孤雌胚胎干细胞移植治疗小鼠心肌梗死的研究
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摘要
心肌梗死（MI）是冠心病中最严重的一种表现，致死率和死亡率极高，严重威胁着人类的健康。临床上对MI的疗法虽然能极大地降低死亡率，但因缺血导致的大量心肌细胞坏死不可逆转，病人的预后很不理想。干细胞研究的发展给MI的治疗带来了新的方向，干细胞移植已成为治疗MI的有效手段。大量的动物实验和临床试验表明，干细胞移植到缺血心肌后可有效减小梗死面积、抑制心室重构并显著改善心脏功能。
胚胎干细胞（ESCs）由于其发育上的全能性一直被视为干细胞治疗中理想的细胞来源，将ESCs移植到缺血心肌中虽然能再生心肌细胞并发挥对损伤心肌的修复作用，但是有生成畸胎瘤的危险。孤雌胚胎干细胞（pESCs）可为ESCs提供另外一种来源，与ESCs具有类似的分化潜能，因而也是一种良好的干细胞来源。pESCs分离自人工激活的卵子发育成的孤雌囊胚，单性来源使其具有低免疫源性，并且可绕过一些伦理争议而被接受。目前还没有关于pESCs移植用于治疗MI的相关报导，我们旨在研究pESCs直接移植到小鼠梗死心脏后的分化情况、其对缺血心肌的修复作用、对心室重构和心功能的影响以及其直接移植的安全性等问题，并探讨相关机制。
本论文应用小鼠心肌梗死模型来探究pESCs对缺血心肌的修复作用，在实验中我们设置了分离自受精卵来源的ESCs移植组为治疗的对照组。通过结扎小鼠（n=89）左前降支冠状动脉致心肌梗死，然后分别移植2.0×10~5pESCs或ESCs，不治疗组注射等量的生理盐水，同时设不结扎LAD的假手术组（n=21）。根据不同研究目的，动物分别于7天、14天、30天和90天处死。我们发现，移植7天时，pESCs可有效增加心肌局部一些促血管生成因子的表达，并显著抑制梗死区内的白细胞浸润。较长期研究显示，移植的pESCs可迁移到梗死区内，并在缺血心肌内环境中可分化成心肌样细胞和血管样细胞，从而参与损伤心肌的修复。对于心脏功能的检测发现，pESC组的心功能得到了显著的改善，并可维持较长时期。组织学分析表面移植pESCs可有效减小梗死面积，并可抑制左室胶原沉积、室腔膨大和心肌肥大等心梗后的心室重构。血管化分析显示pESCs移植可显著增强缺血心肌内的血管密度，进而改善梗死区的血供。值得注意的是，直到30天，移植pESCs的小鼠心脏中未发现有畸胎瘤生成，而ESCs移植组则生成较高比率的畸胎瘤（6/34），但是在长期研究中（90天），pESCs治疗组出现2例心肌内畸胎瘤，说明pESCs直接移植也有一定的安全隐患。
总之，本论文首次阐明了pESCs有望作为治疗心肌梗死的良好干细胞来源，其移植可在缺血心肌内释放旁分泌因子、能够减缓炎症反应、可分化为心肌和血管样细胞、能有效促进血管新生、可显著改善心功能和心室重构情况，并且直接移植较ESCs的致瘤性低。
Myocardial infarction (MI), one kind of the most serious symptoms of coronaryheart disease, is one of the leading causes of morbidity and mortality in the world.The clinical treatments for MI can greatly reduce the mortality, however, theprognosis is not ideal since the necrosis of large amount of cardiomyocytes due toischemic damage can not be reversed. Recent advances in stem cell biology havebrought about considerable hopes for the development of novel therapeutic strategiessuch as stem cell transplantation, which has been considered as one promising andeffective approach. A great deal of animal experiments showed that stem celladministration could effectively reduce the infarct size, restrain the cardiacremodeling and improve the heart function.
