基质细胞衍生因子-1对脑梗死后移植的间质干细胞迁移的影响
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摘要
目的
观察经静脉移植骨髓间质干细胞(MSCs)治疗脑梗塞时,神经功能缺损的恢复情况,以及MSCs在脑梗塞灶的分布、迁移与分化情况。观察基质细胞衍生因子-1 (SDF-1 )在体内外对大鼠骨髓间质干细胞(rMSCs)的趋化诱导作用,探讨SDF-1 对rMSCs迁移影响的可能机制,为实现临床上对移植的rMSCs进行调控提供理论与实验依据。
方法
建立线栓法大鼠大脑中动脉栓塞(MCAO)模型,大脑中动脉血流阻断2小时后再灌注,再灌注后24h经尾静脉将标记的大鼠骨髓间质干细胞(rMSCs)植入脑梗塞鼠体内,于移植后24h、1W、2W时采用mNSS评分法对动物神经功能状况进行评分。应用荧光激发及免疫组化方法于移植后1W、2W时检测移植细胞在脑内存活、迁移及分化情况。细胞化学染色观察rMSCs体外培养时的分化情况。应用体外细胞迁移实验及大鼠脑梗塞模型体内移植,观察在施用和不施用抗SDF-1抗体时,SDF-1 对rMSCs迁移的影响。流式细胞术与RT-PCR检测rMSCs的CXC趋化因子受体4 (CXC chemokine receptor 4, CXCR4)表达。
结果
1.与对照组相比,移植组大鼠在移植后观察的2周内神经功能改善明显(p<0.001)。
2.可观察到移植细胞在脑梗塞区及其周边区聚集并存活,这种聚集于第2周更为明显。在脑梗塞区及其周边区有部分植入细胞分化表达神经细胞表面标志物,而在体外同时程培养的rMSCs未见分化表达类似表面标志物。
3.体外实验示在SDF-1 存在时,rMSCs迁移活跃,应用抗体封闭CXCR4受体后,这种迁移现象显著减弱。
4.体内移植的rMSCs在脑内主要聚集在脑梗死灶及其周边区,但在封闭CXCR4受体后,这种聚集现象大为减弱。
5.流式细胞术示仅小部分rMSCs表面表达CXCR4,但经Triton X-100处理后,表达CXCR4的rMSCs增加。RT-PCR检测显示rMSCs的Cxcr4基因表达CXCR4 mRNA。
结论
1. rMSCs经静脉移植后的2周观察表明移植的rMSCs可向宿主脑内病灶迁移、存活、并分化表达神经细胞表型,有促进脑梗塞后神经功能恢复的作用。
2.经静脉路移植rMSCs不仅可达到治疗目的,而且可以避免直接穿刺移植带来的脑组织损伤,植入的rMSCs能迁移并更好地分布在脑梗塞灶。
3. SDF-1可通过CXCR4受体对rMSCs起趋化作用,植入的rMSCs能聚集分布在脑梗塞灶及其周边区与这种趋化作用有关。利用这种趋化作用可望调控干细胞向靶组织的趋化聚集量,达到治疗目的。
Objective To observe the therapeutic benefit of intravenous administration of rat mesenchymal stem cells(rMSCs)after cerebral ischemia in adult rats, which include the improvement of neurological function, the migration of rMSCs to infarct focus, and the differentiation of rMSCs, the effect of Stromal cell-derived factor-1 (SDF-1) on the migration of Mesenchymal Stem Cells(MSCs), and to explore the possible mechanism of this effect under the condition of brain ischemic injury.
