1.雪旺细胞移植改善急性心肌梗死后神经重构的研究 2.年龄对心脏瓣膜种子细胞体外培养增殖的影响
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摘要
第一部分
雪旺细胞移植改善急性心肌梗死后神经重构的研究
背景:所谓神经重构指的是心肌梗死边缘区交感神经的过度增殖和交感神经纤维的不均衡分布。既往研究表明,神经重构是造成急性心肌梗死后心律失常的重要原因,而后者则是造成急性心肌梗死后死亡的重要原因。但是目前控制急性心肌梗死后心脏神经重构的手段仍十分有限。雪旺细胞具备强大的神经再生功能,多数研究表明,雪旺细胞可以通过旁分泌和细胞接触机制诱导神经轴突再生,并参与神经鞘基质蛋白的合成,对新生神经轴突给与必要的支撑。因此,本研究拟探讨雪旺细胞在促进心脏神经再生和改善心脏神经重构方面的作用。
方法:在lewis大鼠上成功建立急性心肌梗死模型后,将心肌梗死鼠随机分为细胞移植组(n=80)和对照组(n=72)。雪旺细胞取自lewis大鼠坐骨神经,经体外培养后,经爬片S100染色鉴定雪旺细胞表面标记物,经ELISA方法鉴定雪旺细胞在离体环境下释放神经生长因子和血管内皮生长因子的能力。取2代雪旺细胞5×10~6,注射到心肌梗死周边区。在注入雪旺细胞24小时、1周和2周时间点分别取材,进行组织标本的免疫组化、免疫荧光以及蛋白印记试验。其中,免疫组化指标选择S100、BrdU和CD68,免疫荧光的指标选择酪胺酸羟化酶、乙酰胆碱酯酶和生长相关蛋白43;蛋白印记实验指标选择神经生长因子,血管内皮生长因子,生长相关蛋白43,连接蛋白43和层粘连蛋白。
结果:在不同时间点,比较雪旺细胞移植组和对照组S100染色阳性细胞数。在对照组,急性心肌梗死二十四小时后,S100染色阳性细胞急剧减少;在雪旺细胞移植组,急性心肌梗死二十四小时后,可见多量S100和BrdU同时染色阳性的细胞。随着时间推移,两组S100染色阳性的细胞均增多,但雪旺细胞移植组S100染色阳性细胞显著多于对照组(p<0.05),但是BrdU染色阳性细胞随着时间的推移急剧减少。这提示,急性心肌梗死后,随着时间的推移,心肌内自身雪旺细胞不断再生,而移植的雪旺细胞不断死亡。在心肌梗死后24小时,与对照组相比,在雪旺细胞移植组,神经生长因子、血管内皮生长因子、生长相关蛋白43、连接蛋白43以及层粘连蛋白在心肌内表达无显著差异,而在心肌梗死后一周和两周时,雪旺细胞移植组上述蛋白表达均明显增高。在24小时,植入心肌梗死周边区的雪旺细胞对巨噬细胞起到了明显的趋化作用。但心肌梗死后一周和两周时,两组雪旺细胞计数无差别。在心肌梗死后24小时、一周和两周时,两组心肌梗死周边区交感神经、副交感神经和新生神经纤维密度均有所增高,但在雪旺细胞移植组,心肌梗死后两周时副交感密度与交感密度比值显著高于对照组。但雪旺细胞移植未能改善心功能。
结论:在急性心肌梗死后,心肌梗死周边区植入的雪旺细胞可以释放NGF,吸引巨噬细胞,刺激层粘连蛋白表达,从而提高副交感密度与交感密度比值,进而改善急性心肌梗死后神经重构的发生。雪旺细胞移植有望提供一种全新的细胞治疗手段,具备良好的临床应用前景。
第二部分
年龄对心脏瓣膜种子细胞体外培养增殖的影响
背景当前心脏瓣膜病的治疗主要是通过外科手段完成,但目前所采用的机械瓣和人造瓣膜均存在各自的局限性。有鉴于此,通过生物工程构建自体心脏瓣膜显现出了其自身优势。既往文献表明,间充质干细胞是一种可用于生物组织工程学的良好种子细胞。但是在心脏瓣膜构建中,年龄对作为种子细胞的人类间充质干细胞体外生物学特性的影响尚不明了。本研究目的在于比较不同年龄组人类间充质干细胞体外生物学特性,从而为构建自体心脏瓣膜中种子细胞的选择提供依据。
方法人类间充质干细胞采自不同青少年、中年、老年供体。其中青年组供体为简单先心病患者,年龄在18岁以下;中年组供体为瓣膜病患者,年龄在18到40岁之间;老年组供体为瓣膜病患者,年龄在40岁以上。对三种不同来源干细胞体外增殖能力进行组间比较,BrdU法绘制生长曲线、细胞形成集落个数计数和细胞生长形态及数量表述。通过流式细胞对各组细胞表面标记物进行检测和鉴别。在三组间进行细胞分化(内皮分化,脂肪分化,成骨细胞分化)、体外释放VEGF能力和细胞迁移能力的比较。
结果与青少年组和中年组比较,老年组分离骨髓可以成功提取出间充质干细胞,荧光显微镜下观察其生长、形态等方面与另外两组无显著差别,且流式细胞学检查表明,老年组细胞细胞表面标记物与另两组表达无显著统计学差异。在青少年组(32±3),细胞克隆数量显著高于中年组(26±5,p<0.05)和老年组(19±5,p<0.05);增殖曲线表明,青少年组和中年组细胞增殖能力显著高于老年组(p<0.05)。在干细胞定向分化能力、血管内皮生长因子释放和细胞迁移,青少年组和中年组显著高于老年组(p<0.05)。
结论应用老年供体来源间充质干细胞进行自体组织瓣膜工程构建应采取审慎态度。
Background:Neural remodeling refers to hyperinnervation and uneven distribution of sympathetic nerve fibers around the border of infarcted myocardium.Unbalanced neural remodeling could cause fatal ventricular arrhythmia(VA) and increase mortalities but few strategies are available to suppress the sympathetic remodeling after acute myocardial infarction (MI).Schwann cells have the potential to stimulate nerve regeneration. Numerous reports demonstrated that Schwann cells exert their function through paracrine and cell contact.Moreover,Schwann cells help protein expression which is essential for basal lamina formation.Therefore,this study aims at evaluate the Schwann cells' neurogenesis abilities and explore Schwann cells' potential to balance nerve remodeling.
