PGC-1α基因修饰的脂肪干细胞在糖尿病微环境中耐凋亡作用研究
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摘要
研究背景：
糖尿病是一组以慢性血糖水平增高为特征的代谢性疾病，长期的高血糖症常导致的一系列血管和神经并发症，具有患病率高、危害大、常规治疗难、花费大的特点，迫切需要更加有效的治疗手段。近年来兴起的干细胞移植技术为糖尿病及其并发症的治疗带来了新的希望。然而，受局部微环境高糖、缺氧、营养缺乏等因素的影响，移植的干细胞常常大量凋亡或坏死，而少量残留干细胞不能持续分泌足够的促血管生成因子，导致糖尿病血管病变的治疗效果受限。因此，如何提高干细胞的存活率，成为干细胞移植治疗糖尿病及其相关并发症亟待解决的难题。
过氧化物酶体增殖物激活受体γ辅激活因子1α(peroxisome proliferator-activatedreceptor-gamma coactivator1alpha, PGC-1α)是1998年发现的一种调节线粒体功能和能量代谢的关键核转录因子，其通过与多种受体结合，参与线粒体增生、葡萄糖代谢、脂肪酸氧化、细胞分化及血管生成等。与此同时，近年来发现PGC-1α具有抗凋亡的作用。本课题组前期研究发现，PGC-1α能直接或间接通过Bcl/Bax途径和HIF途径，增强骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)抗凋亡和促血管生成潜能，促进糖尿病下肢缺血组织的血管生成。
脂肪干细胞(adipose-derived stem cells, ASCs)是近年来干细胞移植领域研究的热点，与BMSCs相比，具有显著优势。脂肪组织中所含的ASCs比率高，是BMSCs的500多倍，低温冻存对细胞的生长和表型没有影响，具有免疫豁免潜力，获取方法简便，只需简单的抽脂术即可完成，患者较易接受，依从性更好。ASCs被认为是更符合再生医学和组织工程要求的理想干细胞来源。
为此，本研究原代分离培养ASCs，并以ASCs为研究对象，通过检测过表达PGC-1α的ASCs在高糖、缺氧及无血清培养条件下细胞凋亡及活性氧簇物质(reactiveoxygen species, ROS)的产生情况，揭示过表达PGC-1α的ASCs耐凋亡及其机制，为干细胞移植治疗糖尿病及其并发症治疗提供新的靶细胞。
材料与方法
第一部分： Sprague-Dawley(SD)大鼠来源的脂肪干细胞分离培养及鉴定
采用胶原酶消化法从SD大鼠腹股沟皮下脂肪组织分离培养原代ASCs，传至第3代时，进行以下检测：
1.1倒置显微镜观察细胞形态；
1.2流式细胞仪检测细胞表面分子标记：CD90、CD105、CD34、CD45；
1.3多系分化检测：运用SD大鼠ASCs成脂诱导分化试剂盒所提供的特异性培养液对所培养的细胞进行成脂诱导分化后，采用油红O染色检测成脂能力；运用SD大鼠ASCs成骨诱导分化试剂盒所提供的特异性培养液对所培养的细胞进行成骨诱导分化后，采用茜素红染色检测成骨能力；
1.4采用台盼蓝拒染法检测细胞活力。
第二部分：PGC-1α基因修饰的脂肪干细胞在糖尿病微环境中耐凋亡的作用研究
2.1腺病毒扩增及滴度测定
2.1.1培养HEK293细胞用于扩增腺病毒；
2.1.2TCID50(50%组织培养感染剂量)法测定重组腺病毒滴度。
2.2ASCs转染携带绿色荧光蛋白(green fluorescent protein,GFP)和PGC-1α基因的腺病毒载体
2.2.1流式细胞仪检测确立最佳感染系数（multiplicity of infection, MOI）值；
2.2.2WB法检测PGC-1α转染ASCs后蛋白表达水平。
2.3过表达PGC-1α的ASCs在高糖、缺氧及缺乏营养状态下耐凋亡效应
2.3.1Annexin V-APC/7AAD细胞凋亡流式细胞仪检测试剂盒用于检测过表达PGC-1α的ASCs在高糖(30mmol/L)、缺氧(5%O2)、无血清0h、6h及24h状态下细胞凋亡率；
2.3.2在高糖、缺氧、无血清状态下培养GFP-ASC及PGC-1α-ASC24h，ROS荧光探针-DHE标记细胞内ROS，流式细胞仪检测平均荧光强度；
2.3.3Mito Tracker Red CM-H2XRos标记线粒体内ROS，激光共聚焦显微镜下观察线粒体内ROS产生情况；
2.3.4透射电镜下观察细胞超微结构变化。
结果：
第一部分：ASCs分离培养及鉴定
1.1SD大鼠腹股沟脂肪组织来源的多能干细胞可在体外培养并稳定增殖，细胞呈贴壁生长，呈明显的长梭形，细胞体细长，类似于成纤维细胞形态，排列规则，呈鱼群样，具有一定极性；传2-3代后，呈大而扁平的细胞形态。
1.2分离培养ASCs传至第3代，经流式细胞仪检测细胞表面分子标记，结果显示，所培养的细胞CD90、CD105表达率分别为94.26%及95.83%，而CD34、CD45表达率分别仅为0.16%及0.09%。
1.3分离培养的ASCs传至第3代，在成脂诱导分化培养液内能分化成为脂肪细胞，被油红O染成红色；在成骨诱导分化培养液内能分化成为成骨细胞，所形成的矿化结节被茜素红染成红色，而对照组均为阴性。
