牙髓间充质干细胞与巨噬细胞交互作用的研究进展

Progress in the study of cellular interactions between dental pulp mesenchymal stem cells and macrophages

摘要

牙髓间充质干细胞，又称牙髓干细胞，是近年来备受关注的一种具有免疫调节、组织再生等多种能力的间充质干细胞。巨噬细胞是一种经典的免疫细胞，在炎症环境中可极化为多种功能不同的表型，发挥促炎、抗炎等不同作用，还可分化为破骨细胞，在多种疾病中起重要作用。研究牙髓干细胞与巨噬细胞的交互作用具有广阔的临床前景。本文就牙髓干细胞与巨噬细胞两者间的交互作用进行综述，主要探讨了牙髓干细胞对巨噬细胞极化、迁移和分化的调控作用，以及不同表型巨噬细胞对牙髓干细胞增殖、分化等的调控作用，以期为利用牙髓干细胞治疗炎症相关疾病提供理论依据。

Abstract

Dental pulp mesenchymal stem cells (or dental pulp stem cells) are mesenchymal stem cells derived from dental pulp tissues, possessing notable capacities for immunomodulation and tissue regeneration. Macrophages, as key immune effector cells, are prevalent in inflammatory microenvironments and exhibit phenotypic plasticity through polarization into distinct functional subsets. Hence, understanding the bidirectional interactions between dental pulp mesenchymal stem cells and macrophages is essential for advancing the therapeutic application of dental pulp mesenchymal stem cells in inflammation-related diseases. This review explores the mechanisms by which dental pulp mesenchymal stem cells influence macrophage polarization, migration, and differentiation and how macrophages of various phenotypes influence the proliferation and differentiation of dental pulp mesenchymal stem cells.

Graphical abstract

关键词

牙髓间充质干细胞 / 巨噬细胞 / 细胞相互作用 / 免疫调节 / 细胞分化

Key words

dental pulp mesenchymal stem cell / macrophage / cellular interaction / immunoregulation / cellular differentiation

间充质干细胞（mesenchymal stem cells，MSC）具有很强的损伤修复、组织再生、免疫调节能力以及多向分化潜能，是再生医学的研究热点。巨噬细胞（macrophage）是一类源自单核细胞的免疫细胞，参与特异性免疫和非特异性免疫，在炎症的激活和消退中起重要作用。MSC的主要来源是脂肪、骨髓、外周血或脐带组织等。口腔是近年来新发现的MSC来源库，已经陆续发现了牙髓干细胞（dental pulp stem cells，DPSC）、牙周膜干细胞、牙龈干细胞、根尖牙乳头干细胞等间充质干细胞等多种干细胞^[1]。2000年，Gronthos等^[2]从成年人类牙髓中分离出一种克隆源性、高度增殖、可形成类牙本质-牙髓复合体的干细胞，将其定义为DPSC。相较于骨髓、外周血、脂肪等其他组织来源的MSC，DPSC的最大优势是易于获取和分离，且DPSC往往来源于成人拔除的智齿或因正畸等治疗导致拔除的牙齿，避免了伦理上的争议和身体的侵入性损伤^[3]。

巨噬细胞作为免疫系统最具代表性的细胞之一，与DPSC的交互作用在再生修复应用上的潜力得到了越来越多的关注。DPSC促进巨噬细胞向促修复型巨噬细胞（M2型）极化，以及巨噬细胞调控DPSC成牙/成骨向分化等的干细胞疗法或许是未来针对牙髓炎、骨关节炎等诸多疾病的有力治疗手段，具有良好的临床前景。本文旨在对DPSC与巨噬细胞间的交互作用进行综述。

1　 DPSC对巨噬细胞的调控

DPSC对巨噬细胞的调控主要表现在促进巨噬细胞向促修复型巨噬细胞（M2型）极化、抑制其向促炎型巨噬细胞（M1型）极化上，这也是目前临床应用的重要基础；此外，DPSC也对巨噬细胞的迁移、破骨向分化等功能同样具有调控能力（表1）。

