis in mice by facilitating mobilization of hematopoietic stem/progenitor cells[J].BMB Rep,2014,47(8):439–444.
[12]Dar A,Schajnovitz A,Lapid K,et al.Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells[J].Leukemia,2011,25(8):1286-1296.
[13]Otsuka S,Bebb G.The CXCR4/SDF-1 chemokine receptor axis:a new target therapeutic for non-small cell lung cancer[J].J Thor Oncol,2008,3(12):1379-1383.
[14]Perez LE,Alpdogan O,Shieh J H,et al.Increased plasma levels of stromal-derived factor-1(SDF-1/CXCL12)enhance human thrombopoiesis and mobilize human colony-forming cells(CFC)in NOD/SCID mice[J].Exp Hematol,2004,32(3):300-307.
[15]Jujo K,Hamada H,Iwakura A,et al.CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction[J].Proc Natl Acad Sci USA,2010,107(24):11008-11013.
[16]Mehta HM,Malandra M,Corey SJ.G-CSF and GM-CSF in neutropenia[J].J Immunol,2015,195(4):1341-1349.
[17]Hsu YM,Cushing MM.Autologous stem cell mobilization and collection[J].Hematol Oncol Clin North Am,2016,30(3):573-589.
[18]Herrmann M,Zeiter S,Eberli U,et al.Five days granulocyte colony-stimulating factor treatment increases bone formation and reduces gap size of a rat segmental bone defect:a pilot study[J].Front Bioeng Biotechnol,2018,6:5.
[19]Deng MW,Wei SJ,Yew TL,et al.Cell therapy with G-CSF-mobilized stem cells in a rat osteoarthritis model[J].Cell Transplant,2015,24(6):1085-1096.
[20]Fruehauf S,Seeger T,Maier P,et al.The CXCR4 antagonist AMD3100 releases a subset of G-CSF-primed peripheral blood progenitor cells with specific gene expression characteristics[J].Exp Hematol,2006,34(8):1052-1059.
[21]Jantunen E.Novel strategies for blood stem cell mobilization:special focus on plerixafor[J].Expert Opin Biol Ther,2011,11(9):1241-1248.
[22]Fadini GP,Avogaro A.Potential manipulation of endothelial progenitor cells in diabetes and its complications[J].Diabetes Obes Metab,2010,12(7):570-583.
[23]Winkler IG,Pettit AR,Raggatt LJ,et al.Hematopoietic stem cell mobilizing agents G-CSF,cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation[J].Leukemia,2012,26(7):1594-1601.
[24]Broxmeyer HE,Hoggatt J,O’Leary HA,et al.Dipeptidylpeptidase4 negatively regulates colony-stimulating factor activity and stress hematopoiesis[J].Nat Med,2012,18(12):1786-1796.
[25]Albiero M,Poncina N,Tjwa M,et al.Diabetes causes bone marrow autonomic neuropathy and impairs stem cell mobilization via dysregulated p66Shc and Sirt1[J].Diabetes,2014,63(4):1353-1365.
[26]Spinetti G,Cordella D,Fortunato O,et al.Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients:implication of the micro RNA-155/FOXO3a signaling pathway[J].Circ Res,2013,112(3):510-522.
[27]Di Persio JF.Diabetic stem-cell“mobilopathy”[J].N Engl J Med,2011,365(26):2536-2538.
[28]Fadini GP,Fiala M,Cappellari R,et al.Diabetes limits stem cell mobilization following G-CSF but not plerixafor[J].Diabetes,2015,64(8):2969-2977.
[29]Bendall LJ,Bradstock KF.G-CSF:from granulopoietic stimulant to bone marrow stem cell mobilizing agent[J].Cytokine Growth Factor Rev,2014,25(4):355-367.
[30]Tanaka R,Masuda H,Kato S,et al.Autologous G-CSF-mobilized peripheral blood CD34+cell therapy for diabetic patients with chronic nonhealing ulcer[J].Cell Transplant,2014,23(2):167-179.
[31]王钰,龙爽,谭力,等.粒细胞集落刺激因子激活β-catenin促进创面修复[J].第三军医大学学报,2015,37(16):1648-1651.
[32]Zou SB,Yoon WY,Han SK,et al.Cytotoxicity of silver dressings on diabetic fibroblasts[J].Int Wound J,2013,10(3):306-312.
[33]Dulchavsky D,Gao X,Liu YB,et al.Bone marrow-derived stromal cells(BMSCs)interact with fibroblasts in accelerating wound healing[J].J Invest Surg,2008,21(5):270-279.
[34]彭颖,赵阳,解英,等.异体皮肤成纤维细胞在糖尿病小鼠创面愈合中的作用及其机制[J].中华烧伤杂志,2018,34(8):532-541
[35]Lin Q,Wesson RN,Maeda H,et al.Pharmacological mobilization of endogenous stem cells significantly promotes skin regeneration after full thickness excision:the synergistic activity of AMD3100 and tacrolimus[J].J Invest Dermatol,2014,134(9):2458-2468.
[36]张培岩,陈丁丁.内皮祖细胞的迁移及对血管修复作用的研究进展[J].海峡药学,2017,29(3):10-15.
[37]Newey SE,Tsaknakis G,Khoo CP,et al.The hematopoietic chemokine CXCL12 promotes integration of human endothelial colony forming cell-derived cells into immature vessel networks[J].Stem Cells Dev,2014,23(22):2730-2743.
[38]Tanaka R,Masuda H,Fujimura S,et al.Quality-quantity control culture enhances vasculogenesis and wound healingefficacy of human diabetic peripheral blood CD34+cells[J].Stem Cells Transl Med,2018,7(5):428-438.
[39]Sukmawati D,Tanaka R,Ito-Hirano R,et al.The role of Notch signaling in diabetic endothelial progenitor cells dysfunction[J].J Diabetes Complications,2016,30(1):12-20.
[40]Liu J,Deutsch U,Jeong J,et al.Constitutive notch signaling in adult transgenic mice inhibits b FGF-induced angiogenesis and blocks ovarian follicle development[J].Genesis,2014,52(9):809-816.
[41]Hasan SS,Tsaryk R,Lange M,et al.Endothelial Notch signalling limits angiogenesis via control of artery formation[J].Nat Cell Biol,2017,19(8):928-940.
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