1.4对所培养的ASCs经台盼蓝拒染法检测细胞活力，结果显示所培养的细胞台盼蓝拒染率为97%，被染成蓝色的死细胞数目极少，活细胞呈无色透明状，不被台盼蓝着色。
第二部分：PGC-1α基因修饰的脂肪干细胞在糖尿病微环境中耐凋亡的作用研究
2.1腺病毒扩增及滴度测定
2.1.1HEK293细胞扩增腺病毒，Ad-PGC-1α感染HEK293细胞后24h，在荧光显微镜下观察可见约95%的细胞有GFP表达，感染48-72h细胞出现明显的细胞病变效应(cytopathic effect, CPE)，感染96h可见部分细胞呈葡萄串珠样浮起，收获病毒。
2.1.2TCID50法测定重组腺病毒滴度，经计算Ad-PGC-1α-GFP的滴度为2.0×108PFU/ml，Ad-GFP的滴度为2.5×108PFU/ml。
2.2．重组腺病毒转染ASCs
2.2.1最佳MOI值的确定：Ad-PGC-1α及Ad-GFP转染ASCs最佳MOI值为200，转染效率分别为95.3%及95.5%。
2.2.2重组腺病毒转染ASCs48h后，经WB法检测PGC-1α蛋白表达，结果显示PGC-1α-ASC组的表达量是GFP-ASC组的2.8倍(P<0.01)。
2.3过表达PGC-1α的ASCs在高糖、缺氧及缺乏营养状态下耐凋亡效应
2.3.1经Annexin V-APC/7AAD法检测细胞在高糖、缺氧、无血清状态下凋亡率，结果显示：在高糖、缺氧及缺营养条件下培养ASC、GFP-ASC及PGC-1α-ASC24h，ASC组细胞凋亡率为(21.01±3.03%)，GFP-ASCs组为(21.04±2.79%)，显著高于PGC-1α-ASC组(14.73±1.57%)(P<0.01)；在高糖、缺氧及缺营养条件下培养ASC、GFP-ASC及PGC-1α-ASC组6h及24h，PGC-1α-ASC组细胞存活率显著高于ASC组及GFP-ASCs组(P<0.01)，而ASC组与GFP-ASC组比较，无统计学意义(P>0.05)。
2.3.2经ROS荧光探针-DHE标记细胞内ROS，流式细胞仪检测结果表明：GFP-ASC组平均荧光强度为(853.44±76.72)显著高于PGC-1α-ASC组(688.67±43.98)(P<0.01)。
2.3.3经Mito Tracker Red CM-H2XRos检测线粒体内ROS产生，激光共聚焦显微镜下可见PGC-1α-ASC组红色荧光强度明显低于GFP-ASC组。
2.3.4透射电镜观察细胞内超微结构，可见GFP-ASC组细胞内线粒体形态结构异常，线粒体自噬严重，见细胞凋亡，而PGC-1α-ASC组细胞上述病变明显减轻。
结论：
从SD大鼠腹股沟皮下脂肪组织通过胶原酶消化法，可获取高存活率、稳定增殖、符合目前国内及国际鉴定标准的ASCs，为ASCs治疗糖尿病及相关并发症奠定了基础；通过重组腺病毒表达Ad-PGC-1α-GFP特异性上调ASCs中PGC-1α的表达，在高糖、缺氧及营养缺乏条件下，可能通过线粒体途径，抑制ASCs细胞及线粒体内ROS的产生发挥耐凋亡作用。表明，PGC-1α有可能成为糖尿病及其并发症的干细胞治疗关键的作用靶点，转染PGC-1α的ASCs可作为糖尿病及其并发症的干细胞治疗的靶细胞。
Background:
Diabetes mellitus is a group of metabolic disease characterized by chronichyperglycaemia associated with a series of vascular and neural complications, which hassome features with high morbidity, large hazard, hard conventional therapy and expensivecost. The more effective therapeutic options are need badly to develop; stem cell therapyprovides new hope for diabetes and its complications in recent years. However, effect ofhyperglycaemia and deprivation of nutrient and oxygen in the diabetic regionmicroenvironment, the apoptosis or necrosis of a large number of transplanted stem cells isa critical issue that limits the therapeutic efficacy of stem cells. Therefore, how to increasethe survival rates of the stem cells and enchance angiogenesis potential has been an urgentresolved problem in the treatment of the diabetes and its complications.
