Chinese Journal of Tissue Engineering Research ›› 2023, Vol. 27 ›› Issue (15): 2379-2384.doi: 10.12307/2023.376
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Zhang Chuhan1, Zhang Dongmin2, Xu Wenan1
Received:
2022-04-14
Accepted:
2022-07-07
Online:
2023-05-28
Published:
2022-10-18
Contact:
Xu Wenan, Associate professor, Associate chief physician, Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen 510811, Guangdong Province, China
About author:
Zhang Chuhan, Master candidate, Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen 510811, Guangdong Province, China
Supported by:
CLC Number:
Zhang Chuhan, Zhang Dongmin, Xu Wenan. Cell co-culture system of dental pulp regenerative tissue engineering[J]. Chinese Journal of Tissue Engineering Research, 2023, 27(15): 2379-2384.
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2.1 共培养体系的组成 2.1.1 细胞主体 目前用于构建牙髓再生组织工程共培养体系的细胞主体为口腔来源的间充质干细胞,如牙髓干细胞、脱落乳牙牙髓干细胞、牙周膜干细胞、牙囊干细胞和根尖牙乳头干细胞等。牙源性间充质干细胞在体内和体外均具有牙髓组织再生能力,而且具有易获取、易培养的优点,无论是牙髓组织再生领域还是口腔外组织再生均有广泛运用,但由于单一细胞的生成组织的结构与功能与天然组织有差异,因此,引入其他细胞共同培养能提供更好的细胞微环境[4]。 2.1.2 组合细胞 组合细胞的来源主要包括终末分化成熟的成体细胞,如人脐静脉内皮细胞;成体干/祖细胞,如间充质干细胞和内皮祖细胞;胚胎干细胞;诱导多能干细胞。组合细胞要求具有一定的调控增殖分化能力,并且本身细胞源容易获取或可以在细胞主体和组合细胞的相互作用下可分化为组织必需的结构。体外构建细胞共培养系统的方式通过引入组合细胞,可更好地模拟体内细胞生长环境,研究细胞间及细胞与环境之间的相互作用和信号通路[5]。 牙髓再生组织工程中的细胞共培养组合类型众多,多数为牙源性干细胞和内皮细胞共培养,其中牙髓干细胞和人脐静脉内皮细胞联合培养体系应用最为广泛[6]。已知内皮细胞和牙源性干细胞可分泌一系列有利于细胞生长和分化的生长因子,当二者进行共培养时,一方面内皮细胞提供的细胞外基质环境可以促进牙源性干细胞的增殖及分化能力,另一方面,牙源性干细胞作为周细胞样细胞,可为内皮细胞的血管化提供局部微环境,增强新生血管的稳定性[7-9]。 2.2 共培养体系的模型和维度 细胞共培养根据模型一般可分为直接接触共培养、间接接触共培养,而根据形成组织的维度,又可分为二维细胞培养和三维细胞共培养,二者可交叉使用,如直接接触的二维细胞培养等,见图3。目前牙髓再生的共培养模型多为间接接触的二维细胞培养。"
