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瘢痕内注射脂肪来源干细胞对兔耳增生性瘢痕的抑制作用研究

2015-11-28刘李娜邓景成曹卫刚

组织工程与重建外科杂志 2015年3期
关键词:胶原瘢痕纤维化

张 琪 刘李娜 邓景成 曹卫刚

瘢痕内注射脂肪来源干细胞对兔耳增生性瘢痕的抑制作用研究

张 琪 刘李娜 邓景成 曹卫刚

目的研究瘢痕内注射脂肪来源干细胞(ADSC)对兔耳增生性瘢痕的抑制作用及可能机制。方法选取12只新西兰大白兔,制作兔耳增生性瘢痕模型,随机平均分成3组,2周后各组右耳瘢痕内注射DMEM作为自身对照,左耳分别注射ADSCs、脂肪来源干细胞条件培养基(ADSCs-CM)及不作处理。注射前及注射后1、2、3周检测瘢痕增生情况,并于注射后3周取材,行组织化学及基因学检测。结果造模2周后,伤口均完全上皮化;DMEM注射及未处理组的伤口逐渐出现增厚、变红、变硬等增生表现,注射后3周时最为明显;ADSCs及ADSCs-CM注射组均未出现明显增生反应。取材后HE、Masson染色示,ADSCs及ADSCs-CM注射组瘢痕的胶原密度适中、排列整齐;对照及未处理组瘢痕可见大量致密、杂乱的胶原组织。基因检测发现,ADSCs及ADSCs-CM注射组瘢痕的α-SMA、CollagenⅠ表达显著低于对照及未处理组。ADSCs注射组瘢痕冰冻切片Dil荧光染色可见大量存活脂肪来源干细胞。结论瘢痕内注射脂肪来源干细胞可以降低α-SMA、CollagenⅠ基因表达,从而改善瘢痕内胶原堆积,并最终改善瘢痕增生情况。

脂肪来源干细胞增生性瘢痕瘢痕内注射

创面愈合过程包括炎症期、增生期及重塑期。增生性瘢痕的发生是由于伤口愈合过程中某些重要因素的异常所致。T细胞及巨噬细胞免疫功能异常会导致炎症期延长,从而产生过多的无功能的胞外基质导致瘢痕增生[5-7]。中性粒细胞在伤口灭菌过程中产生的活性氧类物质(ROS)亦是瘢痕增生的促进因素[8-9]。TGF-β1是目前已知的致纤维化因子之一,能强效刺激伤口组织中胶原纤维的增生堆积,并抑制基质金属蛋白酶对胶原等胞外基质的分解,从而促进瘢痕增生[10-12]。伤口愈合过程中,肌成纤维细胞能有效缩小伤口,加速上皮化,但同时也合成分泌更多致密无序的胶原纤维,导致增生性瘢痕的挛缩[13-14]。伤口愈合过程中血供不足会导致愈合延迟从而加重瘢痕增生。因而及时、充足的微血管形成及向永久血管网络转化十分重要[15]。伤口愈合过程中的任何异常因素都可以影响组织再生从而产生增生性瘢痕。任何可以纠正或缓和伤口愈合过程中异常因素的药物均可抑制或改善瘢痕增生。在许多纤维化疾病的研究中发现,脂肪来源干细胞(ADSC)治疗可以通过减轻炎症反应、抑制TGF-β1作用并促进组织再生从而抑制纤维化发生及进展[16-18]。本实验通过建立兔耳瘢痕模型,研究瘢痕内注射ADSCs对兔耳增生性瘢痕的抑制作用及其可能的机制。

1 材料与方法

1.1 主要材料与试剂

新西兰大白兔,体质量2.0~2.5 K g,雌雄不限,(我院实验动物中心提供)。

Ⅰ型胶原酶(Sigma公司,美国);Dil(Invitrogen公司,美国);DAPI(Sigma公司,美国);TRIzol(Invitrogen公司,美国);SYBR Green试剂盒(Takara公司,日本);Nanodrop(Isogen公司,英国);小动物超声测量仪(Esaote公司,意大利);倒置相差显微镜(Nikon公司,日本);电动高速匀浆器(新芝公司,中国);PCR仪(Applied Biosystems公司,美国)。

1.2 兔耳瘢痕模型的建立

12只新西兰大白兔随机平均分成3组。麻醉后,以直径1 cm环转于耳腹侧制备6个相同的创面,去除皮肤全层及软骨膜,按压止血后均匀涂抹一层红霉素眼膏,暴露创面,每日清除创面分泌物(图1)。