Peroxisome proliferator-activated receptor-gamma coactivator1alpha (PGC-1α) beinga key transcriptional coactivator involved in the regulation of mitochondrial function andenergy metabolism was found in1998, which binds with many receptors and plays animportant role in mitochondrial biogenesis, glucose metabolism, fatty acid oxidation, celldifferentiation and angiogenesis. In the meantime, many studies have shown that PGC-1αinvolves in anti-apoptosis in recent years. Our recent study suggested that PGC-1α plays animportant role in anti-apoptosis and mediated angiogenesis in mesenchymal stem cells indiabetic hindlimb ischaemia by inducing an increase in hypoxia inducible factor-1α(Hif-1α), a higher ratio of B-celllymphoma/leukaemia-2(Bcl-2)/Bcl-2-associated X protein(Bax) in bone marrow derived mesenchymal stem cells (BMSCs).
Recently, adipose-derived stem cells (ASCs) have become the focus of attention in thefield of stem cells transplantation because of their ease of isolation, relative abundance, andrapidity of growth. Compared with BMSCs, the rate of stem cells derived from of fat tissueis higher than that of bone marrow. There is no influence of cryopreservation on cell growthand phenotype. ASCs have the potential of immune privilege. The method of harvest ASCs is simple and safe, which can be performed by liposuction. Emerging evidence suggests thatASCs will be an ideal source of stem cells in regenerative medicine and tissue engineering.
Therefore, in this study, ASCs were isolated and cultured, whether the overexpressionof PGC-1α protects ASCs from apoptosis by reducing ROS production and ameliorating themitochondrial damage induced by a diabetic environment were examined, which maycontribute to the development of new approaches and provide target cells for preventingcomplications from diabetes.
Materials and methods：
1. Isolation, culture and identification of Sprague-Dawley (SD) rat ASCs
ASCs were isolated and cultured with the method of collagenase digestion; cells wereexamined as follow after three passages.
1.1The cell morphology was observed by inverted microscope.
1.2The cell surface antigens CD90-FITC, CD105-FITC, CD34-PE and CD45-PE weredetected by flow cytometry.
1.3Multilineage differentiation were accomplished using a special kit to determinewhether the culture cells were capable of adipogenic differentiation and osteogenicdifferentiation by oil red O staining and staining calcium deposits with alizarin red.
1.4Trypan blue exclusion test was used to determine viability of cells.
2. Overexpression of PGC-1α in ASCs using adenoviral vector encoding PGC-1α andGFP (Ad-GFP-PGC-1α or PGC-1α-ASC).
2.1Adenovirus amplification and examination of the titer of the adenovirus.
2.1.1HEK293cells were used to amplify the adenovirus.
2.1.2The virus titer was determined by tissue culture infectious dose50(TCID50)assay.
2.2ASCs transfection of adenovirus-mediated gene.
2.2.1Multiplicity of infection (MOI) with high efficiency and low toxicity wasdetected by flow cytometry, and the ideal MOI was selected for the following experiments.
2.2.2Western blotting (WB) was used to examine the protein levels of PGC-1α.
2.3Resistant-apoptosis effect of ASCs with overexpression of PGC-1α under highglucose, hypoxia and serum deprivation conditions.
2.3.1After being infected for48h, the apoptosis of ASCs modified with PGC-1α orGFP was induced by culture conditions of high glucose concentration (30mmol/L), hypoxia (5%O2) and serum deprivation. At0h,6h and24h after culture, the survival ratesof ASCs were measured using an Annexin V-APC/7-Amino-Actinomycin (7-AAD)apoptosis detection kit.
2.3.2After being incubated GFP-ASC and PGC-1α-ASC under high glucose, hypoxiaand serum deprivation conditions for24h, the level of cellular ROS was deteced byfluorescent probe dihydroethidium (DHE) labelling.
2.3.3Mitochondrial ROS production was detected by MitoTracker Red CM-H2XRos.
2.3.4Transmission electron microscopy was used to observe the morphology andstructure of ASCs modified with PGC-1α or GFP under culture conditions of high glucose,hypoxia and serum deprivation for24h.
Results:
1. Isolation, culture and identification of rat ASCs
1.1The multipotent stem cells being isolated from inguinal subcutaneous fat of SDrats could be culture and stable multiplication in vitro. The cells were able to grow adheringto the plastic wall and the morphology is obvious long fusiform shape like fibroblasts,which was present in regular arrange with certain polarity as school of fish. When beinggenerated to two or three passages, the cells morphology became big and flat.