Methods:Immediately after creation of MI,the rats were randomized into cell transplantation(n=80) and control groups(n=72).Schwann Cells(SCs) were obtained from sciatic nerves.The cells was cultured on tiny glass sheet and stained with SIO0 which is a surface marker of $chwann cells.Release of nerve growth factors(NGF) and vascular endothelial growth factor(VEGF) fromSchwann cells was detected by using ELISA.5×10~6 cells of second passage were intramyocardially injected into the infarcted region.Series histological and immunohistochemical studies were performed at 24 hours, 1 and 2 weeks after cell transplantation.In immunohistochemical studies, SIOO,BrdU,and CD68 staining were performed.As for immunofluorescence study,tyrosine hydroxylase(TH),acetycholinesterase enzyme(AChE),and growth associated protein 43(GAP43) staining were performed.NGF,VEGF, GAP 43,connexin 43,and laminin expression were detected by using western blot.
Results:Comparison of S100 positive cells between control and cell transplantation group.Few cells were stained with S100 24 hours after myocardial infarction in control group,and more cells expressed both S100 and BrdU were detected in cell transplantation group.Growing number of S100 positive cells was observed in both groups with significantly more S100 positive cells in cell transplantation group.The number of transplanted BrdU positive SCs dropped sharply with elapse of time.The expressions of NGF,VEGF,GAP 43,connexin 43,laminin in myocardium were of no significant difference 24 hours after cell transplantation.But the above protein expressions in one week and two weeks were significantly higher in Schwann cell group than in control group.At 24 hours,transplanted SCs significantly attracted macrophage.But no differences of macrophage counting were noted between two groups.At 24 hours,one week,and two weeks,density of sympathetic nerves,parasympathetic nerves,and new-born nerve fibers increased in both groups,but SCs transplantation contributed to the increment of parasympathetic/sympathetic ratio at two weeks after MI.But SCs transplantation didn' t restore the damaged heart function.
Conclusions:Transplanted SCs secreted nerve growth factor,attract macrophage,stimulate expression of laminin and connexin 43,and enhance the ratio of parasympathetic/sympathetic.SCs transplantation might be a promising cell-based antiarrhythmic therapy to balance sympathetic nerve sprouting MI.
