Immunomodulation of mesenchymal stem cells in inflammatory microenvironment

doi:10.3969/j.issn.2095-4344.0869

Abstract

Abstract:

BACKGROUND: Mesenchymal stem cells are a kind of adult stem cells with self-renewal and multi-directional differentiation potential. These cells have the functions of immunoregulation, regulation of cell growth and repair of injury. In recent years, it has been found that when inflammatory injury occurs, mesenchymal stem cells can regulate the secretion of inflammatory factors, and function on the damaged region, thereby repairing and improving tissue damage caused by inflammation.
OBJECTIVE: To review the immunoregulatory effects of mesenchymal stem cells on T lymphocytes, B lymphocytes, dendritic cells and natural killer cells when the body is in an inflammatory state.
METHODS: A computer-based search of PubMed and CNKI was performed for articles published from 2000 to 2018 using the keywords of “inflammatory microenvironment, mesenchymal stem cell, immune response, T cell, B cell, DC, NK cell” in English and Chinese, respectively. Seventy-six articles related to the topic and with reliable arguments were finally included in result analysis.
RESULTS AND CONCLUSION: The interaction between mesenchymal stem cells and inflammatory cells determines the result of tissue damage repair. In an inflammatory state, the biological characteristics of mesenchymal stem cells will undergo certain changes, but mesenchymal stem cells can still exert immunomodulatory effects by secretion of various soluble cytokines or via cell contact. There are still many problems to be further explored to facilitate better clinical application of mesenchymal stem cells.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Mesenchymal Stem Cells, Inflammation, Immunomodulation, Tissue Engineering

CLC Number:

R394.2

Zhou Dian, Yan Fei, Zhou Ze-kun, Li Chen, Liu Ou-sheng. Immunomodulation of mesenchymal stem cells in inflammatory microenvironment[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(17): 2747-2754.

Figures/Tables 1

2.1 炎症微环境下MSCs的生物学特性 2.1.1 炎症微环境对MSCs表面标记物的影响特异性的标记物是鉴别细胞的理想条件，而与MSCs相关的表面标记物现尚未完全明确。迄今为止，已经提出了很多的MSCs表面标记物，较为公认的观点为MSCs表达 CD105，CD73，CD44，CD90，CD71和Stro-1以及黏附分子CD106，CD166，ICAM-1和CD29[14-16]，但不表达造血细胞表面标志物(如CD45，CD34，CD14和CD11)，同时也不表达CD80，CD86，CD40以及CD31，CD18，CD56。除此之外，CD146也是MSCs的重要标志物[14，17]。据报道，体外微环境的变化是导致MSCs表型发生变化的最主要因素。Alongi等[18]选择STRO-1，CD90，CD105和CD146这4种用于鉴定MSCs的标记物进行免疫荧光染色，发现炎症牙髓的4种标记物密度明显高于正常牙髓，其可能是由于炎症时血管生成多，而这些标记物都与血管有关。但也有研究表明，炎症微环境并不会影响干细胞的表面标记物[19]。梁媛媛[20]分离及培养健康喉黏膜MSCs和炎症喉黏膜MSCs，两种细胞均表达MSCs特异性表面细胞分子，说明存在于炎症微环境下的MSCs仍具有干细胞的特性。 2.1.2 炎症微环境对MSCs分化的影响很多研究表明，炎症环境会对MSCs的生物学行为产生一定程度的影响。梁媛媛[20]实验结果表明，炎症喉黏膜MSCs增殖能力强于健康喉黏膜MSCs，但成骨、成脂分化能力均显著低于健康喉黏膜MSCs，说明炎症状态下MSCs的分化能力受到抑制，这可能是由于炎症微环境中存在的炎细胞、炎性因子和白细胞代谢产物等各种炎性递质能对MSCs产生持续的刺激，从而改变其增殖和分化能力。有报道表明，牙周膜干细胞在炎性环境中会因非经典Wnt/Ca+信号通路的抑制而使其成骨能力受到影响[18]。在牙周炎环境中，主要致病菌为革兰阴性菌，其细胞壁表面的脂多糖主要激活巨噬细胞而产生肿瘤坏死因子α和白细胞介素1β等，其与牙周炎的病程发展密切相关[21]。牙周膜干细胞是一种成体干细胞，牙周炎状态下脂多糖产生的肿瘤坏死因子α显著抑制牙周膜干细胞的成骨分化，使牙周组织再生能力丧失。在这些炎性因子中，肿瘤坏死因子α被认为是其他因子的上游因子，在炎症发生中起重要作用，其在骨病理生理过程中扮演重要角色，通过抑制转录方式调节Runx2表达[22-24]，还有研究表明，肿瘤坏死因子α能抑制成骨细胞分化及矿化结节的形成[25-26]。此外，白细胞介素1和肿瘤坏死因子α在体外可以抑制MSCs的成脂分化能力。这些研究都表明，炎症因子的分泌，可以通过多种复杂分析信号机制影响干细胞的生物学特性。白细胞介素1β和肿瘤坏死因子α是主要的促炎性因子，在炎症组织中高表达，而现在关于肿瘤坏死因子α对干细胞成骨分化的作用有不同的报道，有研究认为其抑制成骨，如Zhou等[27]发现，在炎症反应发生中，肿瘤坏死因子α可激活成骨细胞中的p38 MAPK[28]，抑制成骨细胞的分化。也有研究表明肿瘤坏死因子α在干细胞成骨分化中起着积极的作用，通过激活核转录因子κB途径[29]，提高成骨相关蛋白的表达，使基质矿化增多[30]。 2.1.3 炎症微环境对MSCs增殖能力的影响炎症是一个复杂的进程，根据炎症刺激的程度，一些轻度的刺激因子可能会激活MSCs的某些特性。如适当的低氧刺激促进细胞的增殖[31]。此外，当前很多研究都已表明Wnt通路与干细胞的干性息息相关。由于Wnt/β-catenin通路激活后，大量LEF-β-catenin复合体形成激活靶基因Cyclin D1，通过此途径来调控细胞的生长周期以促进干细胞增殖，由此解释了炎性环境中MSCs增殖能力增加的原因[32]。同样，李楠[33-34]通过实验得出，在炎症微环境中，牙龈MSCs的增殖、凋亡、多向分化能力(成骨、成脂能力)、细胞外基质、相关蛋白酶和炎性因子均会有改变。众所周知，克隆形成能力是MSCs的重要特性。通过分析实验结果提示炎症状态下牙龈MSCs提前进入瞬时扩增细胞状态，也就是正常牙龈MSCs在炎症微环境中会提早形成瞬时扩增细胞，但是其多向分化能力降低，在多向分化过程中出现大量的凋亡，尽管此时细胞增殖增强。然而，也有学者发现，炎性牙髓干细胞的增殖能力与正常牙髓干细胞无明显差异[35]。还有学者将来源于风湿性关节炎患者骨髓的MSCs与正常骨髓的MSCs进行了对比实验，发现来源于患者骨髓的MSCs的增殖能力和克隆形成能力均降低[36]。炎症环境下间充质干细胞的不同生物学特性的比较，见表1。"

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