2.2.1 直接接触培养 是指将不同细胞放在同一培养体系中,细胞之间直接接触。直接接触共培养中细胞主体和组合细胞间通过细胞外基质或细胞接触相互通信,既促进细胞主体形成目标组织,又使组合细胞形成目标组织必须的周围支持组织,从而实现组织再生。DISSANAYAKA等[10]研究发现将牙髓干细胞与人脐静脉内皮细胞进行直接共培养,可提高牙髓干细胞成牙/成骨潜能和人脐静脉内皮细胞的血管生成能力。 直接接触共培养可形成有整体性的组织,但是也有其短板:因为细胞处于同种环境,无法完全区分不同种细胞分泌的生长因子等物质,无法对相互作用的机制进行更深入的研究。由于培养手段的影响,若无生物支架介入,形成的再生组织则无生理性组织的三维结构,同时直接接触培养体系中不同细胞的接种比例对组织再生的结局有决定性影响[11]。 2.2.2 间接接触培养 是将不同细胞置于同一培养体系中,但不同细胞之间无直接接触,如嵌入式细胞共培养(Transwell小室)、细胞衍生物共培养等,细胞之间通过旁分泌途径产生单向作用或相互作用,从而促进组织再生。MERCKX等[12]通过向牙髓干细胞培养基中添加骨髓间充质干细胞的条件培养基以及细胞外小囊泡,构建了牙髓干细胞-骨髓间充质干细胞间接共培养体系,发现牙髓干细胞的组织再生能力不但有所增强,还可向内皮损伤部位迁移。 相比直接接触培养,间接接触培养不但可以准确说明细胞间通讯作用机制的影响,同时还可以对细胞的趋化、迁移能力进行观察,而细胞衍生物共培养作为一种脱细胞介入手段可以避免免疫排异反应并提高干细胞的利用率,与此同时,对如细胞条件培养基、细胞外囊泡等细胞衍生物的分离、成分分析以及作用机制也成为研究热点之一。但是由于细胞间无直接接触,无法分析细胞直接接触产生的细胞通讯作用,也无法分析复杂组织中细胞外基质介导的细胞间信号传递。 2.2.3 三维细胞共培养 三维细胞共培养即将细胞接种于具有三维结构的生物支架材料上或细胞三维成团培养,为细胞提供近似于体内的生长环境,其优点是能最大限度地有序还原组织原有形态,缺点则是生物支架材料和三维成团培养的成本和技术敏感性过高,并且研究者还在进一步探索最优材料。 安莉等[13]将牙髓干细胞和人脐静脉内皮细胞接种于基质胶上,并且在共培养体系中加入肿瘤坏死因子α,结果表明肿瘤坏死因子α可促进共培养系统体外成血管能力,同时在共培养体系中,牙髓干细胞可分泌血管内皮生长因子、成纤维细胞生长因子及血小板衍生生长因子等多种促血管生长因子,促进内皮细胞的存活和分化;人脐静脉内皮细胞同样分泌信号分子和趋化因子来影响牙髓干细胞的生长和分化能力。体内实验包括免疫缺陷小鼠皮下移植和组织工程牙齿种植。HONDA等[14]将间充质细胞和人口腔上皮细胞以1∶1比例接种于胶原蛋白海绵上,并将其移植到裸鼠皮下,最终发现这种细胞接种技术可以有效地调控再生牙的形态。LIU等[15]将牙周膜干细胞和牙髓干细胞接种到体外制备的羟基磷灰石-磷酸三钙支架材料(HA/TCP)上,将其移入生物根并种植于小型猪的下颌骨中,6个月后观察到牙根样结构和牙本质样结构形成。 2.3 牙髓再生组织工程共培养体系的培养条件 细胞共培养的条件包括:细胞的接种密度与比例、培养基的选择、培养时间和干预因素等。如安莉等[13]还在实验过程中发现的共培养体系中以1∶5的比例进行共培养,其血管的形成优于其他实验组且结构最为稳定,2种细胞的比例是共培养结果的关键,不同比例下细胞之间的交流产生不同的实验效应。 除了细胞主体及组合细胞的选择、共培养体系的选择外,细胞共培养体系的培养条件对组织再生结局也有重要影响[16-21],详见表1。"
2.4 生物支架材料的应用 牙髓再生中三维支架材料的应用不仅能为细胞提供黏附、增殖和迁移的场所,还有构建组织三维结构的功能以及通过不同材料特性达到控释细胞因子的作用,有助于细胞的成血管化和成牙本质分化[22]。常用的支架材料可分为天然材料、人工合成材料和复合材料。天然材料是指由动植物组织中提取的高分子可降解材料,具有良好的生物相容性,如胶原、水凝胶和脱细胞支架等。人工合成材料主要包括聚乳酸、聚乙醇酸等,无机材料主要以钙盐为基础,如羟基磷灰石和聚磷酸钙等。由于任何单一支架材料均难以满足牙髓组织对生长环境的要求,而复合材料是将天然材料与人工合成材料结合,以此不同材料的特点和优势来实现某些特定的功能,已成为目前组织工程生物支架材料研究的热点[23-24]。在牙髓再生研究中首次应用支架材料,是由YOUNG等[25]将牙髓单细胞悬液接种在聚乳酸-聚乙醇酸支架上,将其移植到免疫缺陷大鼠宿主体内生长20-30周后,观察到牙齿结构的形成。目前多数用于牙髓再生研究的材料都具有一定的可塑性和流动性,以适应根管的解剖形态[26],前文所提DISSANAYAKA等[27-28]采用琼脂糖微模具制备牙髓干细胞-人脐带血管内皮细胞共培养的三维微组织球体,结果发现经过预血管化的组织可形成更为稳定的毛细血管结构,在体内体外都表现出更高的骨/牙源性基因表达水平和矿化水平。 3D打印生物材料已在组织工程学中广泛运用,其高个性化、便捷、可设计等性能为未来的组织工程再生提供诸多可能性。随着材料技术发展,3D打印已可以涉猎水凝胶一类形变能力极强、能适应不同解剖结构的材料,因而3D打印生物支架逐步进入到牙髓再生领域中[29-30],因此3D打印生物材料在近5年也在不同研究中发挥着诱导细胞形成三维组织形态、促进细胞增殖分化的重要作用[31-37],见表2。"