Background:Currently,surgical intervention is still the most important option for the treatment of heart valvular diseases.However,although frequently adopted,mechanical valves and bioprosthetic valves have their shortcomings.As a result,autologous heart valve construction catches researchers' eyeballs.Previous studies demonstrated that mesenchymal stem cells are ideal candidates to be seeded on scaffold for valve construction.But the aging effects on the in vitro biological properties of bone marrow-derived mesenchymal stem cells(BMSCs) for construction of tissue engineered heart valves are unclear yet.The aim of this study was to compare in vitro biological properties of BMSCs so as to provide theoretical basis for seed cell selection for autologous heart valve construction.
Methods:BMSCs were taken from teenagers(younger than 18 years) with congenital heart diseases,middle(18-40 years) and elderly patients(over 40 years) with valvular diseases.Proliferative abilities were compared among the three groups by using colony-forming unit counting and growth curves(5-bromo-2'-deoxyuridine assay).The BMSCs morphology among three groups was compared as well.FACS flow cytometry was employed for phenotype analysis of BMSCs from three groups.Cell differentiation (differentiation into endothelial cells,adipose cells,and osteoblasts),in vitro release of vascular endothelial growth factor(VEGF) and migratory abilities were compared as well.
Results:Compared with teenager group and middle age group,BMSCs can be separated successfully from bone marrow of aged group.The morphological comparison revealed no significant differences.No significant differences in terms of cell surface marker were
Results:Compared with teenger group and middle age group,BMSCs can be separated successfully from bone marrow of aged group.The morphological comparison revealed no significant differences.No significant differences in terms of cell surface marker were noted between aged and non-aged groups by using FACS flow cytometry. Colony-forming unit counting in teenage group(32±3) was significantly greater than that in middle age group(26±5,p<0.05) and aged group(19±5,p<0.05) and significantly higher counting was observed in middle age group than in aged group (p<0.05).Growth curves presented similar trends in which cells' proliferative abilities in aged group decreased significantly(P<0.05) while no differences were noted between the two non-aged groups.The differentiation potential to endothelial cells,osteoblasts and adipocytes,VEGF release abilities and migratory abilities differed significantly between aged group and non-aged groups(p<0.05).But no differences were noted between the two non-aged groups.
Conclusion:BMSCs from old patients with heart valve diseases could be harvested and expanded successfully.However,the proliferative and differentiation properties of aged cells,as well as migratory abilities,are significantly impaired.Therefore,construction of autologous tissue engineered valves for the old patients should be performed with cautions.