Embryonic stem cells (ESCs) are a promising source of cardiomyocytes for cardiactherapy owing to their germline competency. Transplantation of ESCs can regeneratecardiomyocytes and repair the damaged myocardium, while, the risk of teratomaformation bothers its application. Parthenogenetic embryonic stem cells (pESCs) canprovide an alternative source for ESCs with strong differentiation capacity and mayserve as attractive candidates for regenerative medicine and stem cell therapy. pESCsare derived from artificially activated oocytes without fertilization and therefore raiseminimal ethical concerns and reduce cell immunogenicity. Since there have been noreports about the use of pESCs in MI treatment, we thought to investigate theircardiac repair capacity and focused on the differentiation, the effect on cardiacremodeling and heart function and the safety issue by intramyocardial-deliveredpESCs into acute MI-modeling mice.
In the current study, we tested the cardiac repair effects and the safety issue ofpESCs transplantation on mouse MI model by direct comparison with those of ESCs.Mice (n=89) survived coronary ligation randomly received undifferentiated pESCs,ESCs, or saline. Sham-operated mice received no treatment (n=21). Animals weresacrificed in batches7,14,30and90days post MI on basis of different study purposes. After7days, pESCs transplantation promoted pro-angiogenic factorssecretion and reduced infiltrated leukocytes. Tissues regenerated from the engraftedpESCs in the infarcted myocardium were positive for cardiomyocyte, endothelial celland smooth muscle cell markers, indicating their cardiac and vascular differentiationin longer term studies. pESCs-treated hearts, superior to ESC group, showedprevented cardiac remodeling and enhanced angiogenesis in14and30days post MI.Heart contractile function was notably improved by administration of pESCs by30days and such benefits could be maintained three months. Furthermore, teratomafomation appeared in ESCs-treated mice in high proportion (6/34), but surprisinglynot found in pESCs-treated mice (0/30) by30days. Two intramyocardial teratomas,while, appeared in pESCs-grafted group in90days, which suggest the transplantationof pESCs was not absoultly safe.
In conclusion, cardiac dysfunction and adverse ventricular remodeling post MIwere attenuated by pESCs transplantation, which may represent an effective andrelatively safer strategy for autologous cell therapy in females.
胚胎干细胞（ESCs）由于其发育上的全能性一直被视为干细胞治疗中理想的细胞来源，将ESCs移植到缺血心肌中虽然能再生心肌细胞并发挥对损伤心肌的修复作用，但是有生成畸胎瘤的危险。孤雌胚胎干细胞（pESCs）可为ESCs提供另外一种来源，与ESCs具有类似的分化潜能，因而也是一种良好的干细胞来源。pESCs分离自人工激活的卵子发育成的孤雌囊胚，单性来源使其具有低免疫源性，并且可绕过一些伦理争议而被接受。目前还没有关于pESCs移植用于治疗MI的相关报导，我们旨在研究pESCs直接移植到小鼠梗死心脏后的分化情况、其对缺血心肌的修复作用、对心室重构和心功能的影响以及其直接移植的安全性等问题，并探讨相关机制。
本论文应用小鼠心肌梗死模型来探究pESCs对缺血心肌的修复作用，在实验中我们设置了分离自受精卵来源的ESCs移植组为治疗的对照组。通过结扎小鼠（n=89）左前降支冠状动脉致心肌梗死，然后分别移植2.0×10~5pESCs或ESCs，不治疗组注射等量的生理盐水，同时设不结扎LAD的假手术组（n=21）。根据不同研究目的，动物分别于7天、14天、30天和90天处死。我们发现，移植7天时，pESCs可有效增加心肌局部一些促血管生成因子的表达，并显著抑制梗死区内的白细胞浸润。较长期研究显示，移植的pESCs可迁移到梗死区内，并在缺血心肌内环境中可分化成心肌样细胞和血管样细胞，从而参与损伤心肌的修复。对于心脏功能的检测发现，pESC组的心功能得到了显著的改善，并可维持较长时期。组织学分析表面移植pESCs可有效减小梗死面积，并可抑制左室胶原沉积、室腔膨大和心肌肥大等心梗后的心室重构。血管化分析显示pESCs移植可显著增强缺血心肌内的血管密度，进而改善梗死区的血供。值得注意的是，直到30天，移植pESCs的小鼠心脏中未发现有畸胎瘤生成，而ESCs移植组则生成较高比率的畸胎瘤（6/34），但是在长期研究中（90天），pESCs治疗组出现2例心肌内畸胎瘤，说明pESCs直接移植也有一定的安全隐患。