1.1　 DPSC对巨噬细胞迁移的调控

炎症状态下，DPSC可招募巨噬细胞，促进其向防御前线迁移。Hu等^[4]的研究表明：未经处理的DPSC有较弱的诱导巨噬细胞迁移能力。Choi等^[5]发现： LPS、IL-1β、TNF-α刺激都会显著增强骨髓来源巨噬细胞向DPSC迁移的能力，表明炎症环境中DPSC可能起到更强的募集巨噬细胞的作用。DPSC募集巨噬细胞可能是通过其较强的分泌MCP-1和趋化因子配体14（C-X-C motif chemokine 14，CXCL14）的能力实现的，这两个趋化因子是调节单核细胞/巨噬细胞迁移的关键趋化因子^[20-22]。Chansaenroj等^[7]发现：DPSC募集巨噬细胞的能力可能依赖于Wnt通路，使用IWP-2阻断Wnt通路可以消除LPS诱导的DPSC表达TNF-α、IL-1β等细胞因子，抑制巨噬细胞的迁移。此外，缺氧环境可能提高DPSC募集巨噬细胞的能力。Martinez等^[6]在DPSC中过表达缺氧诱导因子-1α（hypo-xia-inducible factor 1α，HIF-1 α），发现其在炎症条件下产生更高水平的MCP-1，并诱导更多的单核细胞迁移。

1.2　 DPSC对巨噬细胞极化的调控

目前已有证据^[23-24]表明：DPSC具有很强的抑制巨噬细胞的促炎表型，同时促进其向促修复型巨噬细胞极化的能力，这可能与DPSC分泌抗炎细胞因子如IL-6、TGF-β、HGF和IDO有关。DPSC可以显著降低LPS刺激的RAW264.7细胞的NF-κB信号通路激活和IL-6、TNF-α表达，抑制其M1型极化，并提高其IL-10和CD206（M2型巨噬细胞标志物）的表达^[3,8-10]。Liu等^[11]发现：DPSC通过分泌HGF和TGF-β1以及部分阻断MAPK通路抑制了骨关节炎巨噬细胞的M1型活化。DPSC分泌的基质金属蛋白酶（matrix metalloproteinase，MMP）-3也被发现可以抑制M1型巨噬细胞分泌一氧化氮和炎症介质^[20]。Martínez-Sarrà等^[25]在伤口愈合以及肌营养不良模型小鼠中移植DPSC，结果都发现大量的M2型巨噬细胞浸润。Shen等^[12]和Zheng等^[13]发现：DPSC可能通过其外泌体中的miRNA-1246、miRNA-125a-3p以促进巨噬细胞从M1型转化为M2型。Yang等^[16]还发现DPSC分泌的MCP-1不仅起到募集作用，也在诱导巨噬细胞M2型极化中起到重要作用。

Lee等^[14]发现：从不可逆性牙髓炎组织中分离的DPSC仍然有类似健康牙髓内的DPSC的免疫调节能力，且前者抑制巨噬细胞分泌TNF-α的能力可能与IDO表达的增加有关。值得一提的是，Anderson等^[15]发现：DPSC在炎症因子LPS、TNF-α、IFN-γ诱导下，IL-4、IL-10、IDO等抗炎因子的表达反而上升，其诱导巨噬细胞M2型分化的能力也更强，说明炎症微环境下的DPSC具有更强的调控巨噬细胞极化、抑制炎症过度活化的作用。

