CTGF对人Tenon's囊成纤维细胞（HTCF）的致纤维化作用及相关MicroRNA的研究
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摘要
滤过道瘢痕化是导致滤过性手术——这一治疗青光眼的主流术式——失败的最主要原因。术后联合使用抗代谢药物,如丝裂霉素(mitomycin, MMC)等,虽可减少术后滤过道瘢痕形成,提高手术的成功率。但是可能也导致术后低眼压、滤过泡渗漏等并发症增多,因此需要探索更加安全有效的治疗方法。
人结膜下Tenon's囊成纤维细胞(human tenon's capsule fibroblast, HTCF,HTF)存在于结膜下结缔组织内,手术或损伤后成纤维细胞(fibroblast,FB)表型转化成肌成纤维细胞(myofibroblast, MF),以此启动了瘢痕反应。MF除了可以细胞外基质外,还可发挥其类似于平滑肌细胞的收缩功能,使得局部组织进一步收缩,促进局部愈合。不同的研究证实：HTCF转化为MF,过度合成胶原纤维等细胞外基质成分,是青光眼滤过术后滤过道瘢痕化的关键。
转化生长因子-β(Transforming growth factor-β, TGF-β)是诱导HTCF转化为MF最重要的细胞因子。TGF-β具有多种功能,位于愈合修复调控机制的上游,调控的靶基因众多,对伤口的愈合起关键作用,对其抑制过度会产生术后伤口愈合不良的潜在危险,其有益效应还需保留。因此需要在其下游寻找一个更高效特异的作用点。
结缔组织生长因子(connective growth factor, CTGF)是新近发现的一种富含半胱氨酸的分泌多肽,广泛存在于多种人类组织器官中,有促进细胞有丝分裂和增生、趋化细胞、诱导细胞粘附、促进细胞外基质的合成等功能。它通常被认为是TGF-β的下游协同因子,可以调节TGF-β介导的细胞表型转化和细胞外基质,参与纤维化过程。正常情况下体内的CTGF表达很低或者无表达,但在病理状态下CTGF的过度表达与某些增生性或纤维性疾病的发生密切相关。因此以其为靶点进行治疗相对于TGF-β会更加高效和安全。
此外,我们结合了近年来生命和基因科学中的一大研究进展—对微小RNA(microRNAs, miRNAs)的认识和研究。miRNA对于生物体发育、细胞分化增殖、组织器官形成、肿瘤发生、病原体感染以及炎症反应等生理和病理过程有着影响作用。具体到青光眼术后局部修复和HTCF表型转化领域,目前尚无microRNA相关研究报道。
本课题主要研究CTGF对HTCF的表型转化和增殖、移行、细胞外基质合成等一系列生物学效应的影响,在细胞水平探索其作用机制及可能的信号转导通路,并与传统的TGF-β模型进行了对比；又在miRNA水平探讨了可能参与的相关miRNA。这方面的实验研究将为抑制青光眼滤过术后滤过道瘢痕化提供理论依据,寻找可能的治疗靶点有着重要的开拓意义。
目的：研究CTGF对人Tenon's囊成纤维细胞(human subconjunctival Tenon's capsule fibroblast, HTCF)的致纤维化作用,主要探讨其对表型转化及增殖、移行、细胞外基质合成等生物学特性和功能的影响,并初步探究其信号传导通路。探讨该表型转化过程中MicroRNA的参与和调控作用。
方法：第一部分：白内障手术中取人结膜下Tenon囊组织,以贴块法培养成纤维细胞。取用第5-10代细胞,以不同浓度的CTGF(1,10,25,50,75,100ug/L)诱导作用HTCF不同的时间,采用Western Blot和免疫细胞化学技术来检测平滑肌肌动蛋白(a-SM-actin)的蛋白表达,以实时定量PCR检测其基因表达,来鉴定其表型转化,并在此基础上选取时间点观察该过程中ERK通路的活化情况。MTT法检测不同浓度的CTGF对HTCF增殖的影响。Transwell法研究其对HTCF移行的影响。以50μ g/L的CTGF作用于HTCF观察其对Col Ⅰ(Ⅰ型胶原蛋白)和FN(纤维连结蛋白)的影响。
第二部分：组织贴块法培养HTCF并传代至5代后,将细胞分为未诱导组(空白对照组),TGF-β1组(予10μg/L TGF-p1,诱导48h)和CTGF组(予50μg/LCTGF,诱导48h)共三组,抽提样品RNA后与MicroRNA芯片杂交,扫描荧光信号后记录结果并行统计分析。再以实时定量PCR法检测三组中mir-145和mir-194的表达。
结果：Western Blot和免疫荧光法均证实了CTGF对于HTCF的表型转化具有诱导作用。且该作用在浓度和时间上存在双向依赖性,其促进表型转化的最适作用浓度为50μ g/L,最适作用时间为48小时,但仍弱于10μg/L TGF-β1的该作用(P<0.05)。ERK通路参与了该过程并在1h后迅速达高峰。一定浓度范围内的CTGF对于HTCF有促增殖和促移行作用(P<0.05),可促进细胞外基质的合成(P<0.05),且该作用强于10μ g/L TGF-β1(P<0.05)。两表型转化模型和未诱导组间有多种MicroRNA的表达存在差异。总体上两诱导组和未诱导组之间的差异较大(R1-2=0.9129,R1-3=0.8579)；两诱导组之间的差异较小(R2-3=0.985),且经分层聚类分析可被归为一类。实时定量PCR结果显示,两诱导组中mir-145和mir-194的表达均低于未诱导组,差异均有统计学意义(P<0.05)。
结论：CTGF可以诱导HTCF的表型转化为MF,对于其增殖、移行和细胞外基质合成也有促进作用,提示其可成为比TGF-β1更有效而安全的抑制位点。多种MicroRNA可能参与了HTCF的表型转化,其中mir-145和mir-194的表达显著降低,具有一定提示意义。
