SDF-1/CXCR7在内皮祖细胞参与血管生成中的作用研究
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摘要
内皮祖细胞(endothelial progenitor cells, EPCs)在许多生理、病理的血管生成过程中发挥着重要的作用。EPCs从骨髓中动员、归巢到血管新生部位,参与血管生成是一个受到微环境中多因素调节的级联动态过程。基质衍生因子(Stroma Derived Factor 1, SDF-1)在促进EPCs动员、归巢和新生血管形成等环节中发挥了重要的作用。过去的研究一直认为CXCR4是SDF-1的唯一作用受体,并且是调节SDF-1介导的生物学行为的唯一调节因子。然而,近年来研究发现SDF-1的作用受体除了CXCR4,还有另一新的作用受体CXCR7,并且CXCR7与SDF-1的亲和能力还高于CXCR4。CXCR7的发现让研究者不得不重新审视SDF-1的作用机制。在血管生成过程中,CXCR7的作用尚不明确,尤其是在EPCs中的作用还未见报道。考察CXCR7在EPCs参与血管生成中作用的一个关键问题就是构建一个合适的血管生成模型,而血管生成是血管细胞与微环境微流相互作用的复杂动态过程,传统的体外血管生成模型很难将这一复杂过程体外再现,因此需要寻求新的研究手段。近年来随着微流控技术的发展,为体外构建一个模拟在体微环境的血管生成模型提供了可能。本研究以EPCs为研究对象,利用近年发展起来的微流控技术体外构建血管生成模型并结合体外细胞行为学实验研究CXCR7在SDF-1介导的EPCs参与血管生成过程中的作用,并初步探讨其作用机制,以期为血管生成相关疾病的治疗提供新的作用靶点。本文的主要研究内容和研究结果如下:
①采用密度梯度离心法从大鼠骨髓中分离得到骨髓单个核细胞,并结合差时贴壁法,收集24h后未贴壁细胞,然后用添加有SingleQuots多种细胞因子的EBM-2内皮特异性培养基诱导培养获取EPCs。通过形态学观察、细胞表面特异性抗原标记鉴定和摄取功能等多种方法对EPCs进行鉴定分析,结果发现在EBM-2内皮特异性培养基诱导培养7 d后,出现类似于血岛样的细胞集落,集落中央的细胞呈圆形,周边的细胞呈放射状;采用EPCs表面特异性抗原标记CD133和VEGFR2进行免疫荧光染色鉴定细胞的表型,结果80%以上的细胞都是CD133+/VEGFR2+细胞,并且这些细胞同时能够摄取Ac-LDL和结合UEA-1。以上结果表明,密度梯度离心法结合差时贴壁的方法从骨髓中分离获得的单个核细胞,然后经EBM-2条件培养基诱导培养可获得较高纯度的EPCs,为后续实验奠定了基础。
②通过RT-PCR,Western-blotting和流式细胞术法分别从RNA水平、蛋白质水平以及膜上表达情况分别考察了EPCs中CXCR7的表达情况,结果发现CXCR7和CXCR4均高表达于EPCs中。通过抗体中和法和小分子拮抗剂分别将CXCR7和CXCR4进行封闭阻断,体外考察CXCR7和CXCR4在SDF-1介导的EPCs粘附、增殖、迁移和管样结构形成中所扮演的角色,结果发现CXCR4和CXCR7均在SDF-1调节EPCs粘附、跨内皮迁移、增殖和管样结构形成起着重要作用,SDF-1调节EPCs的趋化迁移是通过CXCR4作用的,而在调节EPCs在应激条件下的存活是通过与CXCR7作用。
③建立一个与生理相关的体外血管生成模型是血管生成研究的基础。本研究利用近年发展起来的微流控技术结合细胞培养技术构建了一个三维的血管生成模型,该模型能实现以下几个功能:
能模拟在体血液流动,提供流体剪应力加载刺激;
能为细胞的生长提供一个3D生长环境,并且能在3D微环境中实现可溶性因子的梯度分布;
能评价内皮细胞的活力、增殖和自组织等行为;
可以实时动态跟踪内皮细胞的运动轨迹。
通过考察促血管生长因子对内皮细胞增殖、迁移和形成管样结构形成能力的影响来评价该系统用于体外血管生成模型研究的可行性,结果发现在促血管生长因子的诱导下,内皮的增殖能力显著提高并能形成复杂的管腔样结构,同时也发现在促血管生长因子浓度梯度的诱导下,内皮细胞高浓度的区域内迁移,侵入3D基质中内皮细胞也组织成血管网络。这些结果表明该系统可以为体外的血管生成机理研究提供一个良好的研究平台,同时也为血管药物的初步筛选提供一个可靠的实验平台。
④利用基于微流控芯片的血管生成模型,考察CXCR7和CXCR4在SDF-1诱导EPCs掺入胞外基质及在胞外基质中形成血管样结构的作用,并初步探讨其作用机制。结果发现,在SDF-1浓度梯度诱导下,当CXCR7或CXCR4其中任何一个受到拮抗剂抑制后,EPCs掺入基质的能力都受到显著的抑制,并且发现SDF-1诱导EPCs在3D基质胶中形成血管样结构也是通过与受体CXCR4和CXCR7共同作用实现的。进一步发现,MMP的抑制剂GM6001明显抑制SDF-1诱导EPCs掺入到细胞外基质和形成血管样结构,与CXCR7或CXCR4的小分子拮抗剂的效果相当,而我们实验室的另一研究小组发现SDF-1能促进MMP2的分泌,但当加入CXCR4或CXCR7拮抗剂后,MMP2的分泌显著下降。通过这些研究结果,我们推测,SDF-1诱导EPCs掺入胞外基质和形成血管样结构的一个可能途径就是促进MMP的分泌,降解胞外基质,从而有利于EPCs的迁移,而SDF-1介导的MMP的分泌可能是通过与其两个受体CXCR4,CXCR7联合作用而实现的,并不是通过其中的某一个受体而发挥作用。
综合以上研究结果,我们推断出如下结论:CXCR7和CXCR4在SDF-1介导EPCs参与血管生成的过程中发挥着不完全一致却又缺一不可的作用;在调节EPCs粘附、掺入基质、跨内膜转移和形成血管样结构的过程中,CXCR7和CXCR4共同参与调节;而在EPCs趋化迁移过程中,SDF-1仅通过与受体CXCR4相互作用而发挥作用;SDF-1调节EPCs在应激条件下的存活能力是通过受体CXCR7而不是CXCR4相互作用而实现的。这些结果表明CXCR7在EPCs归巢和参与血管生成的过程中发挥着重要的作用,可能是血管生成相关疾病治疗的又一新靶点。另外,本研究基于微流控技术构建的血管生成模型不仅可以为细胞的生长提供一个近似于在体的生长环境,同时还能实时监控细胞的行为响应,为血管生成机理的阐明及血管生成相关药物的开发提供良好的研究平台。