雪旺细胞移植改善急性心肌梗死后神经重构的研究
背景:所谓神经重构指的是心肌梗死边缘区交感神经的过度增殖和交感神经纤维的不均衡分布。既往研究表明,神经重构是造成急性心肌梗死后心律失常的重要原因,而后者则是造成急性心肌梗死后死亡的重要原因。但是目前控制急性心肌梗死后心脏神经重构的手段仍十分有限。雪旺细胞具备强大的神经再生功能,多数研究表明,雪旺细胞可以通过旁分泌和细胞接触机制诱导神经轴突再生,并参与神经鞘基质蛋白的合成,对新生神经轴突给与必要的支撑。因此,本研究拟探讨雪旺细胞在促进心脏神经再生和改善心脏神经重构方面的作用。
方法:在lewis大鼠上成功建立急性心肌梗死模型后,将心肌梗死鼠随机分为细胞移植组(n=80)和对照组(n=72)。雪旺细胞取自lewis大鼠坐骨神经,经体外培养后,经爬片S100染色鉴定雪旺细胞表面标记物,经ELISA方法鉴定雪旺细胞在离体环境下释放神经生长因子和血管内皮生长因子的能力。取2代雪旺细胞5×10~6,注射到心肌梗死周边区。在注入雪旺细胞24小时、1周和2周时间点分别取材,进行组织标本的免疫组化、免疫荧光以及蛋白印记试验。其中,免疫组化指标选择S100、BrdU和CD68,免疫荧光的指标选择酪胺酸羟化酶、乙酰胆碱酯酶和生长相关蛋白43;蛋白印记实验指标选择神经生长因子,血管内皮生长因子,生长相关蛋白43,连接蛋白43和层粘连蛋白。
结果:在不同时间点,比较雪旺细胞移植组和对照组S100染色阳性细胞数。在对照组,急性心肌梗死二十四小时后,S100染色阳性细胞急剧减少;在雪旺细胞移植组,急性心肌梗死二十四小时后,可见多量S100和BrdU同时染色阳性的细胞。随着时间推移,两组S100染色阳性的细胞均增多,但雪旺细胞移植组S100染色阳性细胞显著多于对照组(p<0.05),但是BrdU染色阳性细胞随着时间的推移急剧减少。这提示,急性心肌梗死后,随着时间的推移,心肌内自身雪旺细胞不断再生,而移植的雪旺细胞不断死亡。在心肌梗死后24小时,与对照组相比,在雪旺细胞移植组,神经生长因子、血管内皮生长因子、生长相关蛋白43、连接蛋白43以及层粘连蛋白在心肌内表达无显著差异,而在心肌梗死后一周和两周时,雪旺细胞移植组上述蛋白表达均明显增高。在24小时,植入心肌梗死周边区的雪旺细胞对巨噬细胞起到了明显的趋化作用。但心肌梗死后一周和两周时,两组雪旺细胞计数无差别。在心肌梗死后24小时、一周和两周时,两组心肌梗死周边区交感神经、副交感神经和新生神经纤维密度均有所增高,但在雪旺细胞移植组,心肌梗死后两周时副交感密度与交感密度比值显著高于对照组。但雪旺细胞移植未能改善心功能。
结论:在急性心肌梗死后,心肌梗死周边区植入的雪旺细胞可以释放NGF,吸引巨噬细胞,刺激层粘连蛋白表达,从而提高副交感密度与交感密度比值,进而改善急性心肌梗死后神经重构的发生。雪旺细胞移植有望提供一种全新的细胞治疗手段,具备良好的临床应用前景。
第二部分
年龄对心脏瓣膜种子细胞体外培养增殖的影响
背景当前心脏瓣膜病的治疗主要是通过外科手段完成,但目前所采用的机械瓣和人造瓣膜均存在各自的局限性。有鉴于此,通过生物工程构建自体心脏瓣膜显现出了其自身优势。既往文献表明,间充质干细胞是一种可用于生物组织工程学的良好种子细胞。但是在心脏瓣膜构建中,年龄对作为种子细胞的人类间充质干细胞体外生物学特性的影响尚不明了。本研究目的在于比较不同年龄组人类间充质干细胞体外生物学特性,从而为构建自体心脏瓣膜中种子细胞的选择提供依据。
方法人类间充质干细胞采自不同青少年、中年、老年供体。其中青年组供体为简单先心病患者,年龄在18岁以下;中年组供体为瓣膜病患者,年龄在18到40岁之间;老年组供体为瓣膜病患者,年龄在40岁以上。对三种不同来源干细胞体外增殖能力进行组间比较,BrdU法绘制生长曲线、细胞形成集落个数计数和细胞生长形态及数量表述。通过流式细胞对各组细胞表面标记物进行检测和鉴别。在三组间进行细胞分化(内皮分化,脂肪分化,成骨细胞分化)、体外释放VEGF能力和细胞迁移能力的比较。
结果与青少年组和中年组比较,老年组分离骨髓可以成功提取出间充质干细胞,荧光显微镜下观察其生长、形态等方面与另外两组无显著差别,且流式细胞学检查表明,老年组细胞细胞表面标记物与另两组表达无显著统计学差异。在青少年组(32±3),细胞克隆数量显著高于中年组(26±5,p<0.05)和老年组(19±5,p<0.05);增殖曲线表明,青少年组和中年组细胞增殖能力显著高于老年组(p<0.05)。在干细胞定向分化能力、血管内皮生长因子释放和细胞迁移,青少年组和中年组显著高于老年组(p<0.05)。
结论应用老年供体来源间充质干细胞进行自体组织瓣膜工程构建应采取审慎态度。
Background:Neural remodeling refers to hyperinnervation and uneven distribution of sympathetic nerve fibers around the border of infarcted myocardium.Unbalanced neural remodeling could cause fatal ventricular arrhythmia(VA) and increase mortalities but few strategies are available to suppress the sympathetic remodeling after acute myocardial infarction (MI).Schwann cells have the potential to stimulate nerve regeneration. Numerous reports demonstrated that Schwann cells exert their function through paracrine and cell contact.Moreover,Schwann cells help protein expression which is essential for basal lamina formation.Therefore,this study aims at evaluate the Schwann cells' neurogenesis abilities and explore Schwann cells' potential to balance nerve remodeling.