Methods Adult male SD rats were subjected to transient (2 h) middle cerebral artery occlusion (MCAO). rMSCs or PBS were infused into tail vein at 24 h after MCAO respectively. Functional outcome measurements using the modified Neurological Severity Scores (mNSS) were performed at 24 h post-MCAO, 1 week and 2 weeks post-transplantation respectively. Immunohistochemical staining and immunocyto- chemistry were used synchronously to identify rMSCs and their differentiation markers in the brain sections and the cultured rMSCs in vitro. Effects of SDF-1 on the migration of cultural rat MSCs (rMSCs) and N9 microglial cells were observed by counting migrated cells and by calculating the migration indexes to show the difference of rMSCs migration under the conditions with or without the existence of SDF-1. CTO-labeled rMSCs were injected into the tail vein of rat with middle cerebral artery occlusion (MCAO). The migration and congregation of labeled cells in the injured region of brain sections were observed under fluorescence microscope. Anti- CXC chemokine receptor 4 (Anti-CXCR4) antibodies were used for blocking studies, and the expressions of CXC chemokine receptor 4(CXCR4)in rMSCs were observed with RT-PCR and flow cytometry respectively.
Results There was significant neurological function improvement in rats treated with rMSCs compared with that of control group, as evidenced by mNSS scores (p<0.001). After transplantation, rMSCs were survived and localized around the ischemic core and its boundary zone, and a few rMSCs expressed nestin, NF-200 and GFAP, but there were no such expression in rMSCs cultured in vitro. In vitro, the migration indexes of rMSCs and N9 microglial cells in the SDF-1 groups were significantly higher as compared with the medium controls(P<0.01). The CXCR4 antibody blocking significantly impaired the SDF-1 chemotaxis. In vivo, labeled rMSCs mainly migrated and congregated around the injured region in the rMSCs transplantation groups. The CXCR4 antibody also significantly impaired both the migration and congregation of rMSCs.
Conclusions Intravenous administration of rMSCs can promote the neurological functional improvement in rat stroke model. rMSCs can survive and localize to the ischemic area of the brain, and a few cells express the phenotypic protein marker of neural cells. The benefit of intravenous administration of rMSCs are no brain injury and better distribution of grafted cells.The results demonstrate that the chemotactic effect of SDF-1 on the MSCs is introduced by CXCR4. Although only small proportion of rMSCs expresses active extracellular CXCR4 receptor,there are higher level intracellular expression of CXCR4. SDF-1 secreted from injured brain tissue may be responsible for the chemotaxis and congregation of MSCs . This phenomenon will be significant in the therapeutical research of acute injury .
观察经静脉移植骨髓间质干细胞(MSCs)治疗脑梗塞时,神经功能缺损的恢复情况,以及MSCs在脑梗塞灶的分布、迁移与分化情况。观察基质细胞衍生因子-1 (SDF-1 )在体内外对大鼠骨髓间质干细胞(rMSCs)的趋化诱导作用,探讨SDF-1 对rMSCs迁移影响的可能机制,为实现临床上对移植的rMSCs进行调控提供理论与实验依据。
方法
建立线栓法大鼠大脑中动脉栓塞(MCAO)模型,大脑中动脉血流阻断2小时后再灌注,再灌注后24h经尾静脉将标记的大鼠骨髓间质干细胞(rMSCs)植入脑梗塞鼠体内,于移植后24h、1W、2W时采用mNSS评分法对动物神经功能状况进行评分。应用荧光激发及免疫组化方法于移植后1W、2W时检测移植细胞在脑内存活、迁移及分化情况。细胞化学染色观察rMSCs体外培养时的分化情况。应用体外细胞迁移实验及大鼠脑梗塞模型体内移植,观察在施用和不施用抗SDF-1抗体时,SDF-1 对rMSCs迁移的影响。流式细胞术与RT-PCR检测rMSCs的CXC趋化因子受体4 (CXC chemokine receptor 4, CXCR4)表达。
结果
1.与对照组相比,移植组大鼠在移植后观察的2周内神经功能改善明显(p<0.001)。
2.可观察到移植细胞在脑梗塞区及其周边区聚集并存活,这种聚集于第2周更为明显。在脑梗塞区及其周边区有部分植入细胞分化表达神经细胞表面标志物,而在体外同时程培养的rMSCs未见分化表达类似表面标志物。
3.体外实验示在SDF-1 存在时,rMSCs迁移活跃,应用抗体封闭CXCR4受体后,这种迁移现象显著减弱。
4.体内移植的rMSCs在脑内主要聚集在脑梗死灶及其周边区,但在封闭CXCR4受体后,这种聚集现象大为减弱。