Emerging evidences show that Endothelial progenitor cells (EPCs) play a crucial role in physiological and pathological angiogenesis. The process of EPCs participating in neovascularization is a dynamic multi-step cascade process and regulated by a variety of factors in microenvironment. Previous studies confirmed that stromal cell-derived factor 1 (SDF-1) is a principal regulator of retention, migration, and mobilization of EPCs during steady-state homeostasis and injury. For many years, CXC chemokine receptor 4 (CXCR4) has been considered as the unique receptor of SDF-1 and the only mediator of SDF-1-induced biological effects. However, recent studies find that SDF-1 could bind to not only CXCR4 but also CXC chemokine receptor 7(CXCR7). CXCR7 has a significant higher binding affinity for SDF-1 than CXCR4. The evidence that SDF-1 binds to the CXCR7 raises a concern how to distinguish the potential contribution of the SDF-1/CXCR7 pathway from SDF-1/CXCR4 pathway in all the processes that were previously attributed to SDF-1/CXCR4. The role of CXCR7 in angiogenesis remains largely unclear, especially the role of CXCR7 in EPCs participating in angiogenesis has not been reported. To clarify the role of CXCR7 in angiogenesis, one of critical problem is to establish a more physiological in vitro angiogenesis model. Angiogenesis is a multi-step dynamic process involving complex interactions between vascular cells and the corresponding extracellular environment. However, many traditional models can not mimic this complex process. With development of microfluidic technologies, it has paved the way for new approaches to establish an in vitro anigogenesis model mimicking the in vivo conditions. In this study, we established an in-vitro angiogenesis model based on microfluidic technology, combining with cellular behavior experiments in vitro, to study the roles and effects mechanisms of CXCR7 in SDF-1-mediated EPCs homing and participating in angiogenesis, and further to explore the potentiality of CXCR7 as a target to promote or inhibit angiogenesis, which was expected to provide a new therapy for angiogenesis-related diseases. The main research and results were as follows:
①Mononuclear cells (MNCs) were isolated from rat bone marrow by density gradient centrifugation and plated on 6-well plates. After cultured for 24 h, non-adhesion cells were collected and seeded on 6-well plates pre-coated with fibronectin. Bone marrow-derived MNCs cultured under endothelial-specific conditions developed a spindle-shape appearance and typical cell clusters at day 7.The appearance and organization of these cell clusters resembled the characteristic blood island-like cell clusters. Immunofluorescent staining assay demonstrated that most of the cells (up to 80%) were positive for CD133 and VEGFR2. And it was found that the cells were positive for Dil-Ac-LDL uptaking and lectin binding. The double positive cells were identified as differentiating EPCs. The results suggested that high-purity EPCs could be harvested by EBM-2 medium induced-culturing MNCs that were isolated by density gradient centrifugation combining with differential adhersion time methods.
