Smac调节增生性瘢痕成纤维细胞的凋亡
摘要
增生性瘢痕的是一种常见伤口愈合的异常反应，皮损表现为局限于原损伤边界内的隆起性红色斑块，常伴有痒痛，镜下可见成纤维细胞过度增殖和胶原排列紊乱。增生性瘢痕的具体发病机理至今不明，研究认为其可能和炎症反应过度、细胞过度增殖、凋亡减低、表皮再生延迟及新生血管形成增强等多种因素相关。目前，对增生性瘢痕的各种治疗方法，比如外科手术切除、各种药物治疗和激光冷冻等物理疗法，治疗结果都不是很理想，而干细胞及基因疗法等高技术新型治疗手段，目前尚处在实验室研究阶段，疗效还不确定。我单位先前发现了一些促进细胞凋亡和抑制细胞增殖的因子，如第10号染色体缺失的磷酸酶及张力蛋白同源的基因(PTEN)、分泌型卷曲相关蛋白2(SFRP2)、三羟基异黄酮等，能调节增生性瘢痕成纤维细胞增殖、胶原分泌等生物活性，从而影响增生性瘢痕的形成和治疗。
第二个线粒体来源的半胱氨酸蛋白酶激动剂/低等电点的凋亡抑制蛋白直接结合蛋白(Smac/DIABLO)及其类似物能够与凋亡抑制蛋白竞争性结合，促进半胱氨酸蛋白酶从凋亡抑制蛋白分离后剪切激活，Smac/DIABLO又可促进c-IAPl和c-IAP2泛素化降解，从而发挥促进凋亡作用。Smac/DIABLO在许多肿瘤和增生性疾病中的表达常常比在正常组织中的低，提高Smac/DIABLO或其类似物的表达可以促进肿瘤和增生性细胞的凋亡，降低肿瘤和增生性疾病对放化疗的抵抗性，并能增强其他相关治疗手段的促凋亡效应。目前暂未发现Smac/DIABLO在增生性瘢痕组织表达以及其表达变化之后对增生性瘢痕成纤维细胞生物学指标影响的报道。
本研究通过免疫组织化学法、Western blot和Real-time PCR法研究发现Smac/DIABLO蛋白或其mRNA在增生性瘢痕组织成纤维细胞中的表达要低于在正常皮肤成纤维细胞中表达，这和文献报道的增生性疾病中的Smac/DIABLO表达趋势相一致。我们通过构建腺病毒过表达Smac载体和Smac siRNA来转染成纤维细胞以研究Smac/DIABLO表达变化对成纤维细胞生物学功能的影响，发现转染腺病毒过表达Smac载体后，流式细胞学检测发现增生性瘢痕成纤维细胞的凋亡显著升高，CCK8检测发现细胞增殖率显著降低，比色法发现增生性瘢痕成纤维细胞中半胱氨酸蛋白酶3(Caspase3)和半胱氨酸蛋白酶9(Caspase9)的活性显著增加，Real-time PCR检测提示Ⅰ型前胶原和Ⅲ型前胶原的mRNA合成受到抑制，流式细胞学检测发现细胞周期无明显变化；而在转染Smac siRNA后，增生性瘢痕成纤维细胞出现相反的结果。在正常皮肤成纤维细胞的研究中发现，Smac/DIABLO表达增高会导致细胞增殖的抑制，Ⅰ型前胶原和Ⅲ型前胶原的mRNA合成也下调，而Smac siRNA会提高细胞增殖和Ⅰ型前胶原及Ⅲ型前胶原的mRNA水平。
总之，Smac能促进增生性瘢痕成纤维细胞的凋亡、抑制其增殖及前胶原的合成，是创面愈合和增生性瘢痕防治的新的潜在靶点。
Formation of hypertrophic scars (HS) is an ordinary abnormal reaction to woundhealing which generally occurs following surgery, trauma and especially burns. HS areclinically described as raised, pruritic and erythematous fibrous lesions confined within theboundary of the primary trauma. At present, little is known about the incidence and riskfactors for HS. But they are histologically characterized as hypernomic fibroblastshypercellularity, an excessus of extracellular and an inordinate collagen matrix remodelingin the scar tissue. Although the exact mechanism of hypertrophic scars remains unclear,excessive inflammtory reaction, increase of hypertrophic scar fibroblasts proliferation,delayed epidermis regeneration and neovascularization were considered correlated with theformation of HS. Many treatments of HS, such as chirurgic excision, drug treatment andphysical therapy are often incompletely successful and easily recur. The stem cell therapyand the gene therapy of HS have not been mature enough for their application in clinic yet.Our department have found some factors which could alter the cells apoptosis andproliferation, such as phosphatase and tensin homolog deleted on chromosome ten (PTEN),human secreted frizzled-related protein2(SFRP2) and genistein, regulating thehypertrophic scar fibroblasts (HSFBs) biological activity. These factors could suppress thecollagen secreting from HSFBs and might be useful to treat the HS.
