胚胎干细胞的心脏应用

心肌梗死期间死亡的心肌细胞将由没有收缩功能的疤痕组织替代,因而极可能引起心力衰竭。对治疗心衰来说,修复死亡或损伤的心肌以及改善心功能仍面临着极大挑战。干细胞移植已在近年来的实验中用于修复损失的心肌。本文总结了近期在心肌损伤动物中实施胚胎干细胞移植的实验结果,并着重介绍对这类特定细胞的研究进展。胚胎干细胞取源于早期哺乳类胚胎的胚芽细胞,属于多功能干细胞。这类细胞具有长期增殖而不分化的能力,或台色够在培养过程中分化成包括心肌细胞在内的所有特殊体细胞。由于胚胎干细胞具有极大的增殖和分化为成熟组织的能力,它们可能成为一种潜在的很有实用价值的细胞来源,可用于对病态心脏的功能心肌再生的细胞治疗。新近的研究表明,在心肌梗死动物模型中,心肌内移植胚胎干细胞或由其分化成的心肌样细胞,能导致已损伤心肌的再生,并改善心脏功能。另外,在病毒性心肌炎小鼠中,静脉输入胚胎干细胞可明显提高生存率和减轻心肌损伤。有关人类胚胎干细胞在体外分化成心肌细胞以及这些细胞的特性,近来已有报道。然而,要在临床能应用人类胚胎干细胞或由其分化成的心肌细胞来治疗晚期心脏疾病,还必须越过大量的伦理、法律和科学上的障碍。     

骨髓间质干细胞向心肌细胞分化的可塑性及应用研究进展

减少心肌缺血后损伤,促进心肌细胞和血管再生是治疗心肌缺血损伤、心力衰竭的重要思路,而干细胞移植为该思路带来了新的曙光。骨髓间质干细胞（-mesenchymal stem cells,MSCs）,也称为骨髓基质细胞,能分化为骨、软骨和脂肪细胞表型。研究表明,MSCs还能分化为内皮细胞、神经细胞、平滑肌细胞、骨骼肌细胞和心肌细胞表型。MSCs具有多向分化的潜能,且自体移植可以避免免疫排斥反应,同时也易于在体外大量扩增。研究显示,MSCs移植能抑制损伤心肌的重塑和改善心肌功能。因此,骨髓间质干细胞移植给人们展示了一个诱入的前景。本文综述了近年来有关MSCs特性的新认识,尤其是MSCs向心肌细胞方向分化的可塑性、影响因素和信号转导机制,以及MSCs治疗心肌梗死的动物实验和临床研究进展。     

骨髓基质干细胞向心肌细胞诱导分化的实验研究

目的探讨大鼠骨髓基质干细胞在体外和体内向心肌细胞诱导分化的能力,为下一步的细胞移植治疗心肌梗死提供实验基础.方法体外诱导实验中,将不同浓度的5-氮胞苷作用于不同培养时间的骨髓基质干细胞,摸索5-氮胞苷的最佳诱导时机和浓度,观察诱导后细胞形态变化,并用免疫细胞化学染色检测心肌特异性肌钙蛋白T的表达;在体内实验中,培养扩增的骨髓基质干细胞经BrdU标记后,自体移植于正常心肌内,分别通过BrdU和心肌特异性肌钙蛋白T免疫组织化学染色检测移植细胞的存活和分化情况.结果体外诱导实验中,5-氮胞苷的诱导作用以10μmol/L的浓度对传代细胞进行两次诱导,效果最好,不仅能诱导出表达心肌特异蛋白的心肌样细胞,而且这些细胞在体外能够自发搏动.体内诱导实验中,移植的细胞在正常心肌微环境中能够存活并分化为心肌细胞.结论骨髓基质干细胞在体外化学诱导和体内心肌微环境诱导时均能分化为心肌细胞,可用于细胞移植治疗心肌梗死的实验.     

诱导胚胎干细胞心肌定向分化的方法及其机制

胚胎干细胞是具有分化为各种类型组织细胞潜能的全能干细胞,可在体外大量扩增,细胞因子、激素、诱导剂和细胞内转录因子等可诱导和调控胚胎干细胞进行心肌细胞定向分化．这将使干细胞移植治疗心肌损伤性疾病成为可能。该文介绍胚胎干细胞定向心肌分化的诱导因素及其机制的研究进展。     

干细胞移植治疗心力衰竭的研究进展

由于心肌梗死发作等原因可造成心肌受损、心力衰竭。干细胞可以向心肌细胞定向分化,这使得通过细胞移植治疗心力衰竭成为可能。简要综述了有望用于移植的干细胞,以及目前实验与临床研究进展和面临的问题。     