1.2After being generated third passage, the cell surface antigens were examined by theflow cytometry, the results showed that94.26%and95.83%ASCs were CD90and CD105positive respectively; however, only0.16%and0.09%ASCs were CD34and CD45antigenpositive respectively.
1.3Multilineage differentiation was accomplished using a special kit to determinewhether the cultures were capable of adipogenic differentiation and osteogenicdifferentiation. The results indicated that the cultured rat ASCs could differentiate intoadipocytes, which could be stained by oil red O. ASCs could also differentiate intoadipocytes, the calcium deposits could be stained with alizarin red. But these of the controlwere all negative.
1.4Trypan blue exclusion test was used to determine viability of cells; the resultshowed that the viability of cells was97%. The dead cells were few and could be stained bytrypan blue. The live cells were clear and could not be stained by trypan blue.
2. Overexpression of PGC-1α in ASCs using adenoviral vector encoding PGC-1α andGFP (Ad-GFP-PGC-1α or PGC-1α-ASC)
2.1Adenovirus amplification and examination of the titer of the adenovirus
2.1.1HEK293cells were used to amplify the adenovirus.95%HEK293cellsexpressed GFP at24h after being infected with Ad-PGC-1α under fluorescence microscope,the cells appeared obvious cytopathic effect at48-72h after infection. The cells floatinglike string-of-bead grape could be harvested at96h after infection.
2.1.2The virus titer was determined by TCID50assay. The virus titer ofAd-PGC-1α-GFP is2.0×108PFU/ml. The virus titer of Ad-GFP is2.5×108PFU/ml.
2.2ASCs transfection of adenovirus-mediated gene
2.2.1An ideal MOI of200with high efficiency and low toxicity was selected totransfect, the transfection efficiency of Ad-GFP-PGC-1α was95.3%and Ad-GFP was95.5%at48h after transfection, as being quantified to detect the number of GFP-positivecells by flow cytometry.
2.2.2Expression of PGC-1α protein were2.8-fold higher in PGC-1α-transfected ASCsthan that in Ad-GFP transfected ASCs (P<0.01).
2.3Resistant-apoptosis effect of ASCs with overexpression of PGC-1α under highglucose, hypoxia and serum deprivation conditions
2.3.1Apoptosis of ASCs modified with PGC-1α or GFP was measured using anAnnexin V-APC/7-Amino-Actinomycin (7-AAD) apoptosis detection kit after beinginduced by culture conditions of high glucose concentration (30mmol/L), hypoxia (5%O2)and serum deprivation. At24h under conditions of high glucose, hypoxia and serumdeprivation, the apoptosis rate of the ASC group (21.01±3.03%) and the GFP-ASC group(21.04±2.79%) were significantly higher than that of the PGC-1α-ASC group(14.73±1.57%)(P<0.01). The survival rate of the PGC-1α-ASC group was significantlyhigher those of the ASC group and the GFP-ASC group at6h and24h of culture underthese conditions (P<0.01). There was no difference in ASC group and the GFP-ASC group(P>0.05).
2.3.2GFP-ASCs and PGC-1α-ASC being incubated under high glucose, hypoxia andserum deprivation conditions for24h, the level of cellular ROS was estimated byfluorescent probe DHE labelling. The results showed that DHE-associated fluorescencesignificantly increased in GFP-ASCs (853.44±76.72) compared with PGC-1α-ASC(688.67±43.98)(P<0.01).
2.3.3Mitochondrial ROS production being detected by MitoTracker Red CM-H2XRos also showed a reduction in red fluorescence accumulation in the mitochondria of thePGC-1α-ASC group.
2.3.4Transmission electron microscopy was used to observe the morphology andstructure of ASCs modified with PGC-1α or GFP under culture conditions of high glucose,hypoxia and serum deprivation for24h. The results showed that The most striking changeswas abnomality of morphology and structure of mitochondria, obvious mitochondrialautophagia in GFP-ASC, but which relieved significantly in PGC-1α-ASC.
Conclusions：
ASCs can be harvested from inguinal subcutaneous fat pats of SD rats with the methodof collagenase digestion, the ASCs have a high live rate and can multiply in vitro. Themethod of isolation, culture and identification of ASCs is consistent with the standards ofdomestic and international standard, which establish a basis for the treatment of diabetesand its complications based on stem cells. Our data suggest that overexpression PGC-1αmay protect ASCs from apoptosis by reducing the overproduction of intracellular andintramitochondrial ROS, which can induce mitochondrial dysfunction under conditions ofhyperglycaemia and deprivation of nutrients and oxygen. These results have importantimplications because they indicate that PGC-1α is a potential target in the stem celltreatment of diabetes and its complications. PGC-1α transferred to ASCs can be useful stemcells in the treatment of diabetes and its complications.