Filtering surgery is a commonly performed surgical procedure in treating Glaucoma when medications fail to control intraocular pressure (IOP). Non-functioning filtering bleb and excessive scar formation account for the main cause of surgery failure in most cases, as is revealed by pathological findings. Former studies also suggest that, this postoperative process of scar formation is a pathological consequence of tissue remodeling, consisting of the complex interactions between cells, various kinds of cytokines and extracellular matrix (ECM), and implicating the homeostasis of ECM deposition and degradation.
As a response to injury, fibroblasts may transform into another contractile and secretory phenotype, the myofibroblasts (MFs), which behaves like an intermediate form between fibroblast and smooth muscle cell. The pivotal role that MF plays in wound healing and pathological remodeling is well established and amply demonstrated in various organs, with its significant function in ECM synthesis and organization as well as cytokine secretory. It can be identified by the expression of a-smooth muscle actin (a-SMA), which is subsequently organized into stress fibers and furthermore participates in local wound contraction in situ. Among all the various cytokines involved, transforming growth factor β (TGF-β) exerts a critical role in phenotype transition, as is evidenced by numerous publications. It stimulates fibroblast proliferation, extracellular matrix synthesis, and decreases extracellular matrix degradation.
Since TGF-β is an upstream and initial factor with a broad spectrum of biotic effects, the notion gained more attention that blocking TGF-β stimuli at the ligand or receptor level may potentially impair some of its beneficial effect such as epithelial healing, and may result in various adverse consequences. Therefore the emerging trend to seek downstream factors involved in the phenotype conversion introduces connective tissue growth factor (CTGF) into current vision field of study. CTGF (also known as CCN2with regard to the CCN protein family) is a cysteine-rich, heparin binding protein. Multiple studies have suggested that CTGF is a critical downstream mediator of TGF-β activity in fibroblasts, involved to mediate key cellular events of fibroblast subsequently in response to TGF-β-induced proliferation, migration, differentiation, contraction, along with extracellular matrix production and accumulation, which are all essential elements of a fibrotic response.Another important issue on its character is that CTGF is largely absent in normal tissues but highly expressed in scars or lesions with fibrotic disease, qualifying it more feasible and effective as a potential therapy target than TGF-β.
