地黄低聚糖对同种异体脂肪组织来源干细胞移植治疗小型猪急性心肌梗死效应及机制的研究
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摘要
背景：尽管急性心肌梗死（AMI）的治疗取得了一定进步，但仍面临着诸多挑战。干细胞移植治疗AMI是一种很有潜力的方法，但缺血心肌局部恶劣的微环境严重阻碍了其疗效的发挥。
目的：评价地黄低聚糖（RGOs）对同种异体脂肪组织来源干细胞（ASCs）移植治疗小型猪AMI的疗效，探讨其可能的机制。
方法：
第一部分：热水法提取生地黄中的RGOs，经阳离子和阴离子交换树脂洗脱，活性炭柱层析纯化RGOs，以高效液相色谱法（HPLC）检测其水苏糖含量。
第二部分：酶消化法及贴壁法从小型猪腹股沟脂肪组织中分离、培养ASCs，流式细胞仪鉴定其分子表型；CCK-8法观察不同浓度RGOs对ASCs增殖的影响。
第三部分：人ASCs（hASCs）经RGOs(0.1mg/ml)预处理12h并继续干预，ELISA法观察不同时间点hASCs培养上清液中血管内皮生长因子（VEGF），肝细胞生长因子(HGF)，胰岛素样生长因子-1（IGF-1），碱性成纤维细胞生长因子(bFGF)，基质细胞衍生因子-lα（SDF-lα）浓度的变化。
第四部分：过氧化氢（200μM）联合血清饥饿（H2O2/SD，6h）模拟氧化应激微环境，诱导小型猪ASCs凋亡。观察RGOs（0.01mg/ml、0.1mg/ml、1mg/ml、10mg/ml）预处理12h并继续干预对ASCs凋亡的影响。AnnexinV-FITC/PI检测细胞凋亡率，CCK-8法测定细胞活性，酶标仪比色法测定细胞caspase-3的活性，Western-blot法测定细胞Bax、Bcl-2的表达。
第五部分：17头小型猪随机分为4组：对照组（C组，n=5），单纯RGOs组（R组，n=4），单纯ASCs移植组（A组，n=4），RGOs+ASCs联合治疗组（RA组n=4）。球囊封堵左前降支90分钟构建小型猪AMI模型，造模1周后（7～10天）经冠状动脉移植同种异体ASCs（0.8×106/kg）。RGOs组造模前3天及造模后1月饲以RGOs粗提物（4g,2/日）。移植后8周，MRI评价各组心脏结构及功能变化，荧光显微镜及激光共聚焦扫描观察ASCs存活及分化，免疫组织化学法观察梗死区域微血管密度，Masson三色染色法评价梗死区纤维化程度，TUNEL法检测梗死边缘区心肌细胞凋亡，Western blot法测定梗死边缘区心肌细胞Bax、Bcl-2的表达。
结果：
第一部分：地黄粗提物及提纯物得率分别为地黄原药材的41.64%和35.14%，HPLC法检测RGOs提纯物中水苏糖占31.15%。
第二部分：成功从小型猪腹股沟脂肪组织中分离并培养了ASCs，第四代ASCs分子表型CD29、CD44、CD90、CD105呈阳性表达，而CD31、CD34、CD45、HLA-DR均呈阴性表达。RGOs在一定浓度范围(0.01mg/ml～1mg/ml)内对体外培养的小型猪ASCs具有促增殖作用，最佳浓度为0.1mg/ml。
第三部分：RGOs（0.1mg/ml）可以促进体外培养的hASCs分泌VEGF、HGF、IGF-1、SDF-1α，但对于bFGF的分泌无明显影响，其促旁分泌作用具有一定的时效性。
第四部分：RGOs在一定浓度范围(0.1mg/ml～10mg/ml)可以减轻H2O2/SD引起的ASCs损伤，表现在细胞凋亡率下降，细胞活性增加，caspase-3活性降低，Bax表达下调，Bcl-2表达上调。
第五部分：与C组比较，仅RA组可以明显改善左心室功能，增加梗死区室壁厚度,减小左心室质量指数及梗死体积（p <0.05）；RA组ASCs的存活多于A组（p <0.01）；RA组梗死区域微血管密度明显高于其他3组（p <0.01），而3组间无显著差异；与C组比较，A组以及RA组均能明显降低梗死区纤维化程度（p <0.05，p <0.01）；与C组比较，R组及RA组均能明显减少心肌细胞凋亡（p <0.05，p <0.01）；与C组比较，三组Bax的表达均明显下降（p<0.01），R组及RA组Bcl-2的表达明显升高（p <0.01）。
结论：RGOs可以提高ASCs移植的效率，其作用机制可能与RGOs改善缺血心肌局部的微环境，促进ASCs增殖、存活，增强ASCs的旁分泌功能及抗凋亡有关。
Background: Treatment of acute myocardial infarction (AMI) remains muchchallenge, though there have been enormous progresses in ischemic heart disease.Cell-based repair is emerging as a potential novel therapy for AMI. However, theefficacy of cell-based therapy is hindered by the deleterious local milieu of themyocardium.