糖尿病是一组以慢性血糖水平增高为特征的代谢性疾病，长期的高血糖症常导致的一系列血管和神经并发症，具有患病率高、危害大、常规治疗难、花费大的特点，迫切需要更加有效的治疗手段。近年来兴起的干细胞移植技术为糖尿病及其并发症的治疗带来了新的希望。然而，受局部微环境高糖、缺氧、营养缺乏等因素的影响，移植的干细胞常常大量凋亡或坏死，而少量残留干细胞不能持续分泌足够的促血管生成因子，导致糖尿病血管病变的治疗效果受限。因此，如何提高干细胞的存活率，成为干细胞移植治疗糖尿病及其相关并发症亟待解决的难题。
过氧化物酶体增殖物激活受体γ辅激活因子1α(peroxisome proliferator-activatedreceptor-gamma coactivator1alpha, PGC-1α)是1998年发现的一种调节线粒体功能和能量代谢的关键核转录因子，其通过与多种受体结合，参与线粒体增生、葡萄糖代谢、脂肪酸氧化、细胞分化及血管生成等。与此同时，近年来发现PGC-1α具有抗凋亡的作用。本课题组前期研究发现，PGC-1α能直接或间接通过Bcl/Bax途径和HIF途径，增强骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)抗凋亡和促血管生成潜能，促进糖尿病下肢缺血组织的血管生成。
脂肪干细胞(adipose-derived stem cells, ASCs)是近年来干细胞移植领域研究的热点，与BMSCs相比，具有显著优势。脂肪组织中所含的ASCs比率高，是BMSCs的500多倍，低温冻存对细胞的生长和表型没有影响，具有免疫豁免潜力，获取方法简便，只需简单的抽脂术即可完成，患者较易接受，依从性更好。ASCs被认为是更符合再生医学和组织工程要求的理想干细胞来源。
为此，本研究原代分离培养ASCs，并以ASCs为研究对象，通过检测过表达PGC-1α的ASCs在高糖、缺氧及无血清培养条件下细胞凋亡及活性氧簇物质(reactiveoxygen species, ROS)的产生情况，揭示过表达PGC-1α的ASCs耐凋亡及其机制，为干细胞移植治疗糖尿病及其并发症治疗提供新的靶细胞。
材料与方法
第一部分： Sprague-Dawley(SD)大鼠来源的脂肪干细胞分离培养及鉴定
采用胶原酶消化法从SD大鼠腹股沟皮下脂肪组织分离培养原代ASCs，传至第3代时，进行以下检测：
1.1倒置显微镜观察细胞形态；
1.2流式细胞仪检测细胞表面分子标记：CD90、CD105、CD34、CD45；
1.3多系分化检测：运用SD大鼠ASCs成脂诱导分化试剂盒所提供的特异性培养液对所培养的细胞进行成脂诱导分化后，采用油红O染色检测成脂能力；运用SD大鼠ASCs成骨诱导分化试剂盒所提供的特异性培养液对所培养的细胞进行成骨诱导分化后，采用茜素红染色检测成骨能力；
1.4采用台盼蓝拒染法检测细胞活力。
第二部分：PGC-1α基因修饰的脂肪干细胞在糖尿病微环境中耐凋亡的作用研究
2.1腺病毒扩增及滴度测定
2.1.1培养HEK293细胞用于扩增腺病毒；
2.1.2TCID50(50%组织培养感染剂量)法测定重组腺病毒滴度。
2.2ASCs转染携带绿色荧光蛋白(green fluorescent protein,GFP)和PGC-1α基因的腺病毒载体
2.2.1流式细胞仪检测确立最佳感染系数（multiplicity of infection, MOI）值；
2.2.2WB法检测PGC-1α转染ASCs后蛋白表达水平。
2.3过表达PGC-1α的ASCs在高糖、缺氧及缺乏营养状态下耐凋亡效应
2.3.1Annexin V-APC/7AAD细胞凋亡流式细胞仪检测试剂盒用于检测过表达PGC-1α的ASCs在高糖(30mmol/L)、缺氧(5%O2)、无血清0h、6h及24h状态下细胞凋亡率；
2.3.2在高糖、缺氧、无血清状态下培养GFP-ASC及PGC-1α-ASC24h，ROS荧光探针-DHE标记细胞内ROS，流式细胞仪检测平均荧光强度；
2.3.3Mito Tracker Red CM-H2XRos标记线粒体内ROS，激光共聚焦显微镜下观察线粒体内ROS产生情况；
2.3.4透射电镜下观察细胞超微结构变化。
结果：
第一部分：ASCs分离培养及鉴定
1.1SD大鼠腹股沟脂肪组织来源的多能干细胞可在体外培养并稳定增殖，细胞呈贴壁生长，呈明显的长梭形，细胞体细长，类似于成纤维细胞形态，排列规则，呈鱼群样，具有一定极性；传2-3代后，呈大而扁平的细胞形态。
1.2分离培养ASCs传至第3代，经流式细胞仪检测细胞表面分子标记，结果显示，所培养的细胞CD90、CD105表达率分别为94.26%及95.83%，而CD34、CD45表达率分别仅为0.16%及0.09%。
1.3分离培养的ASCs传至第3代，在成脂诱导分化培养液内能分化成为脂肪细胞，被油红O染成红色；在成骨诱导分化培养液内能分化成为成骨细胞，所形成的矿化结节被茜素红染成红色，而对照组均为阴性。
1.4对所培养的ASCs经台盼蓝拒染法检测细胞活力，结果显示所培养的细胞台盼蓝拒染率为97%，被染成蓝色的死细胞数目极少，活细胞呈无色透明状，不被台盼蓝着色。