With this background, we undertook the following study to investigate the effect of CTGF on the proliferation, myofibroblast differentiation, migration and ECM synthesis of HTCF, while comparing with that of TGF-β respectively, aiming to generate new insights into the postoperative scar formation in filtering surgery.Also introduced in our study was the emerging technology of miRNAs as the participation of them were also investigated.
Purpose:To investigate the effect of CTGF on the phenotype-transition, proliferation, migration and ECM synthesis of HTCF, while comparing with those of TGF-β respectively, aiming to generate new insights into the postoperative scar formation in filtering surgery. The participation of miRNAs was also observed.
Methods:HTCF were obtained from patients with cataract during surgery. They were induced by different concerntration of CTGF for different durations. Western Blot as well as Immunofluorescence were used to observe the expression of Alpha smooth muscle actin (α-SM-actin a marker of myofibroblast) protein and certify the existence of phenotype transition, while Real-time-PCR was used quantify the expression lever of mRNAs.ERK pathway was observed as a possible signal transductive way. MTT was performed to observe the effect of CTGF on the proliferation of HTCF and transwell tests arranged for its migration.Col Ⅰ and FN were recruited as bio-markers of fibrosis in which their expression of both proteins and mRNA were tested after induction of CTGF and TGF-β.Two ways of induction were compared with all the above as well as their difference in the expression of various miRNAs
Results:CTGF was capable and sufficient for the phenotype transition of HTCF with the most propriet concerntration at50μ g/L at the peak time of48hours,while still lower than that of TGF-β1(β<0.05)。Immunofluorescence and real-time-PCR also confirmed this process.Erk pathway participated this process activated at the peak time of1h.CTGF could promote the proliferation, migration of HTCF with no obvious difference with TGF-β. Raised Col Ⅰ and FN levels on both protein and mRNAs implied stronge effect of ECM synthesis for CTGF compared to TGF-β (P<0.05).Many miRNAs participated in the process as showed by chip-tese and certified by Real Time PCR. Levels of mir-145and mir-194was reduced in phenotype-induced groups (P<0.05)
Conclusions:CTGF could induce the phenotype transition of HTCF and promotes its migration, proliferation and matrix synthesis, implying itself as a more safer and efficient target for suppression therapy. Many miRNAs participated in the process and levels of mir-145and mir-194was reduced.