Methods:Immediately after creation of MI,the rats were randomized into cell transplantation(n=80) and control groups(n=72).Schwann Cells(SCs) were obtained from sciatic nerves.The cells was cultured on tiny glass sheet and stained with SIO0 which is a surface marker of $chwann cells.Release of nerve growth factors(NGF) and vascular endothelial growth factor(VEGF) fromSchwann cells was detected by using ELISA.5×10~6 cells of second passage were intramyocardially injected into the infarcted region.Series histological and immunohistochemical studies were performed at 24 hours, 1 and 2 weeks after cell transplantation.In immunohistochemical studies, SIOO,BrdU,and CD68 staining were performed.As for immunofluorescence study,tyrosine hydroxylase(TH),acetycholinesterase enzyme(AChE),and growth associated protein 43(GAP43) staining were performed.NGF,VEGF, GAP 43,connexin 43,and laminin expression were detected by using western blot.
Results:Comparison of S100 positive cells between control and cell transplantation group.Few cells were stained with S100 24 hours after myocardial infarction in control group,and more cells expressed both S100 and BrdU were detected in cell transplantation group.Growing number of S100 positive cells was observed in both groups with significantly more S100 positive cells in cell transplantation group.The number of transplanted BrdU positive SCs dropped sharply with elapse of time.The expressions of NGF,VEGF,GAP 43,connexin 43,laminin in myocardium were of no significant difference 24 hours after cell transplantation.But the above protein expressions in one week and two weeks were significantly higher in Schwann cell group than in control group.At 24 hours,transplanted SCs significantly attracted macrophage.But no differences of macrophage counting were noted between two groups.At 24 hours,one week,and two weeks,density of sympathetic nerves,parasympathetic nerves,and new-born nerve fibers increased in both groups,but SCs transplantation contributed to the increment of parasympathetic/sympathetic ratio at two weeks after MI.But SCs transplantation didn' t restore the damaged heart function.
Conclusions:Transplanted SCs secreted nerve growth factor,attract macrophage,stimulate expression of laminin and connexin 43,and enhance the ratio of parasympathetic/sympathetic.SCs transplantation might be a promising cell-based antiarrhythmic therapy to balance sympathetic nerve sprouting MI.
Background:Currently,surgical intervention is still the most important option for the treatment of heart valvular diseases.However,although frequently adopted,mechanical valves and bioprosthetic valves have their shortcomings.As a result,autologous heart valve construction catches researchers' eyeballs.Previous studies demonstrated that mesenchymal stem cells are ideal candidates to be seeded on scaffold for valve construction.But the aging effects on the in vitro biological properties of bone marrow-derived mesenchymal stem cells(BMSCs) for construction of tissue engineered heart valves are unclear yet.The aim of this study was to compare in vitro biological properties of BMSCs so as to provide theoretical basis for seed cell selection for autologous heart valve construction.
Methods:BMSCs were taken from teenagers(younger than 18 years) with congenital heart diseases,middle(18-40 years) and elderly patients(over 40 years) with valvular diseases.Proliferative abilities were compared among the three groups by using colony-forming unit counting and growth curves(5-bromo-2'-deoxyuridine assay).The BMSCs morphology among three groups was compared as well.FACS flow cytometry was employed for phenotype analysis of BMSCs from three groups.Cell differentiation (differentiation into endothelial cells,adipose cells,and osteoblasts),in vitro release of vascular endothelial growth factor(VEGF) and migratory abilities were compared as well.
Results:Compared with teenager group and middle age group,BMSCs can be separated successfully from bone marrow of aged group.The morphological comparison revealed no significant differences.No significant differences in terms of cell surface marker were
Results:Compared with teenger group and middle age group,BMSCs can be separated successfully from bone marrow of aged group.The morphological comparison revealed no significant differences.No significant differences in terms of cell surface marker were noted between aged and non-aged groups by using FACS flow cytometry. Colony-forming unit counting in teenage group(32±3) was significantly greater than that in middle age group(26±5,p<0.05) and aged group(19±5,p<0.05) and significantly higher counting was observed in middle age group than in aged group (p<0.05).Growth curves presented similar trends in which cells' proliferative abilities in aged group decreased significantly(P<0.05) while no differences were noted between the two non-aged groups.The differentiation potential to endothelial cells,osteoblasts and adipocytes,VEGF release abilities and migratory abilities differed significantly between aged group and non-aged groups(p<0.05).But no differences were noted between the two non-aged groups.
Conclusion:BMSCs from old patients with heart valve diseases could be harvested and expanded successfully.However,the proliferative and differentiation properties of aged cells,as well as migratory abilities,are significantly impaired.Therefore,construction of autologous tissue engineered valves for the old patients should be performed with cautions.
引文
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