1.3 ADSCs培养及ADSCs-CM准备

取4周龄新西兰大白兔腹股沟脂肪,0.075%Ⅰ型胶原酶37℃消化45 min;1 200 g离心10 min;沉淀物用常规细胞培养基(低糖DMEM加10%胎牛血清及1%双抗)置于37℃细胞培养箱。取第三代ADSCs接种于六孔板中(5×104cells/cm2),培养16 h后弃去培养基,换无血清DMEM,孵育48 h,收集上清液,300 g离心5 min后过滤(0.22 μm滤器)备用。

1.4 瘢痕内注射

取第三代ADSCs标记Dil,细胞收集离心后PBS洗涤2次,重悬于5 μL/m L Dil稀释液中(溶剂DMEM),避光,37℃孵育20 min,再次洗涤2遍,重悬于低糖DMEM中(2×107cells/mL)。1 mL注射器吸取细胞悬液或ADSCs-CM,用29 G针头从瘢痕边缘进针至中心处,缓慢推注0.2 mL,对照侧同法推注0.2 mL低糖DMEM。

1.5 瘢痕大体观察

术前及术后5周内每周拍照,记录瘢痕组织外观变化,同时采用超声测量仪记录瘢痕内部增生情况。

1.6 组织学检测

术后5周取材,每块瘢痕组织从中间最高处切成两半,分别固定于4%多聚甲醛中,取其中1份行石蜡包埋,切片,HE染色,镜下观察拍照,计算瘢痕增生指数(SEI)。采用Masson三色染色法进一步观察瘢痕组织中胶原的堆积及排列情况。

1.7 ADSCs荧光染色示踪

瘢痕组织取材,4%多聚甲醛固定24 h后,换10%蔗糖溶液,4℃避光脱水12 h,30%蔗糖溶液4℃避光脱水24 h,OCT包埋,置于-80℃保存备用。取OCT包埋组织,冰冻切片10 μm,贴片后PBS洗涤3次,置于空气中干燥10 min,DAPI(1 μg/mL)衬染胞核,荧光显微镜观察拍照。

1.8 实时荧光定量PCR检测

瘢痕组织取材后去除表皮、软骨及下层组织,置于液氮中速冻1 min,电动高速匀浆器匀浆,加入TRIzol(体积比1∶1),按操作说明提取组织总RNA,采用Nanodrop测量其浓度和纯度。用反转录试剂盒生成cDNA,1∶25稀释于去DNase水中备用。实时荧光定量PCR按SYBR Green试剂盒操作,结果采用β-actin为内参,计算2-DDCt及倍数值。引物序列包括α-SMA:F 5’-CAGGGAGTAATGGTTGGAAT-3’,R 5’-TCTCAAACATAATCTGGGTCA-3’;Collagen type Ι:F 5’-CCCAACCAAGGATGCACTA-3’,R 5’-CTTGGCCTTGGAGCTCTTATAC-3’;β-actin:F 5’-GCTATTTGGCGCTGGACTT-3’,R 5’-GCG实验GCTCGTAGCTCTTCTC-3’。

1.9 统计分析

数据统计分析采用GraphPad Prism 6软件,Student’s-t检验比较实验组及其自身对照的SEI值及基因表达。P<0.05为差异有显著性。

2 实验结果

2.1 ADSCs及ADSCs-CM注射均可抑制瘢痕增生

术后2周,大体观察所有创面均已完全上皮化。DMEM注射及未处理组可见创面上皮化后逐渐增厚、变硬、变红,并逐渐明显突出于周围正常组织,而ADSCs及ADSCs-CM注射组瘢痕未见明显增生,并逐渐与正常组织相似(图2)。

超声检查瘢痕组织可清晰观察到表皮、真皮、软骨、软骨下结缔组织,并可同时测量真皮组织的厚度,相比传统测量瘢痕全层厚度的方法,该方法能更准确地反应真皮层的厚度。B超示,DMEM注射及未处理组真皮层逐渐增厚,明显高于周围正常组织;而ADSCs及ADSCs-CM注射组未见明显增厚(图3)。

术后5周,HE染色示DMEM注射及未处理组瘢痕显著增厚,并伴轻度挛缩;而ADSCs及ADSCs-CM注射组平薄,类似正常组织(图4)。

计算并比较SEI值,ADSCs及ADSCs-CM注射组的SEI值均显著低于其自身对照(1.08±0.05 vs 1.93±0.09,**:P<0.01,n=24;1.33±0.10 vs 1.97±0.11,**:P<0.01,n=24)。而未处理组双侧SEI值无明显差异(1.90±0.12 vs 1.94±0.06,P>0.05,n=24)。另外,ADSCs注射组瘢痕的SEI值低于ADSCs-CM注射组(△:P<0.01)(图5)。