人结膜下Tenon's囊成纤维细胞(human tenon's capsule fibroblast, HTCF,HTF)存在于结膜下结缔组织内,手术或损伤后成纤维细胞(fibroblast,FB)表型转化成肌成纤维细胞(myofibroblast, MF),以此启动了瘢痕反应。MF除了可以细胞外基质外,还可发挥其类似于平滑肌细胞的收缩功能,使得局部组织进一步收缩,促进局部愈合。不同的研究证实：HTCF转化为MF,过度合成胶原纤维等细胞外基质成分,是青光眼滤过术后滤过道瘢痕化的关键。
转化生长因子-β(Transforming growth factor-β, TGF-β)是诱导HTCF转化为MF最重要的细胞因子。TGF-β具有多种功能,位于愈合修复调控机制的上游,调控的靶基因众多,对伤口的愈合起关键作用,对其抑制过度会产生术后伤口愈合不良的潜在危险,其有益效应还需保留。因此需要在其下游寻找一个更高效特异的作用点。
结缔组织生长因子(connective growth factor, CTGF)是新近发现的一种富含半胱氨酸的分泌多肽,广泛存在于多种人类组织器官中,有促进细胞有丝分裂和增生、趋化细胞、诱导细胞粘附、促进细胞外基质的合成等功能。它通常被认为是TGF-β的下游协同因子,可以调节TGF-β介导的细胞表型转化和细胞外基质,参与纤维化过程。正常情况下体内的CTGF表达很低或者无表达,但在病理状态下CTGF的过度表达与某些增生性或纤维性疾病的发生密切相关。因此以其为靶点进行治疗相对于TGF-β会更加高效和安全。
此外,我们结合了近年来生命和基因科学中的一大研究进展—对微小RNA(microRNAs, miRNAs)的认识和研究。miRNA对于生物体发育、细胞分化增殖、组织器官形成、肿瘤发生、病原体感染以及炎症反应等生理和病理过程有着影响作用。具体到青光眼术后局部修复和HTCF表型转化领域,目前尚无microRNA相关研究报道。
本课题主要研究CTGF对HTCF的表型转化和增殖、移行、细胞外基质合成等一系列生物学效应的影响,在细胞水平探索其作用机制及可能的信号转导通路,并与传统的TGF-β模型进行了对比；又在miRNA水平探讨了可能参与的相关miRNA。这方面的实验研究将为抑制青光眼滤过术后滤过道瘢痕化提供理论依据,寻找可能的治疗靶点有着重要的开拓意义。
目的：研究CTGF对人Tenon's囊成纤维细胞(human subconjunctival Tenon's capsule fibroblast, HTCF)的致纤维化作用,主要探讨其对表型转化及增殖、移行、细胞外基质合成等生物学特性和功能的影响,并初步探究其信号传导通路。探讨该表型转化过程中MicroRNA的参与和调控作用。
方法：第一部分：白内障手术中取人结膜下Tenon囊组织,以贴块法培养成纤维细胞。取用第5-10代细胞,以不同浓度的CTGF(1,10,25,50,75,100ug/L)诱导作用HTCF不同的时间,采用Western Blot和免疫细胞化学技术来检测平滑肌肌动蛋白(a-SM-actin)的蛋白表达,以实时定量PCR检测其基因表达,来鉴定其表型转化,并在此基础上选取时间点观察该过程中ERK通路的活化情况。MTT法检测不同浓度的CTGF对HTCF增殖的影响。Transwell法研究其对HTCF移行的影响。以50μ g/L的CTGF作用于HTCF观察其对Col Ⅰ(Ⅰ型胶原蛋白)和FN(纤维连结蛋白)的影响。
第二部分：组织贴块法培养HTCF并传代至5代后,将细胞分为未诱导组(空白对照组),TGF-β1组(予10μg/L TGF-p1,诱导48h)和CTGF组(予50μg/LCTGF,诱导48h)共三组,抽提样品RNA后与MicroRNA芯片杂交,扫描荧光信号后记录结果并行统计分析。再以实时定量PCR法检测三组中mir-145和mir-194的表达。
结果：Western Blot和免疫荧光法均证实了CTGF对于HTCF的表型转化具有诱导作用。且该作用在浓度和时间上存在双向依赖性,其促进表型转化的最适作用浓度为50μ g/L,最适作用时间为48小时,但仍弱于10μg/L TGF-β1的该作用(P<0.05)。ERK通路参与了该过程并在1h后迅速达高峰。一定浓度范围内的CTGF对于HTCF有促增殖和促移行作用(P<0.05),可促进细胞外基质的合成(P<0.05),且该作用强于10μ g/L TGF-β1(P<0.05)。两表型转化模型和未诱导组间有多种MicroRNA的表达存在差异。总体上两诱导组和未诱导组之间的差异较大(R1-2=0.9129,R1-3=0.8579)；两诱导组之间的差异较小(R2-3=0.985),且经分层聚类分析可被归为一类。实时定量PCR结果显示,两诱导组中mir-145和mir-194的表达均低于未诱导组,差异均有统计学意义(P<0.05)。
结论：CTGF可以诱导HTCF的表型转化为MF,对于其增殖、移行和细胞外基质合成也有促进作用,提示其可成为比TGF-β1更有效而安全的抑制位点。多种MicroRNA可能参与了HTCF的表型转化,其中mir-145和mir-194的表达显著降低,具有一定提示意义。
Filtering surgery is a commonly performed surgical procedure in treating Glaucoma when medications fail to control intraocular pressure (IOP). Non-functioning filtering bleb and excessive scar formation account for the main cause of surgery failure in most cases, as is revealed by pathological findings. Former studies also suggest that, this postoperative process of scar formation is a pathological consequence of tissue remodeling, consisting of the complex interactions between cells, various kinds of cytokines and extracellular matrix (ECM), and implicating the homeostasis of ECM deposition and degradation.