②Reverse transcriptase PCR (RT-PCR), western-blotting and flow cytometry assay demonstrated that both CXCR4 and CXCR7 were expressed highly in EPCs. We investigated the roles of chemokine receptor CXCR4 and CXCR7 in the adhesion, proliferation and tube formation of EPCs by blocking CXCR4 or CXCR7 with their antibodies or antagonists respectively. The results showed SDF-1 regulated the adhesion, transendothelial migration, proliferation and tube formation of EPCs through both of CXCR4 and CXCR7, and the chemotaxis of EPCs through CXCR4 alone, while SDF-1 regulated the survival of EPCs via CXCR7 not CXCR4.
③It is essential for angiogenesis researches to establish a suitable in vitro angiogenesis model. In this study, we established a novel in vitro angiogenesis model based on microfluidic device, which can provide an in-vivo-like microenvironment for endothelial cell culture and monitor the response of endothelial cells to their microenvironment changes real-time. To evaluate the potential of this microfluidic device for angiogenesis model research, the effects of pro-angiogenic factors on endothelial cell proliferation, migration and tube-like structure formation were investigated. The results showed the proliferation rate of endothelial cells in 3D matrix was significantly promoted by the pro-angiogenic factors. With the stimulation of pro-angiogenic factors gradients, endothelial cells directly migrated into matrigel from low concentration to high concentration and consequently formed multi-cell chords and tube-like structures. The results suggested that the device could provide a suitable platform for elucidating the mechanism of angiogenesis and screening pro-angiogenic or anti-angiogenic drugs for‘angiogenesis-dependent’diseases.
④By the angiogenesis model based on microfluidic device, we further investigated the role of CXCR7 and CXCR4 in SDF-1-induced EPCs incorporating into extracelluar matrix and forming tube-like structures in 3D matrix to explore their functional mechanisms. The results showed that both CXCR7 and CXCR4 were essential for EPCs incorporating into matrix under the induction of SDF-1 gradient. And it was also found that SDF-1 induced EPCs forming tube-like structures in 3D matrix via both CXCR7 and CXCR4. We further demonstrated the effect of MMP inhibitor (GM6001) as an agent against SDF-1-promoted EPCs incorporating into matrix and forming tube-like structures. The inhibition effects GM6001 were correspondent with CXCR7 or CXCR4 antagonist. Another research team in our lab demonstrated that SDF-1 could promote MMP2 secretion through its two receptors CXCR4 and CXCR7. Taking the results together, we deduced that SDF-1 promoted EPCs incorporating into matrix and forming tube-like structures partially through up-regulating the secretion of MMP to degrade extracellular matrix, which will facilitate EPCs migrating.