Masson染色观察胶原增生及排列可见自身对照及未处理组胶原致密,排列杂乱,而ADSCs及ADSCs-CM注射组胶原较稀疏且排列整齐(图6)。

2.2 ADSCs及ADSCs-CM抑制基因表达

实时荧光定量检测示,ADSCs及ADSCs-CM注射可抑制α-SMA及Ι型胶原mRNA表达(**:P<0.01),而DMEM注射及未处理组基因表达无明显差异。亦可见ADSCs注射组瘢痕α-SMA及Ι型胶原mRNA表达量显著低于ADSCs-CM注射组(*:P<0.05)(图7)。

2.3 荧光染色示踪结果

Dil标记ADSCs荧光染色示大量绿色荧光细胞,表明ADSCs注射后3周瘢痕内存在大量存活的ADSCs(图8)。

图1 兔耳增生性瘢痕模型Fig.1 Hypertrophic scar model of rabbit ear

图2 各组兔耳增生性瘢痕注射前后照片Fig.2 Photos of the hypertrophic scar of rabbit ear before and after injection in each group

图3 各组兔耳增生性瘢痕注射前后B超检测Fig.3 Utrasonography of the hypertrophic scar of rabbit ear before and after injection in each group

图4 不同处理组术后5周HE染色结果Fig.4 H istological observation in each group 5 weeks after operation

图5 各组瘢痕增生指数Fig.5 Calculation of scar elevated index in each group

图6 不同处理组术后5周M asson染色结果Fig.6 Histological observation in each group by M asson staining 5 weeks after operation

图7 各组α-SMA及Ι型胶原基因表达Fig.7 Gene expression of α-SMA and collagen Ι in each group

图8 ADSCs的Dil荧光染色Fig.8 Dil staining of ADSCs

3 讨论

术后或创伤后瘢痕,轻者影响外观,重者可导致器官功能障碍。临床发现,部分烧伤后瘢痕行脂肪填充后,瘢痕组织可能软化,质地向正常皮肤转变,其组织学结构亦趋于正常皮肤组织。该现象的机制目前并不清楚,可能是脂肪组织中ADSCs促进了瘢痕组织学及临床表现的改变[19-21]。

对于创面愈合机制的研究理论可以用于解释瘢痕增生的可能原因[1-2,22]。创面愈合过程较为复杂,可分为序贯并相互重叠的3个时期,即炎症期、增生期及重塑期。此过程中的任何异常均可导致瘢痕增生。多项研究证实,间充质干细胞(MSCs)可通过促进创面愈合,从而抑制增生性瘢痕产生。

2001年Zuk等发现了ADSCs,属于MSCs的一种,但具有易获取、易分离培养、量多的优势,被广泛应用于组织工程种子细胞,以及促进创面愈合、抗衰老、抗纤维化方面[23-27]。ADSCs应用于各种纤维化疾病的治疗已有广泛研究。已在动物模型中证实,声带受损后注射ADSCs,可有效抑制萎缩性或增生性瘢痕形成[16];在急性心梗小鼠模型中注射ADSCs,可以缩小梗死面积、减轻心肌瘢痕形成,并促进心功能恢复。研究发现,ADSCs可以迁移至心梗处,并表达内皮细胞标志,与血管重建密切相关[17]。

但是,ADSCs在皮肤瘢痕形成中的作用并未有相关研究。本实验探索ADSCs在体内瘢痕形成过程中的抗纤维化作用。实验结果表明,ADSCs及其条件培养基对瘢痕增生均有不同程度的抑制作用,并可促进瘢痕向正常组织转化。ADSCs-CM是ADSCs体外培养48小时内的上清液,其中含有多种ADSCs分泌的细胞因子,如IL-10和HGF等。这些细胞因子可降低TGF-β1及胶原表达,促进MMPs表达,从而加速细胞外基质更新,抑制纤维化[28-31]。其中,HGF还可抑制成纤维细胞向肌成纤维细胞分化,从而抑制其致纤维化作用[14]。在创面愈合的增生期,血管形成可以为成纤维细胞形成肉芽组织提供充足营养基质[15]。ADSCs分泌的VEGF-A和b-FGF可以强效促进血管内皮细胞迁移、增殖及分化,从而有利于血管生成及稳定[32-35]。