As a response to injury, fibroblasts may transform into another contractile and secretory phenotype, the myofibroblasts (MFs), which behaves like an intermediate form between fibroblast and smooth muscle cell. The pivotal role that MF plays in wound healing and pathological remodeling is well established and amply demonstrated in various organs, with its significant function in ECM synthesis and organization as well as cytokine secretory. It can be identified by the expression of a-smooth muscle actin (a-SMA), which is subsequently organized into stress fibers and furthermore participates in local wound contraction in situ. Among all the various cytokines involved, transforming growth factor β (TGF-β) exerts a critical role in phenotype transition, as is evidenced by numerous publications. It stimulates fibroblast proliferation, extracellular matrix synthesis, and decreases extracellular matrix degradation.
Since TGF-β is an upstream and initial factor with a broad spectrum of biotic effects, the notion gained more attention that blocking TGF-β stimuli at the ligand or receptor level may potentially impair some of its beneficial effect such as epithelial healing, and may result in various adverse consequences. Therefore the emerging trend to seek downstream factors involved in the phenotype conversion introduces connective tissue growth factor (CTGF) into current vision field of study. CTGF (also known as CCN2with regard to the CCN protein family) is a cysteine-rich, heparin binding protein. Multiple studies have suggested that CTGF is a critical downstream mediator of TGF-β activity in fibroblasts, involved to mediate key cellular events of fibroblast subsequently in response to TGF-β-induced proliferation, migration, differentiation, contraction, along with extracellular matrix production and accumulation, which are all essential elements of a fibrotic response.Another important issue on its character is that CTGF is largely absent in normal tissues but highly expressed in scars or lesions with fibrotic disease, qualifying it more feasible and effective as a potential therapy target than TGF-β.
With this background, we undertook the following study to investigate the effect of CTGF on the proliferation, myofibroblast differentiation, migration and ECM synthesis of HTCF, while comparing with that of TGF-β respectively, aiming to generate new insights into the postoperative scar formation in filtering surgery.Also introduced in our study was the emerging technology of miRNAs as the participation of them were also investigated.
Purpose:To investigate the effect of CTGF on the phenotype-transition, proliferation, migration and ECM synthesis of HTCF, while comparing with those of TGF-β respectively, aiming to generate new insights into the postoperative scar formation in filtering surgery. The participation of miRNAs was also observed.
Methods:HTCF were obtained from patients with cataract during surgery. They were induced by different concerntration of CTGF for different durations. Western Blot as well as Immunofluorescence were used to observe the expression of Alpha smooth muscle actin (α-SM-actin a marker of myofibroblast) protein and certify the existence of phenotype transition, while Real-time-PCR was used quantify the expression lever of mRNAs.ERK pathway was observed as a possible signal transductive way. MTT was performed to observe the effect of CTGF on the proliferation of HTCF and transwell tests arranged for its migration.Col Ⅰ and FN were recruited as bio-markers of fibrosis in which their expression of both proteins and mRNA were tested after induction of CTGF and TGF-β.Two ways of induction were compared with all the above as well as their difference in the expression of various miRNAs
Results:CTGF was capable and sufficient for the phenotype transition of HTCF with the most propriet concerntration at50μ g/L at the peak time of48hours,while still lower than that of TGF-β1(β<0.05)。Immunofluorescence and real-time-PCR also confirmed this process.Erk pathway participated this process activated at the peak time of1h.CTGF could promote the proliferation, migration of HTCF with no obvious difference with TGF-β. Raised Col Ⅰ and FN levels on both protein and mRNAs implied stronge effect of ECM synthesis for CTGF compared to TGF-β (P<0.05).Many miRNAs participated in the process as showed by chip-tese and certified by Real Time PCR. Levels of mir-145and mir-194was reduced in phenotype-induced groups (P<0.05)
Conclusions:CTGF could induce the phenotype transition of HTCF and promotes its migration, proliferation and matrix synthesis, implying itself as a more safer and efficient target for suppression therapy. Many miRNAs participated in the process and levels of mir-145and mir-194was reduced.
引文
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