Biological characteristics of perivascular cells and their supporting effects on hematopoietic stem/progenitor cells

doi:10.3969/j.issn.2095-4344.1796

Abstract

Abstract:

BACKGROUND: Perivascular cells/pericytes are the important core component of the perivascular microenvironment that are widely distributed throughout the body’s capillary and microvessel wall. These cells can support the growth and reproduction of other cells, and regulate the body’s immune status and immune defenses. In recent years, increasing studies have shown that perivascular cells are the precursor cells of mesenchymal stem/stromal cells, which regulate the behavior of hematopoietic stem cells and support hematopoiesis through cell-to-cell contact or paracrine effects.
OBJECTIVE: To review the distribution and function of perivascular cell/pericytes and their supporting effect on hematopoietic stem/progenitor cells.
METHODS: The key words of “pericyte, perivascular cell, hematopoietic stem/progenitor cells, mesenchymal stem/stromal cells” in Chinese and English were used to retrieve PubMed and CNKI databases for related literature published from 2008 to 2018. Finally, 64 articles were selected to review.
RESULTS AND CONCLUSION: Perivascular cells are the precursor cells of mesenchymal stem cells, which have the similar biological characteristics of mesenchymal stem cells, and express the surface markers of mesenchymal stem cells. In addition, perivascular cells can differentiate into osteoblasts, adipocytes and chondrocytes, regulate hematopoietic stem cell behavior and support hematopoiesis.

Key words: perivascular cells, hematopoietic stem/progenitor cells, mesenchymal stem cells, pericytes, endothelial cells, hematopoiesis, National Natural Science Foundation of China

CLC Number:

Yang Xiaoping, Zheng Bo. Biological characteristics of perivascular cells and their supporting effects on hematopoietic stem/progenitor cells[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(29): 4728-4734.