第二部分：PGC-1α基因修饰的脂肪干细胞在糖尿病微环境中耐凋亡的作用研究
2.1腺病毒扩增及滴度测定
2.1.1HEK293细胞扩增腺病毒，Ad-PGC-1α感染HEK293细胞后24h，在荧光显微镜下观察可见约95%的细胞有GFP表达，感染48-72h细胞出现明显的细胞病变效应(cytopathic effect, CPE)，感染96h可见部分细胞呈葡萄串珠样浮起，收获病毒。
2.1.2TCID50法测定重组腺病毒滴度，经计算Ad-PGC-1α-GFP的滴度为2.0×108PFU/ml，Ad-GFP的滴度为2.5×108PFU/ml。
2.2．重组腺病毒转染ASCs
2.2.1最佳MOI值的确定：Ad-PGC-1α及Ad-GFP转染ASCs最佳MOI值为200，转染效率分别为95.3%及95.5%。
2.2.2重组腺病毒转染ASCs48h后，经WB法检测PGC-1α蛋白表达，结果显示PGC-1α-ASC组的表达量是GFP-ASC组的2.8倍(P<0.01)。
2.3过表达PGC-1α的ASCs在高糖、缺氧及缺乏营养状态下耐凋亡效应
2.3.1经Annexin V-APC/7AAD法检测细胞在高糖、缺氧、无血清状态下凋亡率，结果显示：在高糖、缺氧及缺营养条件下培养ASC、GFP-ASC及PGC-1α-ASC24h，ASC组细胞凋亡率为(21.01±3.03%)，GFP-ASCs组为(21.04±2.79%)，显著高于PGC-1α-ASC组(14.73±1.57%)(P<0.01)；在高糖、缺氧及缺营养条件下培养ASC、GFP-ASC及PGC-1α-ASC组6h及24h，PGC-1α-ASC组细胞存活率显著高于ASC组及GFP-ASCs组(P<0.01)，而ASC组与GFP-ASC组比较，无统计学意义(P>0.05)。
2.3.2经ROS荧光探针-DHE标记细胞内ROS，流式细胞仪检测结果表明：GFP-ASC组平均荧光强度为(853.44±76.72)显著高于PGC-1α-ASC组(688.67±43.98)(P<0.01)。
2.3.3经Mito Tracker Red CM-H2XRos检测线粒体内ROS产生，激光共聚焦显微镜下可见PGC-1α-ASC组红色荧光强度明显低于GFP-ASC组。
2.3.4透射电镜观察细胞内超微结构，可见GFP-ASC组细胞内线粒体形态结构异常，线粒体自噬严重，见细胞凋亡，而PGC-1α-ASC组细胞上述病变明显减轻。
结论：
从SD大鼠腹股沟皮下脂肪组织通过胶原酶消化法，可获取高存活率、稳定增殖、符合目前国内及国际鉴定标准的ASCs，为ASCs治疗糖尿病及相关并发症奠定了基础；通过重组腺病毒表达Ad-PGC-1α-GFP特异性上调ASCs中PGC-1α的表达，在高糖、缺氧及营养缺乏条件下，可能通过线粒体途径，抑制ASCs细胞及线粒体内ROS的产生发挥耐凋亡作用。表明，PGC-1α有可能成为糖尿病及其并发症的干细胞治疗关键的作用靶点，转染PGC-1α的ASCs可作为糖尿病及其并发症的干细胞治疗的靶细胞。
Background:
Diabetes mellitus is a group of metabolic disease characterized by chronichyperglycaemia associated with a series of vascular and neural complications, which hassome features with high morbidity, large hazard, hard conventional therapy and expensivecost. The more effective therapeutic options are need badly to develop; stem cell therapyprovides new hope for diabetes and its complications in recent years. However, effect ofhyperglycaemia and deprivation of nutrient and oxygen in the diabetic regionmicroenvironment, the apoptosis or necrosis of a large number of transplanted stem cells isa critical issue that limits the therapeutic efficacy of stem cells. Therefore, how to increasethe survival rates of the stem cells and enchance angiogenesis potential has been an urgentresolved problem in the treatment of the diabetes and its complications.