In summary, CXCR7 and CXCR4 play essential, but differential roles in EPCs participating in angiogenesis. Both CXCR7 and CXCR4 are essential for SDF-1-mediated EPCs adhering, incorporating into matrix, transendothelial migrating and forming tube-like structures in 3D matrix. SDF-1 regulates the survival of EPCs via CXCR7 not CXCR4, while SDF-1 mediates the chemotaxis of EPCs through CXCR4 alone. These evidences indicate that CXCR7 plays a critical role in EPC homing and participating in angiogenesis, and CXCR7 may be another potential target molecule for angiogenesis-dependent diseases. In addition, a novel in vitro angiogenesis model was developed based on a microfluidic device, which could provide an in-vivo-like microenvironment for cell culture and monitor cell response in real-time. Thus this angiogenesis model will be a suitable platform for elucidating the mechanism of angiogenesis and testing pro-angiogenic or anti-angiogenic drugs for‘angiogenesis- dependent’diseases.
①采用密度梯度离心法从大鼠骨髓中分离得到骨髓单个核细胞,并结合差时贴壁法,收集24h后未贴壁细胞,然后用添加有SingleQuots多种细胞因子的EBM-2内皮特异性培养基诱导培养获取EPCs。通过形态学观察、细胞表面特异性抗原标记鉴定和摄取功能等多种方法对EPCs进行鉴定分析,结果发现在EBM-2内皮特异性培养基诱导培养7 d后,出现类似于血岛样的细胞集落,集落中央的细胞呈圆形,周边的细胞呈放射状;采用EPCs表面特异性抗原标记CD133和VEGFR2进行免疫荧光染色鉴定细胞的表型,结果80%以上的细胞都是CD133+/VEGFR2+细胞,并且这些细胞同时能够摄取Ac-LDL和结合UEA-1。以上结果表明,密度梯度离心法结合差时贴壁的方法从骨髓中分离获得的单个核细胞,然后经EBM-2条件培养基诱导培养可获得较高纯度的EPCs,为后续实验奠定了基础。
②通过RT-PCR,Western-blotting和流式细胞术法分别从RNA水平、蛋白质水平以及膜上表达情况分别考察了EPCs中CXCR7的表达情况,结果发现CXCR7和CXCR4均高表达于EPCs中。通过抗体中和法和小分子拮抗剂分别将CXCR7和CXCR4进行封闭阻断,体外考察CXCR7和CXCR4在SDF-1介导的EPCs粘附、增殖、迁移和管样结构形成中所扮演的角色,结果发现CXCR4和CXCR7均在SDF-1调节EPCs粘附、跨内皮迁移、增殖和管样结构形成起着重要作用,SDF-1调节EPCs的趋化迁移是通过CXCR4作用的,而在调节EPCs在应激条件下的存活是通过与CXCR7作用。
③建立一个与生理相关的体外血管生成模型是血管生成研究的基础。本研究利用近年发展起来的微流控技术结合细胞培养技术构建了一个三维的血管生成模型,该模型能实现以下几个功能:
能模拟在体血液流动,提供流体剪应力加载刺激;
能为细胞的生长提供一个3D生长环境,并且能在3D微环境中实现可溶性因子的梯度分布;
能评价内皮细胞的活力、增殖和自组织等行为;
可以实时动态跟踪内皮细胞的运动轨迹。
通过考察促血管生长因子对内皮细胞增殖、迁移和形成管样结构形成能力的影响来评价该系统用于体外血管生成模型研究的可行性,结果发现在促血管生长因子的诱导下,内皮的增殖能力显著提高并能形成复杂的管腔样结构,同时也发现在促血管生长因子浓度梯度的诱导下,内皮细胞高浓度的区域内迁移,侵入3D基质中内皮细胞也组织成血管网络。这些结果表明该系统可以为体外的血管生成机理研究提供一个良好的研究平台,同时也为血管药物的初步筛选提供一个可靠的实验平台。
④利用基于微流控芯片的血管生成模型,考察CXCR7和CXCR4在SDF-1诱导EPCs掺入胞外基质及在胞外基质中形成血管样结构的作用,并初步探讨其作用机制。结果发现,在SDF-1浓度梯度诱导下,当CXCR7或CXCR4其中任何一个受到拮抗剂抑制后,EPCs掺入基质的能力都受到显著的抑制,并且发现SDF-1诱导EPCs在3D基质胶中形成血管样结构也是通过与受体CXCR4和CXCR7共同作用实现的。进一步发现,MMP的抑制剂GM6001明显抑制SDF-1诱导EPCs掺入到细胞外基质和形成血管样结构,与CXCR7或CXCR4的小分子拮抗剂的效果相当,而我们实验室的另一研究小组发现SDF-1能促进MMP2的分泌,但当加入CXCR4或CXCR7拮抗剂后,MMP2的分泌显著下降。通过这些研究结果,我们推测,SDF-1诱导EPCs掺入胞外基质和形成血管样结构的一个可能途径就是促进MMP的分泌,降解胞外基质,从而有利于EPCs的迁移,而SDF-1介导的MMP的分泌可能是通过与其两个受体CXCR4,CXCR7联合作用而实现的,并不是通过其中的某一个受体而发挥作用。
综合以上研究结果,我们推断出如下结论:CXCR7和CXCR4在SDF-1介导EPCs参与血管生成的过程中发挥着不完全一致却又缺一不可的作用;在调节EPCs粘附、掺入基质、跨内膜转移和形成血管样结构的过程中,CXCR7和CXCR4共同参与调节;而在EPCs趋化迁移过程中,SDF-1仅通过与受体CXCR4相互作用而发挥作用;SDF-1调节EPCs在应激条件下的存活能力是通过受体CXCR7而不是CXCR4相互作用而实现的。这些结果表明CXCR7在EPCs归巢和参与血管生成的过程中发挥着重要的作用,可能是血管生成相关疾病治疗的又一新靶点。另外,本研究基于微流控技术构建的血管生成模型不仅可以为细胞的生长提供一个近似于在体的生长环境,同时还能实时监控细胞的行为响应,为血管生成机理的阐明及血管生成相关药物的开发提供良好的研究平台。