Figures/Tables 3

在不同的器官组织中，血管外膜细胞与内皮细胞也有不同的接触关系，如紧密连接、缝隙连接、钉-槽复合体和黏附斑等[3，16-17]，这些接触有助于细胞之间信号的传递[18-19]。缝隙连接允许离子和小分子的交换；紧密连接点和黏附斑支持收缩力的传递，从而调节血管直径和血流[3]；钉-槽复合体允许分子和离子在2种细胞的细胞质之间扩散[20]。血管外膜细胞与内皮细胞之间通过上述连接对血管的形成、稳定以及渗透性方面起到了至关重要的作用。 2.2 血管外膜细胞标记物目前有许多标记物已经被应用于血管外膜细胞的鉴定，然而迄今为止，没有一个标记物是血管外膜细胞特异性的，因为大部分血管外膜细胞标记物也存在于其他细胞类型中[10]。目前常用于鉴定血管外膜细胞的典型特征性标记分子包括CD146黏附分子(M-CAM或MUC18)、神经胶质抗原2(neural glial antigen 2，NG2)、血小板源性生长因子β受体(platelet derived growth factor receptors，PDGFRβ)、α-平滑肌肌动蛋白、瘦素受体(leptinReceptor，LepR)、巢蛋白(nestin)[1，4]，其他标志物如CD73、血小板源性生长因子α受体、结蛋白、G蛋白信号传导调节因子5(regulator of G protein signaling 5，RGS-5)和细胞表面神经节苷脂3G5也已被用于鉴定血管外膜细胞及其子集[1]。但是，上述这些标记分子的特异性不高，如血小板源性生长因子β受体在成纤维细胞、平滑肌细胞及神经胶质细胞中表达[14]；而神经胶质抗原2蛋白聚糖可在巨噬细胞、神经胶质细胞和各种肿瘤细胞上表达[21]。而且，并非所有的血管外膜细胞都表达相同的标记，如神经胶质抗原2仅在动脉系统的血管外膜细胞中表达，而与毛细血管相关的血管外膜细胞缺乏α-平滑肌肌动蛋白[22]。血管外膜细胞在不同物种、组织或发育阶段表达不同的标记。然而，所有血管外膜细胞均表达CD146。因此，需要联合标记才能正确表达血管外膜细胞特征。这种表型异质性表明，围绕不同血管类型的血管外膜细胞也可能发挥不同的功能[23]。 2.3 血管外膜细胞的功能血管外膜细胞广泛分布于全身组织的微血管壁中，是血管生成早期的主导细胞，可分泌碱性成纤维细胞生长因子和血管内皮生长因子，从而促进内皮细胞的迁移、聚集、增殖和分化，促进血管的芽生、塑形和延长[5，24]。血管外膜细胞具有收缩性，通过调节毛细血管的管腔大小来控制血流量，防止血管过度扩张，保持血管完整性和渗透性[21]，维持内环境的稳定和局部组织的代谢平衡[25]。在中枢神经系统中，血管外膜细胞与内皮细胞、星形胶质细胞构成血脑屏障，限制血液中的神经毒性物质进入中枢神经系统，同时将中枢神经系统中的代谢产物和神经毒性物质排出，维持大脑微环境的稳态，保证神经系统功能的正常发挥[26]。血管外膜细胞也可通过调节淋巴细胞活化和吞噬活性来影响免疫功能，同时也是抗原递呈细胞，可诱导和调控T淋巴细胞[24，27]。血管外膜细胞具有间充质细胞及干细胞潜能，从不同组织中分离的血管外膜细胞经体外培养可分化为多种细胞类型[3，5]，如成骨细胞、成软骨细胞、脂肪细胞、树突状细胞、星形胶质细胞、少突胶质细胞[28]。在体内，血管外膜细胞也可参与各种组织和器官的修复和再生，并且可以进一步促进组织愈合。有研究者将血管外膜细胞注入急性心肌梗死大鼠心脏，血管外膜细胞的再生能力促进了心脏的修复[29]，且血管外膜细胞通过调节心肌毛细血管的收缩性来控制心肌的有效血流灌注，参与心肌梗死后的重建过程[6]。但是，血管外膜细胞也可引发过度的纤维化、脂肪增生和沉积，甚至最终形成肿瘤[30]。 2.4 血管外膜细胞与间充质干细胞的关系 Friedenstein于1974年首先在骨髓中表述了间充质干细胞，这类细胞通常是指胚胎发育期在多种成体间叶组织中存留下来的未分化的原始细胞，其具有长期自我更新和多向分化的潜能，广泛分布于各种不同的组织中。间充质干细胞是在体外培养过程中获得的，其在体内的组织来源尚不明确[31]，一直是人们研究的焦点。研究显示，不同组织来源的间充质干细胞主要位于其所在组织的血管壁周围[32-33]，而血管外膜细胞分布于全身的毛细血管和微血管的管壁上，且血管外膜细胞亦具有多向分化潜能，部分学者推测，间充质干细胞和血管外膜细胞可能存在共同的起源[34]。在一项通过流式细胞仪进行严格细胞纯化并结合培养和体内分化的实验方法中证明人CD146+血管外膜细胞代表了普遍存在的间充质干细胞的前体细胞[35]。在分离培养人体多个组织来源的间充质干细胞时发现，它们都表达血管外膜细胞表面标记物：神经胶质抗原2、CD146和血小板源性生长因子β受体，却均不表达任何已知的内皮细胞标记物CD144、vWF、CD31及造血细胞表面标记物CD34、CD45、CD14、CD19[24，36]。Crisan等[34]证实血管外膜细胞在培养前后依然保持间充质干细胞的表面标志物，如CD44、CD73、CD90和CD105，见表1。Corselli等[37]发现血管外膜细胞中有一部分细胞虽然表达神经胶质抗原2、CD146和血小板源性生长因子β受体，但不表达α-平滑肌肌动蛋白，他们推测这些血管外膜细胞或许是更原始的前体细胞，可能是间充质干细胞的前体细胞。Feng等[38]使用遗传谱系追踪技术，首次证实了在牙齿生长和损伤时血管外膜细胞能够分化为间充质干细胞-成牙本质细胞。这些研究提示在其他组织中血管外膜细胞也存在分化为间充质干细胞的可能性。"