Peroxisome proliferator-activated receptor-gamma coactivator1alpha (PGC-1α) beinga key transcriptional coactivator involved in the regulation of mitochondrial function andenergy metabolism was found in1998, which binds with many receptors and plays animportant role in mitochondrial biogenesis, glucose metabolism, fatty acid oxidation, celldifferentiation and angiogenesis. In the meantime, many studies have shown that PGC-1αinvolves in anti-apoptosis in recent years. Our recent study suggested that PGC-1α plays animportant role in anti-apoptosis and mediated angiogenesis in mesenchymal stem cells indiabetic hindlimb ischaemia by inducing an increase in hypoxia inducible factor-1α(Hif-1α), a higher ratio of B-celllymphoma/leukaemia-2(Bcl-2)/Bcl-2-associated X protein(Bax) in bone marrow derived mesenchymal stem cells (BMSCs).
Recently, adipose-derived stem cells (ASCs) have become the focus of attention in thefield of stem cells transplantation because of their ease of isolation, relative abundance, andrapidity of growth. Compared with BMSCs, the rate of stem cells derived from of fat tissueis higher than that of bone marrow. There is no influence of cryopreservation on cell growthand phenotype. ASCs have the potential of immune privilege. The method of harvest ASCs is simple and safe, which can be performed by liposuction. Emerging evidence suggests thatASCs will be an ideal source of stem cells in regenerative medicine and tissue engineering.
Therefore, in this study, ASCs were isolated and cultured, whether the overexpressionof PGC-1α protects ASCs from apoptosis by reducing ROS production and ameliorating themitochondrial damage induced by a diabetic environment were examined, which maycontribute to the development of new approaches and provide target cells for preventingcomplications from diabetes.
Materials and methods：
1. Isolation, culture and identification of Sprague-Dawley (SD) rat ASCs
ASCs were isolated and cultured with the method of collagenase digestion; cells wereexamined as follow after three passages.
1.1The cell morphology was observed by inverted microscope.
1.2The cell surface antigens CD90-FITC, CD105-FITC, CD34-PE and CD45-PE weredetected by flow cytometry.
1.3Multilineage differentiation were accomplished using a special kit to determinewhether the culture cells were capable of adipogenic differentiation and osteogenicdifferentiation by oil red O staining and staining calcium deposits with alizarin red.
1.4Trypan blue exclusion test was used to determine viability of cells.
2. Overexpression of PGC-1α in ASCs using adenoviral vector encoding PGC-1α andGFP (Ad-GFP-PGC-1α or PGC-1α-ASC).
2.1Adenovirus amplification and examination of the titer of the adenovirus.
2.1.1HEK293cells were used to amplify the adenovirus.
2.1.2The virus titer was determined by tissue culture infectious dose50(TCID50)assay.
2.2ASCs transfection of adenovirus-mediated gene.
2.2.1Multiplicity of infection (MOI) with high efficiency and low toxicity wasdetected by flow cytometry, and the ideal MOI was selected for the following experiments.
2.2.2Western blotting (WB) was used to examine the protein levels of PGC-1α.
2.3Resistant-apoptosis effect of ASCs with overexpression of PGC-1α under highglucose, hypoxia and serum deprivation conditions.
2.3.1After being infected for48h, the apoptosis of ASCs modified with PGC-1α orGFP was induced by culture conditions of high glucose concentration (30mmol/L), hypoxia (5%O2) and serum deprivation. At0h,6h and24h after culture, the survival ratesof ASCs were measured using an Annexin V-APC/7-Amino-Actinomycin (7-AAD)apoptosis detection kit.
2.3.2After being incubated GFP-ASC and PGC-1α-ASC under high glucose, hypoxiaand serum deprivation conditions for24h, the level of cellular ROS was deteced byfluorescent probe dihydroethidium (DHE) labelling.
2.3.3Mitochondrial ROS production was detected by MitoTracker Red CM-H2XRos.
2.3.4Transmission electron microscopy was used to observe the morphology andstructure of ASCs modified with PGC-1α or GFP under culture conditions of high glucose,hypoxia and serum deprivation for24h.
Results:
1. Isolation, culture and identification of rat ASCs
1.1The multipotent stem cells being isolated from inguinal subcutaneous fat of SDrats could be culture and stable multiplication in vitro. The cells were able to grow adheringto the plastic wall and the morphology is obvious long fusiform shape like fibroblasts,which was present in regular arrange with certain polarity as school of fish. When beinggenerated to two or three passages, the cells morphology became big and flat.