Objective: The study was conducted to evaluate whether Rehmannia GlutinosaOligosaccharides (RGOs) treatment can increase the efficacy of allogenic adiposetissue-derived stem cells (ASCs) transplantation in Chinese miniswine with AMIand to explore the potential mechanisms.
Methods and results:
The first part: Crude extract RGOs was extracted by boiled water fromRehmannia root and was further separated by cation exchange resin and anionexchange resin eluting and by charcoal column chromatography. The stachyose,the main component in the RGOs, was determined by High Performance LiquidChromatography (HPLC). The outputs of crude extract RGOs and purifiedproduct from raw material were41.64%and35.14%, respectively; and purifiedRGOs contained31.15%stachyose.
The second part: The ASCs of miniswine were isolated and cultured from adiposetissue harvested from inguinal regions by enzyme digestion and adherent. Themolecular phenotypes of ASCs at passages4were examined by flow cytometry,and results showed that ASCs were positive for CD29, CD44, CD90and CD105,but negative for CD31, CD34, CD45and HLA-DR. According to CCK-8colorimetry's results, RGOs could accelerate proliferation of ASCs in vitro in acertain range of concentration (0.01mg/ml~1mg/ml), and the best proliferative effect was observed at concentration of0.1mg/ml.
The third part: To determine whether RGOs (0.1mg/ml) pretreatment for12hourscauses increase of vascular endothelial growth factor (VEGF), hepatocyte growthfactor (HGF), insulin-like growth factor-1(IGF-1), basic fibroblast growth factor(bFGF) and stromal cell derived factor-lα (SDF-lα) release from human ASCs(hASCs) in vitro. The levels of VEGF, HGF, IGF-1, bFGF, SDF-1α in the hASCssupernatant were determined by enzyme-linked immunosorbent assay (ELISA).The results indicated that RGOs could promote the secretion of VEGF, HGF,IGF-1and SDF-1α in a time-dependent manner, but the secretion of bFGF did notincrease significantly.
The fourth part: To investigate whether RGOs (0.01mg/ml,0.1mg/ml,1mg/ml,10mg/ml) pretreatment for12hours and continued presence could protect ASCsagainst apoptosis in a model of oxidative stress consisting of hydrogen peroxide-and serum deprivation-induced in vitro. Apoptosis of ASCs was assessed using anAnnexin V-FITC/PI apoptosis kit. Cell activity was determined by CCK-8assay.Caspase-3activity was detected by applying a caspase-3assay kit. Expression ofBax and Bcl-2was investigated using Western blot analysis. We found that RGOssignificantly attenuated hydrogen peroxide-and serum deprivation-induced ASCsapoptosis, showing a decreased apoptosis rate, an increase in cell activity, adecreased caspase-3activity, a down-regulated Bax expression and anup-regulated Bcl-2expression.
The fifth part: Seventeen Chinese miniswine were divided into four groups:control (group C, n=5); RGOs alone (group R, n=4), administration crude extractalone from the3rd day prior to AMI to one month post AMI (4g, two times perday); ASCs transplantation alone (group A, n=4) and RGOs+ASCs (group RA,n=4). AMI models were created by occlusion of the left anterior descendingcoronary artery for90minutes. One week later (the7th to10th day post AMI),allogenic ASCs (0.8×106/kg) were injected into left anterior descending coronaryartery. At8weeks post transplantation, magnetic resonance imaging (MRI) showed that the left ventricular ejection fraction and wall thickness of infarctedregions were increased while the left ventricular mass index, the infarct size weredecreased only in group RA compared with group C (P＜0.05). ASCs survivalwas significantly better in group RA than in group A (P＜0.01). Microvasculardensities both in the infracted zone and the peri-infarct zone also increasedsignificantly in group RA but not in other three groups (P＜0.01). Massontrichrome stain showed that there was less fibrosis with more survivingmyocardium in group A and group RA than that in group C (P＜0.05and P＜0.01). TUNEL assay indicated that RGOs administration significantly decreasedcell apoptosis in peri-infarct myocardium in group R and group RA (P＜0.05andP＜0.01). Western blot analysis indicated that the expression levels of Bax ingroup R, group A and group RA were significantly decreased (P＜0.01,versusgroup C). However, the expression levels of Bcl-2in group R and group RA weresignificantly increased (P＜0.01,versus group C).