就发育潜能来讲，血管外膜细胞与间充质干细胞具有相似性，即在一定的诱导条件下可以分化成骨、软骨、脂肪细胞等中胚层谱系，在体内和器官培养实验中可以再生肌肉、骨、皮肤。一项研究显示，将牛视网膜血管外膜细胞植入裸鼠体内可分化成软骨细胞和脂肪细胞[34]。血管外膜细胞也可促进成骨再生[34，39]，在成骨培养基中培养的血管外膜细胞表达碱性磷酸酶并表现出矿物质沉积，且可造成血管、心脏瓣膜和骨骼肌的病理性钙化。血管外膜细胞在骨骼肌损伤的免疫缺陷小鼠模型中显示出再生能力。将流式细胞术纯化的人骨骼肌源性血管外膜细胞注射到被心脏毒素损伤的NOD/SCID小鼠后肢肌肉中，能再生肌纤维，这种再生能力比CD56+人骨骼肌成肌细胞更显著。来自脂肪组织、胰腺和胎盘的血管外膜细胞注射到mdx/SCID或心脏毒素处理的NOD/SCID小鼠肌肉中时，它们促进血管生成和人血影蛋白或肌营养不良蛋白阳性肌纤维的再生[34，40-42]。将来自人体肌肉的血管外膜细胞移植到急性心肌梗死NOD/SCID小鼠心脏中，与未注射血管外膜细胞的对照组相比显著改善了心脏功能[20，43]。然而，心脏源性的血管外膜细胞不能分化成骨骼肌纤维，但是它们可以分化成其他中胚层谱系-脂肪细胞、成骨细胞和软骨细胞，这表明不同器官血管外膜细胞之间存在异质性[44]。 2.5 对造血干细胞的支持机体的正常造血依赖造血干/祖细胞以及支持造血细胞生长发育的造血微环境-龛(Niche)，这一概念最早由Schofield提出[45]，造血干细胞龛是造血组织中造血干/祖细胞定居和调节干细胞活动、静止、自我更新和分化并能产生大量造血祖细胞的特定场所[46]。间充质干细胞作为机体的一种成体干细胞，最早在骨髓基质中发现，除可形成骨髓微环境外，还同基质细胞一样表达多种造血相关因子，促进造血干/祖细胞增殖、分化、成熟及进入血窦，并最终进入血液循环，在造血调控中发挥重要的作用。在胚胎造血发生过程中，造血干/祖细胞从卵黄囊、主动脉-性腺-中肾区到胎盘、胚胎肝脏、脾脏，最后定位到骨髓，均在血管壁附近发生并发育，且这些组织中都会存在造血干细胞龛[45]。有研究显示，在成年小鼠骨髓中，位于血管壁上的血管外膜细胞参与形成造血干/祖细胞龛，而支持造血的间充质干细胞本身部分来源于血管外膜细胞[35]。研究显示血管外膜细胞是体内间充质干细胞的贮存池，因此越来越多的研究集中在血管外膜细胞在造血干/祖细胞调节中的作用。骨髓位于高度血管化的骨髓腔中，尤其富含由平滑肌细胞包绕且由薄壁神经支配的小动脉，以及分布均匀、管腔大且有孔的血窦，这些血窦允许骨髓和血流之间的细胞运输[47]。目前研究者使用以下不同的标记，如CD146、CXCL12、Nestin和瘦素受体(leptin receptor，LepR)等将小动脉血管外膜细胞和血窦血管外膜细胞群体作为造血龛的一部分进行研究，见图3。"

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