本实验同时发现,ADSCs的抑制瘢痕增生作用显著强于ADSCs-CM。ADSCs除通过分泌一些抗纤维化细胞因子抑制瘢痕增生外,还存在着其他抑制纤维化的作用机制。研究表明,MSCs可被创面的炎症环境所激发,启动其免疫调节作用,上调前列腺素E2及环氧化酶-2的表达,减轻炎症反应并抑制炎症反应延长导致的T细胞及巨噬细胞免疫功能紊乱[6-7]。ROS是创面愈合过程中的一类致纤维化物质,可以诱导TGF-β1表达增强[8,36]。MSCs可以通过促进T细胞产生诱导性NO,从而改变ROS/RNS(反应活性氮类物质)平衡,阻止纤维化形成[9]。另有研究表明,ADSCs能在伤口真表皮细胞的影响下通过表型转换,分化成为成纤维细胞及角质形成细胞,直接参与真皮和表皮的组织结构再生[37]。本实验发现,ADSCs注射组在注射后3周,瘢痕组织内存在大量存活的ADSCs,推测ADSCs积极参与了创面愈合及组织再生。由于Dil标记荧光染色的时效性有限,未能追踪到ADSCs的最终转化,因而有待于进一步的研究,以证实ADSCs是否向创面愈合相关细胞转化,如血管内皮细胞、成纤维细胞及表皮细胞等。

4 结论

本实验采用稳定的兔耳增生性瘢痕模型,研究ADSCs及其条件培养基的瘢痕增生抑制作用。我们证实,ADSCs及其条件培养基对瘢痕增生均有抑制作用,但ADSCs作用显著强于ADSCs-CM,推测ADSCs不仅通过分泌抗纤维化因子抑制瘢痕增生,还可能通过ADSCs与创面内细胞间相互作用,及ADSCs向其他细胞分化,参与创面愈合及组织再生。

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The Inhibition Effect of Intra-cicatrix Injection of ADSCs on Ear Hypertrophic Scar of Rabbit


ZHANG QI,LIU Lina,DENG Jingcheng,CAO Weigang.
Department of Plastic and Reconstructive Surgery,Shanghai Ninth peop le's Hospital, Shanghai Jiaotong University School of Medicine,Shanghai 200011,China.Corresponding author:CAO Weigang(E-mail: wgcao@sina.com).

Objective To investigate the inhibition effect and mechanism of intra-cicatrix injection of adipose derived stem cells on hypertrophic scar in rabbit ear.M ethods Twelve New Zealand white rabbits were used for establishing scar model and were random ly divided into 3 groups.Two weeks after the operation,all the right ears were injected DMEM as internal control while left ears of group 1,2 were injected ADSCs,ADSCs-CM respectively.Left ears in the third group were remained untouched.Photos and ultrasonography were taken before and 1,2,3 weeks after injection.Histochemical and genetic detection were used 3 weeks after the rabbits were sacrificed for offering scar tissue.Results All wounds were reepithelized 2 weeks after the injection.Wounds injected DMEM and untouched gradually grew thick,red and stiff which are the symptoms of hypertrophic scars,while ADSCs and ADSCs-CM injected ones showed no sign of growing hypertrophic.HE and Masson's staining showed collagen deposit and irregularly arrangement in the DMEM injection and untouched scars, while much less and better arranged collagen deposit were shown in both ADSCs and ADSCs-CM treated ones.Genetic detection showed lower expression of α-SMA,CollagenⅠin ADSCs and ADSCs-CM injection scars,compared with DMEM treated and untreated ones.Dil label staining showed a larger amount of ADSCs in the scar tissue of ADSCs treated group. Conclusion Intra-cicatrix injection of ADSCs can inhibit hypertrophic scar through ameliorating collagen deposit by down regulate the expression of α-SMA,CollagenⅠ.

Adipose derived stem cells;Hypertrophic scar;Intra-cicatrix injection增生性瘢痕的发生是由于真皮组织损伤导致细胞外基质,尤其是胶原组织的异常堆积及重塑[1]。其典型表现是增厚、变红、变硬及伴痒感,影响美观,甚至造成功能障碍[2]。目前,瘢痕的治疗方法很多,包括切除、皮内激素注射、加压、激光等,但尚未有一种方法可单独持久有效地抑制或治疗瘢痕增生[3-4]。

R619+.6

A

1673-0364(2015)03-0139-05

10.3969/j.issn.1673-0364.2015.03.006

2015年3月20日;

2015年4月28日)

200011上海市上海交通大学医学院附属第九人民医院整复外科。

曹卫刚(E-mail:wgcao@sina.com)。

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