Emerging evidences show that Endothelial progenitor cells (EPCs) play a crucial role in physiological and pathological angiogenesis. The process of EPCs participating in neovascularization is a dynamic multi-step cascade process and regulated by a variety of factors in microenvironment. Previous studies confirmed that stromal cell-derived factor 1 (SDF-1) is a principal regulator of retention, migration, and mobilization of EPCs during steady-state homeostasis and injury. For many years, CXC chemokine receptor 4 (CXCR4) has been considered as the unique receptor of SDF-1 and the only mediator of SDF-1-induced biological effects. However, recent studies find that SDF-1 could bind to not only CXCR4 but also CXC chemokine receptor 7(CXCR7). CXCR7 has a significant higher binding affinity for SDF-1 than CXCR4. The evidence that SDF-1 binds to the CXCR7 raises a concern how to distinguish the potential contribution of the SDF-1/CXCR7 pathway from SDF-1/CXCR4 pathway in all the processes that were previously attributed to SDF-1/CXCR4. The role of CXCR7 in angiogenesis remains largely unclear, especially the role of CXCR7 in EPCs participating in angiogenesis has not been reported. To clarify the role of CXCR7 in angiogenesis, one of critical problem is to establish a more physiological in vitro angiogenesis model. Angiogenesis is a multi-step dynamic process involving complex interactions between vascular cells and the corresponding extracellular environment. However, many traditional models can not mimic this complex process. With development of microfluidic technologies, it has paved the way for new approaches to establish an in vitro anigogenesis model mimicking the in vivo conditions. In this study, we established an in-vitro angiogenesis model based on microfluidic technology, combining with cellular behavior experiments in vitro, to study the roles and effects mechanisms of CXCR7 in SDF-1-mediated EPCs homing and participating in angiogenesis, and further to explore the potentiality of CXCR7 as a target to promote or inhibit angiogenesis, which was expected to provide a new therapy for angiogenesis-related diseases. The main research and results were as follows:
①Mononuclear cells (MNCs) were isolated from rat bone marrow by density gradient centrifugation and plated on 6-well plates. After cultured for 24 h, non-adhesion cells were collected and seeded on 6-well plates pre-coated with fibronectin. Bone marrow-derived MNCs cultured under endothelial-specific conditions developed a spindle-shape appearance and typical cell clusters at day 7.The appearance and organization of these cell clusters resembled the characteristic blood island-like cell clusters. Immunofluorescent staining assay demonstrated that most of the cells (up to 80%) were positive for CD133 and VEGFR2. And it was found that the cells were positive for Dil-Ac-LDL uptaking and lectin binding. The double positive cells were identified as differentiating EPCs. The results suggested that high-purity EPCs could be harvested by EBM-2 medium induced-culturing MNCs that were isolated by density gradient centrifugation combining with differential adhersion time methods.