胚胎干细胞及诱导多能干细胞向心肌细胞分化和调控的研究进展

胚胎干细胞（embryonic stem cells,ESCs）具有自我更新、无限增殖和多向分化的特性,包括分化成心脏组织的多种类型细胞。经体细胞重编程产生的诱导多能干细胞（induced pluripotent stem cells,iPS）也被证明有类似胚胎干细胞的特性。但这些多能干细胞向心肌细胞自发分化的效率非常低,因此,如何有效地诱导这些多能干细胞向心肌细胞的定向分化对深入认识心肌发生发育的关键调控机制和实现其在药物发现和再生医学,如心肌梗塞、心力衰竭的细胞治疗以及心肌组织工程中的应用均具有非常重要的意义。该文重点综述了近年来胚胎干细胞及诱导多能干细胞向心肌细胞分化和调控的研究进展,并探讨了这一研究领域亟待解决的关键问题和这些多能干细胞的应用前景。     

心脏干/祖细胞与心肌损伤修复

细胞移植是一种有希望的组织再生的治疗手段.多种类型的细胞已经用于动物心 肌损伤的修复中,包括胚胎干细胞、胚胎和新生动物的心肌细胞、骨骼肌成肌细胞、 骨髓干细胞、脂肪来源的干细胞、可诱导的多能干细胞等.但是,这些用于移植的细胞 存在成活率低、在心脏局部存留少、与宿主心肌细胞不能整合和免疫排斥等问题,这 些问题限制了它们的应用.心脏自身存在的干细胞因为没有其他来源细胞存在的种种 问题,因而成为备受关注的治疗心肌梗死的种子细胞.但是,心脏干/祖细胞也有自身 弊端,包括干细胞群的细胞生物学或遗传学标志没有统一,在心肌中数量极少,体外 扩增能力有限等,因而限制了心脏干/祖细胞的有效应用.如何能有效动员和促进心脏 干/祖细胞增殖,依赖于人们对心脏干/祖细胞增殖、分化、归巢的调控机制,包括心 脏干/祖细胞修复损伤心肌的分子机制的深入了解.本文将就近年来在心脏再生领域中 ,心脏干/祖细胞的研究新进展进行综述.     

脂肪间充质干细胞体外分化成心肌样细胞

探讨大鼠脂肪间充质干细胞（adipose-derived mesenchymal stem cells,AMSC）体外分化成心肌样细胞的潜能,为自体干细胞移植治疗心肌梗死提供理论基础.采用消化法分离大鼠AMSC,培养于RPMI1640生长培养基中,倒置相差显微镜观察细胞形态发现,随着培养时间的延长,细胞形态趋向于心肌细胞,SQ RT-PCR检测表达心肌特异性基因：β-肌球蛋白重链（β-MHC）、α-肌球蛋白重链（α-MHC）、心房利钠肽（ANP）、心肌肌钙蛋白（cTnT）、心肌肌动蛋白、肌肉增强因子和GATA-4;免疫细胞化学和免疫荧光染色检测表达心肌细胞特异性蛋白：结蛋白、横纹肌辅肌动蛋白、心肌肌动蛋白和间隙连接蛋白45(connexin 45);Western印迹检测表达心肌特异性蛋白Nkx2.5. 实验表明,大鼠AMSC在体外培养条件下能分化成心肌样细胞,在组织工程学及干细胞移植领域有着良好的应用前景.     

胚胎干细胞治疗心肌梗死的研究进展

胚胎干细胞 (ES细胞 )是一种多能细胞 ,来源于囊胚期胚胎 ,具有很强的自我更新能力 ,并能分化成很多细胞类型。体外 ,ES细胞能自发聚集形成胚胎体 (EB) ,分化成许多种细胞类型 ;ES细胞注射到免疫缺陷的小鼠体内 ,产生畸胎瘤 ,其中包含有三个胚层的细胞。添加生长因子或与其它细胞共培养等方法可以促进ES细胞体外分化为心肌细胞 ,筛选后移植到梗死的心肌 ,可以提高心脏功能 ,是治疗心肌梗死的一种很有潜力的方法     

间充质干细胞分化为心肌细胞的诱导方法研究进展

间充质干细胞作为一种取材方便、易于分离培养、体外扩增快、免疫原性低的成体干细胞,具有自我更新和多向分化潜能,可在体内外不同的诱导条件下分化为心肌细胞,是理想的心肌再生治疗的种子细胞。本文综述了间充质干细胞分化为心肌细胞的诱导方法,包括化学试剂、中药制剂、机械力和电磁刺激、心肌环境因子、损伤组织条件培养、组织工程方法等,为其在心肌损伤性疾病尤其是心肌梗死治疗中的应用提供基础。     

TGF-β superfamily regulates a switch that mediates differentiation either into adipocytes or myocytes in left atrium derived pluripotent cells (LA-PCS)