总之，本论文首次阐明了pESCs有望作为治疗心肌梗死的良好干细胞来源，其移植可在缺血心肌内释放旁分泌因子、能够减缓炎症反应、可分化为心肌和血管样细胞、能有效促进血管新生、可显著改善心功能和心室重构情况，并且直接移植较ESCs的致瘤性低。
Myocardial infarction (MI), one kind of the most serious symptoms of coronaryheart disease, is one of the leading causes of morbidity and mortality in the world.The clinical treatments for MI can greatly reduce the mortality, however, theprognosis is not ideal since the necrosis of large amount of cardiomyocytes due toischemic damage can not be reversed. Recent advances in stem cell biology havebrought about considerable hopes for the development of novel therapeutic strategiessuch as stem cell transplantation, which has been considered as one promising andeffective approach. A great deal of animal experiments showed that stem celladministration could effectively reduce the infarct size, restrain the cardiacremodeling and improve the heart function.
Embryonic stem cells (ESCs) are a promising source of cardiomyocytes for cardiactherapy owing to their germline competency. Transplantation of ESCs can regeneratecardiomyocytes and repair the damaged myocardium, while, the risk of teratomaformation bothers its application. Parthenogenetic embryonic stem cells (pESCs) canprovide an alternative source for ESCs with strong differentiation capacity and mayserve as attractive candidates for regenerative medicine and stem cell therapy. pESCsare derived from artificially activated oocytes without fertilization and therefore raiseminimal ethical concerns and reduce cell immunogenicity. Since there have been noreports about the use of pESCs in MI treatment, we thought to investigate theircardiac repair capacity and focused on the differentiation, the effect on cardiacremodeling and heart function and the safety issue by intramyocardial-deliveredpESCs into acute MI-modeling mice.
In the current study, we tested the cardiac repair effects and the safety issue ofpESCs transplantation on mouse MI model by direct comparison with those of ESCs.Mice (n=89) survived coronary ligation randomly received undifferentiated pESCs,ESCs, or saline. Sham-operated mice received no treatment (n=21). Animals weresacrificed in batches7,14,30and90days post MI on basis of different study purposes. After7days, pESCs transplantation promoted pro-angiogenic factorssecretion and reduced infiltrated leukocytes. Tissues regenerated from the engraftedpESCs in the infarcted myocardium were positive for cardiomyocyte, endothelial celland smooth muscle cell markers, indicating their cardiac and vascular differentiationin longer term studies. pESCs-treated hearts, superior to ESC group, showedprevented cardiac remodeling and enhanced angiogenesis in14and30days post MI.Heart contractile function was notably improved by administration of pESCs by30days and such benefits could be maintained three months. Furthermore, teratomafomation appeared in ESCs-treated mice in high proportion (6/34), but surprisinglynot found in pESCs-treated mice (0/30) by30days. Two intramyocardial teratomas,while, appeared in pESCs-grafted group in90days, which suggest the transplantationof pESCs was not absoultly safe.
In conclusion, cardiac dysfunction and adverse ventricular remodeling post MIwere attenuated by pESCs transplantation, which may represent an effective andrelatively safer strategy for autologous cell therapy in females.
引文
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