Conclusion: RGOs treatment improves the therapeutic efficacy of ASCstransplantation by improving the local milieu of the ischemic myocardium，promoting ASCs proliferation and survival, enhancing paracrine function and byanti-apoptosis.
目的：评价地黄低聚糖（RGOs）对同种异体脂肪组织来源干细胞（ASCs）移植治疗小型猪AMI的疗效，探讨其可能的机制。
方法：
第一部分：热水法提取生地黄中的RGOs，经阳离子和阴离子交换树脂洗脱，活性炭柱层析纯化RGOs，以高效液相色谱法（HPLC）检测其水苏糖含量。
第二部分：酶消化法及贴壁法从小型猪腹股沟脂肪组织中分离、培养ASCs，流式细胞仪鉴定其分子表型；CCK-8法观察不同浓度RGOs对ASCs增殖的影响。
第三部分：人ASCs（hASCs）经RGOs(0.1mg/ml)预处理12h并继续干预，ELISA法观察不同时间点hASCs培养上清液中血管内皮生长因子（VEGF），肝细胞生长因子(HGF)，胰岛素样生长因子-1（IGF-1），碱性成纤维细胞生长因子(bFGF)，基质细胞衍生因子-lα（SDF-lα）浓度的变化。
第四部分：过氧化氢（200μM）联合血清饥饿（H2O2/SD，6h）模拟氧化应激微环境，诱导小型猪ASCs凋亡。观察RGOs（0.01mg/ml、0.1mg/ml、1mg/ml、10mg/ml）预处理12h并继续干预对ASCs凋亡的影响。AnnexinV-FITC/PI检测细胞凋亡率，CCK-8法测定细胞活性，酶标仪比色法测定细胞caspase-3的活性，Western-blot法测定细胞Bax、Bcl-2的表达。
第五部分：17头小型猪随机分为4组：对照组（C组，n=5），单纯RGOs组（R组，n=4），单纯ASCs移植组（A组，n=4），RGOs+ASCs联合治疗组（RA组n=4）。球囊封堵左前降支90分钟构建小型猪AMI模型，造模1周后（7～10天）经冠状动脉移植同种异体ASCs（0.8×106/kg）。RGOs组造模前3天及造模后1月饲以RGOs粗提物（4g,2/日）。移植后8周，MRI评价各组心脏结构及功能变化，荧光显微镜及激光共聚焦扫描观察ASCs存活及分化，免疫组织化学法观察梗死区域微血管密度，Masson三色染色法评价梗死区纤维化程度，TUNEL法检测梗死边缘区心肌细胞凋亡，Western blot法测定梗死边缘区心肌细胞Bax、Bcl-2的表达。
结果：
第一部分：地黄粗提物及提纯物得率分别为地黄原药材的41.64%和35.14%，HPLC法检测RGOs提纯物中水苏糖占31.15%。
第二部分：成功从小型猪腹股沟脂肪组织中分离并培养了ASCs，第四代ASCs分子表型CD29、CD44、CD90、CD105呈阳性表达，而CD31、CD34、CD45、HLA-DR均呈阴性表达。RGOs在一定浓度范围(0.01mg/ml～1mg/ml)内对体外培养的小型猪ASCs具有促增殖作用，最佳浓度为0.1mg/ml。
第三部分：RGOs（0.1mg/ml）可以促进体外培养的hASCs分泌VEGF、HGF、IGF-1、SDF-1α，但对于bFGF的分泌无明显影响，其促旁分泌作用具有一定的时效性。
第四部分：RGOs在一定浓度范围(0.1mg/ml～10mg/ml)可以减轻H2O2/SD引起的ASCs损伤，表现在细胞凋亡率下降，细胞活性增加，caspase-3活性降低，Bax表达下调，Bcl-2表达上调。
第五部分：与C组比较，仅RA组可以明显改善左心室功能，增加梗死区室壁厚度,减小左心室质量指数及梗死体积（p <0.05）；RA组ASCs的存活多于A组（p <0.01）；RA组梗死区域微血管密度明显高于其他3组（p <0.01），而3组间无显著差异；与C组比较，A组以及RA组均能明显降低梗死区纤维化程度（p <0.05，p <0.01）；与C组比较，R组及RA组均能明显减少心肌细胞凋亡（p <0.05，p <0.01）；与C组比较，三组Bax的表达均明显下降（p<0.01），R组及RA组Bcl-2的表达明显升高（p <0.01）。
结论：RGOs可以提高ASCs移植的效率，其作用机制可能与RGOs改善缺血心肌局部的微环境，促进ASCs增殖、存活，增强ASCs的旁分泌功能及抗凋亡有关。
Background: Treatment of acute myocardial infarction (AMI) remains muchchallenge, though there have been enormous progresses in ischemic heart disease.Cell-based repair is emerging as a potential novel therapy for AMI. However, theefficacy of cell-based therapy is hindered by the deleterious local milieu of themyocardium.