5.流式细胞术示仅小部分rMSCs表面表达CXCR4,但经Triton X-100处理后,表达CXCR4的rMSCs增加。RT-PCR检测显示rMSCs的Cxcr4基因表达CXCR4 mRNA。
结论
1. rMSCs经静脉移植后的2周观察表明移植的rMSCs可向宿主脑内病灶迁移、存活、并分化表达神经细胞表型,有促进脑梗塞后神经功能恢复的作用。
2.经静脉路移植rMSCs不仅可达到治疗目的,而且可以避免直接穿刺移植带来的脑组织损伤,植入的rMSCs能迁移并更好地分布在脑梗塞灶。
3. SDF-1可通过CXCR4受体对rMSCs起趋化作用,植入的rMSCs能聚集分布在脑梗塞灶及其周边区与这种趋化作用有关。利用这种趋化作用可望调控干细胞向靶组织的趋化聚集量,达到治疗目的。
Objective To observe the therapeutic benefit of intravenous administration of rat mesenchymal stem cells(rMSCs)after cerebral ischemia in adult rats, which include the improvement of neurological function, the migration of rMSCs to infarct focus, and the differentiation of rMSCs, the effect of Stromal cell-derived factor-1 (SDF-1) on the migration of Mesenchymal Stem Cells(MSCs), and to explore the possible mechanism of this effect under the condition of brain ischemic injury.
Methods Adult male SD rats were subjected to transient (2 h) middle cerebral artery occlusion (MCAO). rMSCs or PBS were infused into tail vein at 24 h after MCAO respectively. Functional outcome measurements using the modified Neurological Severity Scores (mNSS) were performed at 24 h post-MCAO, 1 week and 2 weeks post-transplantation respectively. Immunohistochemical staining and immunocyto- chemistry were used synchronously to identify rMSCs and their differentiation markers in the brain sections and the cultured rMSCs in vitro. Effects of SDF-1 on the migration of cultural rat MSCs (rMSCs) and N9 microglial cells were observed by counting migrated cells and by calculating the migration indexes to show the difference of rMSCs migration under the conditions with or without the existence of SDF-1. CTO-labeled rMSCs were injected into the tail vein of rat with middle cerebral artery occlusion (MCAO). The migration and congregation of labeled cells in the injured region of brain sections were observed under fluorescence microscope. Anti- CXC chemokine receptor 4 (Anti-CXCR4) antibodies were used for blocking studies, and the expressions of CXC chemokine receptor 4(CXCR4)in rMSCs were observed with RT-PCR and flow cytometry respectively.
Results There was significant neurological function improvement in rats treated with rMSCs compared with that of control group, as evidenced by mNSS scores (p<0.001). After transplantation, rMSCs were survived and localized around the ischemic core and its boundary zone, and a few rMSCs expressed nestin, NF-200 and GFAP, but there were no such expression in rMSCs cultured in vitro. In vitro, the migration indexes of rMSCs and N9 microglial cells in the SDF-1 groups were significantly higher as compared with the medium controls(P<0.01). The CXCR4 antibody blocking significantly impaired the SDF-1 chemotaxis. In vivo, labeled rMSCs mainly migrated and congregated around the injured region in the rMSCs transplantation groups. The CXCR4 antibody also significantly impaired both the migration and congregation of rMSCs.
Conclusions Intravenous administration of rMSCs can promote the neurological functional improvement in rat stroke model. rMSCs can survive and localize to the ischemic area of the brain, and a few cells express the phenotypic protein marker of neural cells. The benefit of intravenous administration of rMSCs are no brain injury and better distribution of grafted cells.The results demonstrate that the chemotactic effect of SDF-1 on the MSCs is introduced by CXCR4. Although only small proportion of rMSCs expresses active extracellular CXCR4 receptor,there are higher level intracellular expression of CXCR4. SDF-1 secreted from injured brain tissue may be responsible for the chemotaxis and congregation of MSCs . This phenomenon will be significant in the therapeutical research of acute injury .