1.2After being generated third passage, the cell surface antigens were examined by theflow cytometry, the results showed that94.26%and95.83%ASCs were CD90and CD105positive respectively; however, only0.16%and0.09%ASCs were CD34and CD45antigenpositive respectively.
1.3Multilineage differentiation was accomplished using a special kit to determinewhether the cultures were capable of adipogenic differentiation and osteogenicdifferentiation. The results indicated that the cultured rat ASCs could differentiate intoadipocytes, which could be stained by oil red O. ASCs could also differentiate intoadipocytes, the calcium deposits could be stained with alizarin red. But these of the controlwere all negative.
1.4Trypan blue exclusion test was used to determine viability of cells; the resultshowed that the viability of cells was97%. The dead cells were few and could be stained bytrypan blue. The live cells were clear and could not be stained by trypan blue.
2. Overexpression of PGC-1α in ASCs using adenoviral vector encoding PGC-1α andGFP (Ad-GFP-PGC-1α or PGC-1α-ASC)
2.1Adenovirus amplification and examination of the titer of the adenovirus
2.1.1HEK293cells were used to amplify the adenovirus.95%HEK293cellsexpressed GFP at24h after being infected with Ad-PGC-1α under fluorescence microscope,the cells appeared obvious cytopathic effect at48-72h after infection. The cells floatinglike string-of-bead grape could be harvested at96h after infection.
2.1.2The virus titer was determined by TCID50assay. The virus titer ofAd-PGC-1α-GFP is2.0×108PFU/ml. The virus titer of Ad-GFP is2.5×108PFU/ml.
2.2ASCs transfection of adenovirus-mediated gene
2.2.1An ideal MOI of200with high efficiency and low toxicity was selected totransfect, the transfection efficiency of Ad-GFP-PGC-1α was95.3%and Ad-GFP was95.5%at48h after transfection, as being quantified to detect the number of GFP-positivecells by flow cytometry.
2.2.2Expression of PGC-1α protein were2.8-fold higher in PGC-1α-transfected ASCsthan that in Ad-GFP transfected ASCs (P<0.01).
2.3Resistant-apoptosis effect of ASCs with overexpression of PGC-1α under highglucose, hypoxia and serum deprivation conditions
2.3.1Apoptosis of ASCs modified with PGC-1α or GFP was measured using anAnnexin V-APC/7-Amino-Actinomycin (7-AAD) apoptosis detection kit after beinginduced by culture conditions of high glucose concentration (30mmol/L), hypoxia (5%O2)and serum deprivation. At24h under conditions of high glucose, hypoxia and serumdeprivation, the apoptosis rate of the ASC group (21.01±3.03%) and the GFP-ASC group(21.04±2.79%) were significantly higher than that of the PGC-1α-ASC group(14.73±1.57%)(P<0.01). The survival rate of the PGC-1α-ASC group was significantlyhigher those of the ASC group and the GFP-ASC group at6h and24h of culture underthese conditions (P<0.01). There was no difference in ASC group and the GFP-ASC group(P>0.05).
2.3.2GFP-ASCs and PGC-1α-ASC being incubated under high glucose, hypoxia andserum deprivation conditions for24h, the level of cellular ROS was estimated byfluorescent probe DHE labelling. The results showed that DHE-associated fluorescencesignificantly increased in GFP-ASCs (853.44±76.72) compared with PGC-1α-ASC(688.67±43.98)(P<0.01).
2.3.3Mitochondrial ROS production being detected by MitoTracker Red CM-H2XRos also showed a reduction in red fluorescence accumulation in the mitochondria of thePGC-1α-ASC group.
2.3.4Transmission electron microscopy was used to observe the morphology andstructure of ASCs modified with PGC-1α or GFP under culture conditions of high glucose,hypoxia and serum deprivation for24h. The results showed that The most striking changeswas abnomality of morphology and structure of mitochondria, obvious mitochondrialautophagia in GFP-ASC, but which relieved significantly in PGC-1α-ASC.
Conclusions：
ASCs can be harvested from inguinal subcutaneous fat pats of SD rats with the methodof collagenase digestion, the ASCs have a high live rate and can multiply in vitro. Themethod of isolation, culture and identification of ASCs is consistent with the standards ofdomestic and international standard, which establish a basis for the treatment of diabetesand its complications based on stem cells. Our data suggest that overexpression PGC-1αmay protect ASCs from apoptosis by reducing the overproduction of intracellular andintramitochondrial ROS, which can induce mitochondrial dysfunction under conditions ofhyperglycaemia and deprivation of nutrients and oxygen. These results have importantimplications because they indicate that PGC-1α is a potential target in the stem celltreatment of diabetes and its complications. PGC-1α transferred to ASCs can be useful stemcells in the treatment of diabetes and its complications.
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