Objective: The study was conducted to evaluate whether Rehmannia GlutinosaOligosaccharides (RGOs) treatment can increase the efficacy of allogenic adiposetissue-derived stem cells (ASCs) transplantation in Chinese miniswine with AMIand to explore the potential mechanisms.
Methods and results:
The first part: Crude extract RGOs was extracted by boiled water fromRehmannia root and was further separated by cation exchange resin and anionexchange resin eluting and by charcoal column chromatography. The stachyose,the main component in the RGOs, was determined by High Performance LiquidChromatography (HPLC). The outputs of crude extract RGOs and purifiedproduct from raw material were41.64%and35.14%, respectively; and purifiedRGOs contained31.15%stachyose.
The second part: The ASCs of miniswine were isolated and cultured from adiposetissue harvested from inguinal regions by enzyme digestion and adherent. Themolecular phenotypes of ASCs at passages4were examined by flow cytometry,and results showed that ASCs were positive for CD29, CD44, CD90and CD105,but negative for CD31, CD34, CD45and HLA-DR. According to CCK-8colorimetry's results, RGOs could accelerate proliferation of ASCs in vitro in acertain range of concentration (0.01mg/ml~1mg/ml), and the best proliferative effect was observed at concentration of0.1mg/ml.
The third part: To determine whether RGOs (0.1mg/ml) pretreatment for12hourscauses increase of vascular endothelial growth factor (VEGF), hepatocyte growthfactor (HGF), insulin-like growth factor-1(IGF-1), basic fibroblast growth factor(bFGF) and stromal cell derived factor-lα (SDF-lα) release from human ASCs(hASCs) in vitro. The levels of VEGF, HGF, IGF-1, bFGF, SDF-1α in the hASCssupernatant were determined by enzyme-linked immunosorbent assay (ELISA).The results indicated that RGOs could promote the secretion of VEGF, HGF,IGF-1and SDF-1α in a time-dependent manner, but the secretion of bFGF did notincrease significantly.
The fourth part: To investigate whether RGOs (0.01mg/ml,0.1mg/ml,1mg/ml,10mg/ml) pretreatment for12hours and continued presence could protect ASCsagainst apoptosis in a model of oxidative stress consisting of hydrogen peroxide-and serum deprivation-induced in vitro. Apoptosis of ASCs was assessed using anAnnexin V-FITC/PI apoptosis kit. Cell activity was determined by CCK-8assay.Caspase-3activity was detected by applying a caspase-3assay kit. Expression ofBax and Bcl-2was investigated using Western blot analysis. We found that RGOssignificantly attenuated hydrogen peroxide-and serum deprivation-induced ASCsapoptosis, showing a decreased apoptosis rate, an increase in cell activity, adecreased caspase-3activity, a down-regulated Bax expression and anup-regulated Bcl-2expression.
The fifth part: Seventeen Chinese miniswine were divided into four groups:control (group C, n=5); RGOs alone (group R, n=4), administration crude extractalone from the3rd day prior to AMI to one month post AMI (4g, two times perday); ASCs transplantation alone (group A, n=4) and RGOs+ASCs (group RA,n=4). AMI models were created by occlusion of the left anterior descendingcoronary artery for90minutes. One week later (the7th to10th day post AMI),allogenic ASCs (0.8×106/kg) were injected into left anterior descending coronaryartery. At8weeks post transplantation, magnetic resonance imaging (MRI) showed that the left ventricular ejection fraction and wall thickness of infarctedregions were increased while the left ventricular mass index, the infarct size weredecreased only in group RA compared with group C (P＜0.05). ASCs survivalwas significantly better in group RA than in group A (P＜0.01). Microvasculardensities both in the infracted zone and the peri-infarct zone also increasedsignificantly in group RA but not in other three groups (P＜0.01). Massontrichrome stain showed that there was less fibrosis with more survivingmyocardium in group A and group RA than that in group C (P＜0.05and P＜0.01). TUNEL assay indicated that RGOs administration significantly decreasedcell apoptosis in peri-infarct myocardium in group R and group RA (P＜0.05andP＜0.01). Western blot analysis indicated that the expression levels of Bax ingroup R, group A and group RA were significantly decreased (P＜0.01,versusgroup C). However, the expression levels of Bcl-2in group R and group RA weresignificantly increased (P＜0.01,versus group C).
Conclusion: RGOs treatment improves the therapeutic efficacy of ASCstransplantation by improving the local milieu of the ischemic myocardium，promoting ASCs proliferation and survival, enhancing paracrine function and byanti-apoptosis.
引文
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