引文
1. Bacon KB,Harrison JK. Chemokines and their receptors in neurobiology: perspectives in physiology and homeostasis,J Neuroimmunol, 2000,104:92-97.
2. Wakitani S, Goto T, Pineda SJ, et al. Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage , J Bone Joint Surg Am, 1994, 76(4):579-592.
3. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro,Exp Neurol,2000,164(2):247-256.
4. Li Y, Chopp M, Chen J, et al. Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice,J Cereb Blood Flow Metab,2000,20(9):1311-1319.
5. Chen J, Li Y, Wang L, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats,Stroke,2001,32(4): 1005-1011.
6. Chen J, Li Y, Chopp M. Intracerebral transplantation of bone marrow with BDNF after MCAo in rat,Neuropharmacology, 2000, 39(5): 711-716.
7. Li Y, Chen J, Zhang CL, et al. Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells,Glia, 2005, 49(3): 407-417.
8. Woodbury D, Schwarz EJ, Prockop DJ, et al. Adult rat and human bone marrow stromal cells differentiate into neurons,J Neurosci Res, 2000, 61(4): 364-370.
9.潘兴华,贺斌,庞荣清等.猴脑血管缺血模型复制及骨髓间充质干细胞移植治疗,热带医学杂志,2006,6(5):533-536.
10.吴功雄,杨志华,张海伟等.间质干细胞移植在大鼠缺血性脑卒中的实验研究,中国病理生理杂志,2004,20(6):990–993.
11.桂莉,李露斯,范文辉.骨髓间质干细胞移植对脑梗死大鼠神经功能的恢复作用,中国临床康复,2004,8(8):6060-6062.
12.王伟,张志坚,林建华,等.大鼠骨髓间质干细胞培养扩增及表面标志,福建医科大学学报,2005,39(1):5-7.
13. Goolsby J, Marie C. Marty MC, Dafna Heletz D, et al. Hematopoietic progenitorsexpress neural genes,PANS,2003,100(25):14926-14931.
14. Zea Longa E ,Weistein PR ,Calson S ,et al. Reversible middle cerebral artery occlusion without craniectomy in rats,Stroke , 1989, 20(11): 84-91
15. Quesenberry PJ, Becker PS. Stem cell homing: rolling, crawling,and nesting. ,PNAS USA., 1998,95(26):15155-15157.
16. Wang L, Li Y, Chen J, et al. Ischemic cerebral tissue and MCP-1 enchance rat bone marrow stromal cell migration in interface culture,Exp Hematol, 2002, 30(7): 831-836.
17. Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocyte,Nature, 2003, 422 (6934): 897-901.
18. Kurozumi K, Nakamura K, Tamiya T, et al. BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model,Mol Ther, 2004, 9(2):189-197.
19. Zhong C, Qin Z, Zhong CJ, et al. Neuroprotective effects of bone marrow stromal cells on rat organtypic hippcampal slice culture model of cerebral ischemia,Neurosci Lett, 2003, 342(1-2): 93-96.
20. Chen J , Katakowski M, Chen X, et al. Intravenous bone marrow stromal cells therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in femal rat,Neurosci Res, 2003, 73(6): 778-786.
21. Mahmood A , Lu D, Chopp M. Intravenous administration of marrow stromal cells increases the expression of growth factors in rat brain after traumatic brain injury, Neurotrauma, 2004, 21(1): 33-39.
22. Filipov NM, Seegal RF, Lawrence DA, et al. Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism , Toxicological Science,2005,84: 139-148.
23. Imai S, Kaksonen M, Raulo E,et al. Osteoblast recruitment and bone formation enhanced by cell matrix-associated heparin-binding growthassociated molecule (HB-GAM),Cell Biol, 1998, 143:1113-11128.