1.3　 DPSC对巨噬细胞破骨向分化的调控

DPSC还有调控巨噬细胞向破骨细胞分化的能力。Kanji等^[17]发现：DPSC可以通过组成型分泌途径分泌OPG以减少RAW264.7细胞中活化T-细胞核因子1、RANK和MMP-9等破骨细胞标志物的表达，并抑制破骨细胞的生成。Kong等^[18]发现：通过直接向小鼠静脉输注DPSC，可改变骨质疏松小鼠的RANKL/OPG比例升高的现象，减少早期骨丧失。Zheng等^[19]发现：DPSC中OPG的表达约为牙槽骨细胞的2倍，相对的，RANKL的表达仅为牙槽骨细胞的1/20，提示DPSC具有抑制破骨向分化的能力。

1.4　 提高DPSC对巨噬细胞调控功能的探索

近年来有一些针对提高DPSC对巨噬细胞调控功能的探索研究。Murakami等^[26]利用不同亚群DPSC对粒细胞集落刺激因子（granulocyte colony-stimulating　factor，G-CSF）的迁移作用，分离出免疫抑制能力更强的DPSC。Iohara等^[27]在后续实验中尝试联合移植DPSC和G-CSF进行牙本质-牙髓再生治疗，发现联合移植G-CSF后M1型巨噬细胞显著减少。低氧预处理作为一种被广泛研究的增强MSC迁移、再生、免疫调节等多项能力的方法^[28]，对DPSC的作用仍有一定争议。有研究^[29-30]发现：低氧条件下DPSC的增殖、迁移、促血管生成、免疫调节等能力得到了增强；但另有研究^[31]对比了在常氧与缺氧环境下培养DPSC的条件培养基对RAW246.7细胞的影响，发现虽然两者都起到了抑制巨噬细胞促炎表型的作用，但常氧条件培养DPSC的条件培养基作用更强。低氧预处理对DPSC的影响尚没有明确的结论。如何行之有效地提高DPSC对巨噬细胞的调控能力，提高其临床应用效果，仍亟待研究。

2　 巨噬细胞对DPSC的调控

不同极化表型的巨噬细胞对间充质干细胞的细胞行为有不同影响。Zhang等^[32]通过不同极化表型的巨噬细胞和脂肪组织来源的MSC共培养发现：巨噬细胞和M1型巨噬细胞可以促进MSC的早期矿化，但在中晚期矿化过程中，只有M2型巨噬细胞表现出较高的促矿化作用。骨损伤中，从炎症早期到骨折愈合期，起主导的M1型巨噬细胞逐渐极化为M2型巨噬细胞的过程对于MSC的成骨向分化同样不可或缺^[33]。在牙髓组织损伤中也存在着类似的生物学过程。在深龋或牙髓炎刺激下，巨噬细胞迅速被招募至牙髓并向M1型巨噬细胞极化，并在炎症得到控制时向M2型巨噬细胞极化，而DPSC也在受损伤处相对的髓室壁处分化为成牙本质细胞并形成修复性牙本质，阻挡外界的损害。目前的研究^[13]表明：M2型巨噬细胞对DPSC分化的调控作用主要是促进其成牙/成骨向分化，而M1型巨噬细胞对DPSC的调控作用尚缺乏直接证据。

虽然当前绝大多数有关巨噬细胞调控DPSC的探讨都基于炎症环境，但有研究^[34-35]发现：在牙齿发育的钟状期，巨噬细胞就定植于牙乳头中，且牙齿发育完成后巨噬细胞在成牙本质细胞周围有明显聚集，提示正常牙髓中巨噬细胞与DPSC间可能存在未知的相互作用，有待进一步探明。