The second mitochondria derived activator of caspase/direct IAP binding protein withlow PI (Smac/DIABLO) and it's mimetics promote apoptosis through their abilities toinhibit inhibitors of apoptosis (IAPs), by direct inhibition and/or proteasomal degenerationof some members of the IAPs, and therefore cleave and disinhibit cysteine-aspartic acidprotease (caspase), and while promoting c-IAPl and c-IAP2ubiquitination and degradation.The expression of Smac/DIABLO is down-regulated in many neoplasma or proliferateddiseases as compared to the abnormal tissue. The over-expression of Smac/DIABLO or itsmimetics could promote the cell's apoptosis of neoplasma or proliferative diseases. Smacplays an important role in treating the tumor cells that resist to chemotherapy andradiotherapy. It can reduce the tumor cells' resistance and significantly enhance the pro-apoptotic effects of chemotherapy and radiotherapy. Interestingly, little is known aboutthe role in HS of the Smac/DIABLO protein which is able regulates the caspase inhibitionof IAPs.
We assessed the expression of Smac/DIABLO protein or mRNA in HS tissues andHSFBs through the immunochemical and Western blot, Real-time PCR. Then we observeda significant downregulation of Smac/DIABLO expression in HS or HSFBs than normalskin tissues or normal skin tissue fibroblasts. The results are consistent with previousstudies in various proliferative diseases. In order to demonstrate the effects of theSmac/DIABLO to skin fibroblasts, we over-expressed the Smac/DIABLO by adenoviruscarrying the Smac/DIABLO gene (AD-Smac) and silenced the Smac/DIABLO by SmacsiRNA in normal fibroblasts and HSFBs. The Smac/DIABLO over-expression significantlyincreased apoptosis rate of HSFBs detected using fluorescence-activated cell sorting (FACS)and down-regulated HSFBs proliferation detected by Cell Counting Kit (CCK8), andelevated caspase3and9activity detected by spectrofluorimetry. In addition, mRNAexpressions of type I and type III procollagen detected in hypertrophic scar fibroblastscould be significantly inhibited by Smac/DIABLO over-expression using Real-time PCR.Significant changing hasn't been found in the cell cycle after transfected with AD-Smacdetected using FACS. Remarkably, the transfection of normal fibroblasts and HSFBs withSmac siRNA leaded to the opposite result, with a significant reduction of apoptosis and arestoration of the proliferation rate, induced a noticeable depression of caspase3and9activities, leading to significant decreases in apoptosis. The mRNA expression of type I andIII procollagen could be significantly increased by the silencing of Smac with siRNA.
In summary, Smac/DIABLO can impair proliferation and promote apoptosis ofhypertrophic scar fibroblasts, and will be a novel therapeutic target for hypertrophic scarsand wound healing.
第二个线粒体来源的半胱氨酸蛋白酶激动剂/低等电点的凋亡抑制蛋白直接结合蛋白(Smac/DIABLO)及其类似物能够与凋亡抑制蛋白竞争性结合，促进半胱氨酸蛋白酶从凋亡抑制蛋白分离后剪切激活，Smac/DIABLO又可促进c-IAPl和c-IAP2泛素化降解，从而发挥促进凋亡作用。Smac/DIABLO在许多肿瘤和增生性疾病中的表达常常比在正常组织中的低，提高Smac/DIABLO或其类似物的表达可以促进肿瘤和增生性细胞的凋亡，降低肿瘤和增生性疾病对放化疗的抵抗性，并能增强其他相关治疗手段的促凋亡效应。目前暂未发现Smac/DIABLO在增生性瘢痕组织表达以及其表达变化之后对增生性瘢痕成纤维细胞生物学指标影响的报道。
本研究通过免疫组织化学法、Western blot和Real-time PCR法研究发现Smac/DIABLO蛋白或其mRNA在增生性瘢痕组织成纤维细胞中的表达要低于在正常皮肤成纤维细胞中表达，这和文献报道的增生性疾病中的Smac/DIABLO表达趋势相一致。我们通过构建腺病毒过表达Smac载体和Smac siRNA来转染成纤维细胞以研究Smac/DIABLO表达变化对成纤维细胞生物学功能的影响，发现转染腺病毒过表达Smac载体后，流式细胞学检测发现增生性瘢痕成纤维细胞的凋亡显著升高，CCK8检测发现细胞增殖率显著降低，比色法发现增生性瘢痕成纤维细胞中半胱氨酸蛋白酶3(Caspase3)和半胱氨酸蛋白酶9(Caspase9)的活性显著增加，Real-time PCR检测提示Ⅰ型前胶原和Ⅲ型前胶原的mRNA合成受到抑制，流式细胞学检测发现细胞周期无明显变化；而在转染Smac siRNA后，增生性瘢痕成纤维细胞出现相反的结果。在正常皮肤成纤维细胞的研究中发现，Smac/DIABLO表达增高会导致细胞增殖的抑制，Ⅰ型前胶原和Ⅲ型前胶原的mRNA合成也下调，而Smac siRNA会提高细胞增殖和Ⅰ型前胶原及Ⅲ型前胶原的mRNA水平。
总之，Smac能促进增生性瘢痕成纤维细胞的凋亡、抑制其增殖及前胶原的合成，是创面愈合和增生性瘢痕防治的新的潜在靶点。