24. Wu JY, Feng LL, Park HT,et al. The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors,Nature, 2001,410: 948-952.
25. Chen JL, Sanberg PR, Li Y, et al. Intravenous Administration of Human Umbilical Cord Blood Reduces Behavioral Deficits After Stroke in Rats, Stroke,2001,32: 2682-2688.
26. Tanabe S, Heesen M, Yoshizawa I, et al. Functional expression of the CXC-chemokine receptor-4/fusin on mouse microglial cells and astrocytes, J Immunol,1997, 159: 905-911.
27. Horuk R. Chemokines beyond inflammation,Nature, 1998, 393(6685): 524-525.
28. Psenak O. Stromal cell-derived factor 1 (SDF-1). Its structure and function ,Cas Lek Cesk, 2001 ,140: 355-363.
29. Gear AR, Suttitanamongkol S, Viisoreanu D, et al. Adenosine diphosphate strongly potentiates the ability of the chemokines MDC, TARC, and SDF-1 to stimulate platelet function,Blood,2001, 97: 937-945.
30. Bleul CC, Farzan M, Choe H, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry,Nature, 1996, 382(6594): 829-833.
31. Bleul CC, Fuhlbrigge RC, Casasnovas JM, et al. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1(SDF-1),J Exp Med ,1996, 184: 1101-1109.
32. Zhu Y, Yu T, Zhang XC, et al. Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons,Nat Neurosci, 2002,5:719-720.
33. Wynn RF, Hart CA, Corradi-Perini C, et al. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow,Blood, 2004,104:2643-2645.
34. Tanabe S, Heesen M, Yoshizawa I, et al. Functional expression of the CXC-chemokine receptor-4/fusin on mouse microglial cells and astrocytes, J Immunol, 1997,159:905-911.
35. Lavi E, Strizki JM, Ulrich AM, et al. CXCR-4 (Fusin), a co-receptor for the type 1 human immunodeficiency virus (HIV-1), is expressed in the human brain in a variety of cell types, including microglia and neurons,Am J Pathol, 1997,151:1035-1042.
36. Heveker N,Tissot M,Thuret A,et al. Pharmacological properties of peptides derived from stromal cell-derived factor 1: study on human polymorphonuclear cells,MolPharmacol,2001,59:1418-1425.
37. Wang JF, Park IW, Groopman JE. Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells:roles of phosphoinositide-3 kinase and protein kinase C,Blood,2000, 95: 2505-2513.
38. Sotsios Y, Whittaker GC, Westwick J, et al. The CXC chemokine stromal cell-derived factor activates a Gi-coupled phosphoinositide 3-kinase in T lymphocytes , J Immunol,1999,163:5954-5963.
39. Tilton B, Ho L, Oberlin E, et al. Signal transduction by CXC chemokine receptor 4. Stromal cell-derived factor 1 stimulates prolonged protein kinase B and extracellular signal-regulated kinase 2 activation in T lymphocytes,J Exp Med, 2000, 192:313-324.
2. Wakitani S, Goto T, Pineda SJ, et al. Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage , J Bone Joint Surg Am, 1994, 76(4):579-592.
3. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro,Exp Neurol,2000,164(2):247-256.
4. Li Y, Chopp M, Chen J, et al. Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice,J Cereb Blood Flow Metab,2000,20(9):1311-1319.
5. Chen J, Li Y, Wang L, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats,Stroke,2001,32(4): 1005-1011.
6. Chen J, Li Y, Chopp M. Intracerebral transplantation of bone marrow with BDNF after MCAo in rat,Neuropharmacology, 2000, 39(5): 711-716.
7. Li Y, Chen J, Zhang CL, et al. Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells,Glia, 2005, 49(3): 407-417.
8. Woodbury D, Schwarz EJ, Prockop DJ, et al. Adult rat and human bone marrow stromal cells differentiate into neurons,J Neurosci Res, 2000, 61(4): 364-370.