2.1　 M2型巨噬细胞对DPSC的调控

Neves等^[36]发现：巨噬细胞耗竭会明显减少小鼠受损牙齿在盖髓治疗后髓室内修复性牙本质的形成，且受损部位牙髓的Wnt反应性细胞也明显减少。Park等^[37]发现：培养M2型巨噬细胞的条件培养基可以增加DPSC的牙本质涎磷蛋白（dentin sialophosphoprotein，DSPP）表达和碱性磷酸酶（alkaline phosphatase，ALP）活性，这可能与M2型巨噬细胞的条件培养基中含有大量的TGF-β有关，而培养M1型巨噬细胞的条件培养基对ALP活性没有明显影响。M2型巨噬细胞的分泌产物TGF-β可以促进DPSC的成牙本质分化和成骨分化^[38-41]；但值得一提的是，有研究^[42]发现TGF-β会抑制成骨分化，这可能与其浓度有关。此外TGF-β还会抑制DPSC的成脂分化^[38,43]。此外，M2型巨噬细胞分泌的IL-10可以促进DPSC的增殖，并通过增强其氧化磷酸化促进成骨分化^[44]。Zheng等^[13]发现：使用DPSC的外泌体诱导的M2型巨噬细胞的条件培养基，可以反过来促进DPSC的成牙本质分化。总结来看，M2型巨噬细胞能促进DPSC的成牙和成骨向分化。

2.2　 M1型巨噬细胞对DPSC的调控

虽然目前尚缺乏直接证据表明M1型巨噬细胞对DPSC分化有调控作用，但已经发现许多M1型巨噬细胞的经典分泌产物可以调控DPSC的分化。研究^[45-47]发现：TNF-α、IL-1β、IL-6可以促进DPSC的成牙本质细胞分化，提高DSPP、DMP-1和骨钙素（osteocalcin，OCN）、Runt相关转录因子2（Runt-related transcription factor 2，RUNX2）、ALP等的表达。Zhai等^[48]也发现：TNF-α和IL-1α刺激DPSC会上调人β防御素4（human β-defensin 4，HBD4）表达，HBD4又可以通过Notch通路促进DPSC向成牙本质细胞分化。有研究^[49]认为：TNF-α和IL-1β会导致DPSC过早衰老，可能影响其分化能力。有趣的是，Nozu等^[50]发现：多次传代后，衰老的DPSC相较于年轻的DPSC，具有更多的TNF-α受体1，且TNF-α会上调衰老的DPSC的矿化能力而下调年轻的DPSC的矿化能力。M1型巨噬细胞与DPSC之间的相互作用仍需要进一步深入研究。

3　 总结与展望

DPSC与巨噬细胞的交互机制如图1所示。炎症环境下，DPSC与巨噬细胞之间存在DPSC促进巨噬细胞M2型极化，而M2型巨噬细胞又反过来促进DPSC成骨/成牙本质分化这样一个缓解炎症同时促进组织修复的交互机制。这种促进组织稳态的交互作用可能是牙髓炎组织常表现为慢性炎症的原因。同时，处于长期炎症环境下的DPSC的分化、组织再生和免疫调节能力在一定程度上会受到损害^[49,51]。如何提高和维持DPSC对巨噬细胞的调控能力，是目前DPSC应用于临床的难题之一^[52]。这可能需要对生物支架材料进一步改造，以改善DPSC受体微环境，从而维持DPSC的干细胞功能。

近年来，随着单细胞转录组等新技术的发展，对于DPSC的认识也进一步深入。目前发现DPSC内也存在具有不同分化倾向的干细胞亚群^[53]。未来，单细胞转录组、空间转录组等技术的发展或可进一步揭示DPSC与巨噬细胞的交互机制，并筛选出对巨噬细胞调控能力更强的亚群。

目前DPSC在口腔领域的临床应用研究，还主要集中于牙槽骨再生及牙髓再生方面^[54]。在一项对健康牙髓和龋坏牙齿牙髓组织的单细胞测序研究^[55]表明：龋坏牙齿牙髓中DPSC的占比反而更高，同时龋坏牙齿牙髓中免疫细胞及炎症细胞因子也明显增加，充分说明了炎症环境下DPSC的潜力；但DPSC本身的促巨噬细胞M2型极化的能力还不被重视，这可能是未来治疗早期牙髓炎甚至其他炎症性疾病的重要研究方向。

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基金资助

国家自然科学基金(82270964)