②Reverse transcriptase PCR (RT-PCR), western-blotting and flow cytometry assay demonstrated that both CXCR4 and CXCR7 were expressed highly in EPCs. We investigated the roles of chemokine receptor CXCR4 and CXCR7 in the adhesion, proliferation and tube formation of EPCs by blocking CXCR4 or CXCR7 with their antibodies or antagonists respectively. The results showed SDF-1 regulated the adhesion, transendothelial migration, proliferation and tube formation of EPCs through both of CXCR4 and CXCR7, and the chemotaxis of EPCs through CXCR4 alone, while SDF-1 regulated the survival of EPCs via CXCR7 not CXCR4.
③It is essential for angiogenesis researches to establish a suitable in vitro angiogenesis model. In this study, we established a novel in vitro angiogenesis model based on microfluidic device, which can provide an in-vivo-like microenvironment for endothelial cell culture and monitor the response of endothelial cells to their microenvironment changes real-time. To evaluate the potential of this microfluidic device for angiogenesis model research, the effects of pro-angiogenic factors on endothelial cell proliferation, migration and tube-like structure formation were investigated. The results showed the proliferation rate of endothelial cells in 3D matrix was significantly promoted by the pro-angiogenic factors. With the stimulation of pro-angiogenic factors gradients, endothelial cells directly migrated into matrigel from low concentration to high concentration and consequently formed multi-cell chords and tube-like structures. The results suggested that the device could provide a suitable platform for elucidating the mechanism of angiogenesis and screening pro-angiogenic or anti-angiogenic drugs for‘angiogenesis-dependent’diseases.
④By the angiogenesis model based on microfluidic device, we further investigated the role of CXCR7 and CXCR4 in SDF-1-induced EPCs incorporating into extracelluar matrix and forming tube-like structures in 3D matrix to explore their functional mechanisms. The results showed that both CXCR7 and CXCR4 were essential for EPCs incorporating into matrix under the induction of SDF-1 gradient. And it was also found that SDF-1 induced EPCs forming tube-like structures in 3D matrix via both CXCR7 and CXCR4. We further demonstrated the effect of MMP inhibitor (GM6001) as an agent against SDF-1-promoted EPCs incorporating into matrix and forming tube-like structures. The inhibition effects GM6001 were correspondent with CXCR7 or CXCR4 antagonist. Another research team in our lab demonstrated that SDF-1 could promote MMP2 secretion through its two receptors CXCR4 and CXCR7. Taking the results together, we deduced that SDF-1 promoted EPCs incorporating into matrix and forming tube-like structures partially through up-regulating the secretion of MMP to degrade extracellular matrix, which will facilitate EPCs migrating.
In summary, CXCR7 and CXCR4 play essential, but differential roles in EPCs participating in angiogenesis. Both CXCR7 and CXCR4 are essential for SDF-1-mediated EPCs adhering, incorporating into matrix, transendothelial migrating and forming tube-like structures in 3D matrix. SDF-1 regulates the survival of EPCs via CXCR7 not CXCR4, while SDF-1 mediates the chemotaxis of EPCs through CXCR4 alone. These evidences indicate that CXCR7 plays a critical role in EPC homing and participating in angiogenesis, and CXCR7 may be another potential target molecule for angiogenesis-dependent diseases. In addition, a novel in vitro angiogenesis model was developed based on a microfluidic device, which could provide an in-vivo-like microenvironment for cell culture and monitor cell response in real-time. Thus this angiogenesis model will be a suitable platform for elucidating the mechanism of angiogenesis and testing pro-angiogenic or anti-angiogenic drugs for‘angiogenesis- dependent’diseases.
引文
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