2.5 牙髓再生组织工程共培养体系的作用机制 细胞之间的交互作用通过以下3种机制实现:①细胞表面分子的直接接触;②邻近细胞间的缝隙连接;③分泌到细胞外环境中的信号分子与目标细胞的特异受体相互作用:细胞之间释放扩散性分泌因子,如细胞因子、生长因子等[38-39]。无论是细胞表面分子的直接接触还是缝隙连接,由于细胞间有直接接触且细胞交流时不向外分泌信号分子等介质,可将二者归类为细胞间的直接通讯,故文章根据细胞间的直接作用和间接作用展开阐述牙髓再生组织工程共培养体系中的细胞交互机制。 2.5.1 共培养细胞间的直接作用 细胞表面分子的直接接触多见于免疫反应中的抗原呈递过程,在共培养中细胞主体与组合细胞间鲜有涉及。而缝隙连接是一种细胞间直接通讯方式,相邻细胞间通过细胞膜上的连接子相互锚定,允许相对分子质量小于 1 500的离子、小分子代谢物 (如氨基酸、核苷酸、维生素和糖类等)及第二信使(如cAMP,Ca2+,IP3)通过[40-41]。缝隙连接蛋白(connexin,Cx)是构成缝隙连接的基本单位,在哺乳动物体内分布广泛。牙髓组织中主要表达Cx26,Cx32和Cx43[42-43],成骨细胞的主要连接蛋白为Cx43[44],内皮细胞为Cx37,Cx40和Cx4[45]。在牙髓再生组织工程共培养体系中关于细胞间直接通讯作用的研究较少,但在其他学科领域的细胞共培养体系中,细胞间的信号通讯作用主要通过Cx43介导实现,如成骨细胞与血管内皮细胞[46]、单核细胞与内皮细胞[47-48]。同样地,亦有研究表明成牙本质细胞间的缝隙连接是由Cx43所介导的[49],LI等[50]研究发现牙髓干细胞通过Cx43介导的Ca2+在细胞间相互交流,促进牙本质涎磷蛋白的表达和成牙分化。因此在牙髓再生共培养体系中,细胞间的直接作用很有可能是通过Cx43介导实现,但仍需更多证据支持。 2.5.2 共培养细胞间的间接作用 共培养体系中细胞之间通过分泌到细胞外环境中的信号分子与目标细胞的特异受体相互作用,即通过旁分泌/自分泌的生长因子/细胞因子发挥间接接触作用[51-66]。 健康牙髓由血管、神经和胶原纤维等部分组成,对于牙髓再生组织工程而言,需要形成与之形态功能相似的牙髓样组织。在此过程中,不同方向的分化与组织形成具有不同机制,其中成血管是牙髓组织再生的关键,健康组织中血管提供细胞和组织生命活动所必须的营养物质,而在组织再生相关组织工程研究中,血管不仅是物质运输的通道,还是富含趋化因子的细胞归巢支架,同时还承担血管化骨再生的功能[51],因此文章主要对牙髓再生中成血管机制进行总结,见表3。 IWAYA等[52]在2001年的病例报道中首次引用牙髓血运重建这一概念,而与此同时血管内皮生长因子的发现改变了研究者对血管生成和发育过程中血管生成以及生理稳态的理解[53],在牙髓再生过程中,血管内皮生长因子通过与细胞膜上的受体结合,发生一系列的生理过程从而影响细胞增殖、新生血管生成,具体过程如下:血管内皮生长因子A与细胞膜上的受体及跨膜蛋白结合,受体自身磷酸化或二聚化,经过胞内一系列底物及蛋白的活化水解,引起信号级联反应,使细胞大量钙离子通道开放,引发钙内流,进而释放一氧化氮和前列腺素,从而调节血管的生成[54-56]。在牙髓干细胞-人脐静脉内皮细胞共培养体系中,肿瘤坏死因子α和脂多糖可激活血管内皮生长因子-SIRT1信号通路,并激活下游核转录因子κB信号从而增强人脐静脉内皮细胞和牙髓干细胞的迁移能力和新形成血管结构的稳定性[57]。此外,其他的研究表明血管内皮生长因子调节血管生成还有可能与PI3K/AKT信号通路以及MEK1/2/ERK1/2信号通路[58]。随着细胞间交流关键生物因子的提纯以及信号通路的发现,研究者揭示了越来越多与牙髓再生成血管相关的关键因子以及被关键因子激活的信号通路,且时至今日牙髓再生的成血管机制依旧是研究热点。"
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