9.潘兴华,贺斌,庞荣清等.猴脑血管缺血模型复制及骨髓间充质干细胞移植治疗,热带医学杂志,2006,6(5):533-536.
10.吴功雄,杨志华,张海伟等.间质干细胞移植在大鼠缺血性脑卒中的实验研究,中国病理生理杂志,2004,20(6):990–993.
11.桂莉,李露斯,范文辉.骨髓间质干细胞移植对脑梗死大鼠神经功能的恢复作用,中国临床康复,2004,8(8):6060-6062.
12.王伟,张志坚,林建华,等.大鼠骨髓间质干细胞培养扩增及表面标志,福建医科大学学报,2005,39(1):5-7.
13. Goolsby J, Marie C. Marty MC, Dafna Heletz D, et al. Hematopoietic progenitorsexpress neural genes,PANS,2003,100(25):14926-14931.
14. Zea Longa E ,Weistein PR ,Calson S ,et al. Reversible middle cerebral artery occlusion without craniectomy in rats,Stroke , 1989, 20(11): 84-91
15. Quesenberry PJ, Becker PS. Stem cell homing: rolling, crawling,and nesting. ,PNAS USA., 1998,95(26):15155-15157.
16. Wang L, Li Y, Chen J, et al. Ischemic cerebral tissue and MCP-1 enchance rat bone marrow stromal cell migration in interface culture,Exp Hematol, 2002, 30(7): 831-836.
17. Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocyte,Nature, 2003, 422 (6934): 897-901.
18. Kurozumi K, Nakamura K, Tamiya T, et al. BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model,Mol Ther, 2004, 9(2):189-197.
19. Zhong C, Qin Z, Zhong CJ, et al. Neuroprotective effects of bone marrow stromal cells on rat organtypic hippcampal slice culture model of cerebral ischemia,Neurosci Lett, 2003, 342(1-2): 93-96.
20. Chen J , Katakowski M, Chen X, et al. Intravenous bone marrow stromal cells therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in femal rat,Neurosci Res, 2003, 73(6): 778-786.
21. Mahmood A , Lu D, Chopp M. Intravenous administration of marrow stromal cells increases the expression of growth factors in rat brain after traumatic brain injury, Neurotrauma, 2004, 21(1): 33-39.
22. Filipov NM, Seegal RF, Lawrence DA, et al. Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism , Toxicological Science,2005,84: 139-148.
23. Imai S, Kaksonen M, Raulo E,et al. Osteoblast recruitment and bone formation enhanced by cell matrix-associated heparin-binding growthassociated molecule (HB-GAM),Cell Biol, 1998, 143:1113-11128.
24. Wu JY, Feng LL, Park HT,et al. The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors,Nature, 2001,410: 948-952.
25. Chen JL, Sanberg PR, Li Y, et al. Intravenous Administration of Human Umbilical Cord Blood Reduces Behavioral Deficits After Stroke in Rats, Stroke,2001,32: 2682-2688.
26. Tanabe S, Heesen M, Yoshizawa I, et al. Functional expression of the CXC-chemokine receptor-4/fusin on mouse microglial cells and astrocytes, J Immunol,1997, 159: 905-911.
27. Horuk R. Chemokines beyond inflammation,Nature, 1998, 393(6685): 524-525.
28. Psenak O. Stromal cell-derived factor 1 (SDF-1). Its structure and function ,Cas Lek Cesk, 2001 ,140: 355-363.
29. Gear AR, Suttitanamongkol S, Viisoreanu D, et al. Adenosine diphosphate strongly potentiates the ability of the chemokines MDC, TARC, and SDF-1 to stimulate platelet function,Blood,2001, 97: 937-945.
30. Bleul CC, Farzan M, Choe H, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry,Nature, 1996, 382(6594): 829-833.
31. Bleul CC, Fuhlbrigge RC, Casasnovas JM, et al. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1(SDF-1),J Exp Med ,1996, 184: 1101-1109.
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33. Wynn RF, Hart CA, Corradi-Perini C, et al. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow,Blood, 2004,104:2643-2645.
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