Formation of hypertrophic scars (HS) is an ordinary abnormal reaction to woundhealing which generally occurs following surgery, trauma and especially burns. HS areclinically described as raised, pruritic and erythematous fibrous lesions confined within theboundary of the primary trauma. At present, little is known about the incidence and riskfactors for HS. But they are histologically characterized as hypernomic fibroblastshypercellularity, an excessus of extracellular and an inordinate collagen matrix remodelingin the scar tissue. Although the exact mechanism of hypertrophic scars remains unclear,excessive inflammtory reaction, increase of hypertrophic scar fibroblasts proliferation,delayed epidermis regeneration and neovascularization were considered correlated with theformation of HS. Many treatments of HS, such as chirurgic excision, drug treatment andphysical therapy are often incompletely successful and easily recur. The stem cell therapyand the gene therapy of HS have not been mature enough for their application in clinic yet.Our department have found some factors which could alter the cells apoptosis andproliferation, such as phosphatase and tensin homolog deleted on chromosome ten (PTEN),human secreted frizzled-related protein2(SFRP2) and genistein, regulating thehypertrophic scar fibroblasts (HSFBs) biological activity. These factors could suppress thecollagen secreting from HSFBs and might be useful to treat the HS.
The second mitochondria derived activator of caspase/direct IAP binding protein withlow PI (Smac/DIABLO) and it's mimetics promote apoptosis through their abilities toinhibit inhibitors of apoptosis (IAPs), by direct inhibition and/or proteasomal degenerationof some members of the IAPs, and therefore cleave and disinhibit cysteine-aspartic acidprotease (caspase), and while promoting c-IAPl and c-IAP2ubiquitination and degradation.The expression of Smac/DIABLO is down-regulated in many neoplasma or proliferateddiseases as compared to the abnormal tissue. The over-expression of Smac/DIABLO or itsmimetics could promote the cell's apoptosis of neoplasma or proliferative diseases. Smacplays an important role in treating the tumor cells that resist to chemotherapy andradiotherapy. It can reduce the tumor cells' resistance and significantly enhance the pro-apoptotic effects of chemotherapy and radiotherapy. Interestingly, little is known aboutthe role in HS of the Smac/DIABLO protein which is able regulates the caspase inhibitionof IAPs.
We assessed the expression of Smac/DIABLO protein or mRNA in HS tissues andHSFBs through the immunochemical and Western blot, Real-time PCR. Then we observeda significant downregulation of Smac/DIABLO expression in HS or HSFBs than normalskin tissues or normal skin tissue fibroblasts. The results are consistent with previousstudies in various proliferative diseases. In order to demonstrate the effects of theSmac/DIABLO to skin fibroblasts, we over-expressed the Smac/DIABLO by adenoviruscarrying the Smac/DIABLO gene (AD-Smac) and silenced the Smac/DIABLO by SmacsiRNA in normal fibroblasts and HSFBs. The Smac/DIABLO over-expression significantlyincreased apoptosis rate of HSFBs detected using fluorescence-activated cell sorting (FACS)and down-regulated HSFBs proliferation detected by Cell Counting Kit (CCK8), andelevated caspase3and9activity detected by spectrofluorimetry. In addition, mRNAexpressions of type I and type III procollagen detected in hypertrophic scar fibroblastscould be significantly inhibited by Smac/DIABLO over-expression using Real-time PCR.Significant changing hasn't been found in the cell cycle after transfected with AD-Smacdetected using FACS. Remarkably, the transfection of normal fibroblasts and HSFBs withSmac siRNA leaded to the opposite result, with a significant reduction of apoptosis and arestoration of the proliferation rate, induced a noticeable depression of caspase3and9activities, leading to significant decreases in apoptosis. The mRNA expression of type I andIII procollagen could be significantly increased by the silencing of Smac with siRNA.
In summary, Smac/DIABLO can impair proliferation and promote apoptosis ofhypertrophic scar fibroblasts, and will be a novel therapeutic target for hypertrophic scarsand wound healing.
引文
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