Many stem cell studies have focused on the subject of cell fate and the signal molecules that modulate the regulatory switches for a given differentiation pathway. Genome-wide screens for cell fate determination signals require a cell source that differentiates purely into a single cell type. From adult rat left atrium, we established LA-PCs that differentiates into cardiac/skeletal myocytes or adipocytes with almost 100% purity. In this study, we compared gene expression profiles of undifferentiated LA-PCs with those of differentiated cells [adipocytes (Adi) or cardiac/skeletal myocytes (Myo)] to identify the signals that set the regulatory switch for adipocyte or myocyte differentiation. Microarray analysis verified the feasibility of genome-wide screening by this method. Using a pathway analysis screen, we found that members of the TGF-β superfamily signal transduction pathways modulate the adipocyte/myocyte differentiation switch. Further analysis determined that recombinant TGF-β inhibits adipogenesis and induces myogenesis simultaneously in a dose-dependent manner. Moreover, noggin induces differentiation into fully developed beating cardiac myocytes in vitro. These results provided new insight into the molecules that modulate the differentiation switch and validated a screening method for their identification.     

Cardiac stem/progenitor cells, secreted proteins, and proteomics

Stem cell-based therapy is emerging as a novel approach for myocardial repair over conventional cardiovascular therapies. In addition to embryonic stem cells and adult stem cells from noncardiac sources, there is a small population of resident stem cells in the heart from which new cardiac cells (myocytes, vascular endothelial cells and smooth muscle cells) can be derived and used for cardiac repair in case of heart injury. It has been proposed that the clinical benefit of stem cells may arise from secreted proteins that mediate regeneration in a paracrine/autocrine manner. To be able to track the regulatory pathway on a molecular basis, utilization of proteomics in stem cell research is essential. Proteomics offers a tool that can address questions regarding stem cell response to disease/injury.     

胚胎干细胞分化过程中的表观遗传调控

作为一类既有自我更新能力,并具有多向分化潜能的细胞,胚胎干细胞具有非常重要的理论研究意义和临床应用前景。近期以胚胎干细胞为模型,研究有关干细胞分化的表观遗传调控已成为新的研究热点。本文就胚胎干细胞分化过程中DNA甲基化、组蛋白修饰、非编码RNA调控以及与胚胎干细胞分化密切相关的表观遗传学动态变化做一概述,对表观遗传学改变与胚胎干细胞分化关系的基础研究进行探讨。     

The cardiac differentiation of bone marrow stem cells might be not important for heart repair

Lots of evidence showed that bone marrow stem cells can differentiate into cardiac myocytes so as to treat damaged hearts. However, the following studies revealed that bone marrow stem cells also produced protective effects on hearts by releasing some beneficial cytokines and suppressing inflammatory effects and so on. Therefore, we speculated that the cardiac differentiation of bone marrow stem cells did not play an important role in cardiac repair.     

干细胞治疗糖尿病的研究进展

糖尿病是严重危害人类健康的疾病,近年来,随着干细胞理论及技术的发展,很多科学家都致力于应用干细胞治疗糖尿病,并取得了显著成效。干细胞移植治疗糖尿病的关键是干细胞的来源和定向诱导分化的手段,该文简要综述了目前在这些方面取得了诸多成果以及存在的问题。     

干细胞向甲状旁腺细胞的分化及在甲状旁腺功能减退中的研究进展

干细胞是一类能够自我复制、自我更新,具有多向分化潜能,能产生多种分化细胞类型的细胞,由于它的自我复制和多向分化潜能,干细胞技术已经被广泛的应用于细胞移植治疗中。甲状旁腺功能减退作为一种内分泌疾病,目前的治疗方案都不能从根本上治疗该疾病。因此应用干细胞来源的甲状旁腺细胞移植治疗甲状旁腺功能减退越来越受到医学界的重视。目前,已有科研团队报道了应用胚胎干细胞（ESCs）、胸腺上皮细胞和扁桃体间充质细胞向甲状旁腺细胞分化及其在甲状旁腺功能减退中的治疗。本文将干细胞向甲状旁腺细胞的分化及在甲状旁腺功能减退治疗中的研究进展进行综述。     

Enhancement by growth factors of cardiac myocyte differentiation from embryonic stem cells: a promising foundation for cardiac regeneration

Cell transplantation is a promising, still novel, potentially therapeutic approach for the treatment of heart diseases. Clinical applications require generation of large number of donor cells. Embryonic stem (ES) cells are capable of self-renewal apparently in an unlimited fashion, in vitro. Theoretically, they can differentiate into any cell type required for cell transplantation, including cardiac myocytes. Diverse growth factors have been implicated in programming diverse cellular processes, including development of the embryonic heart, ES cell self-renewal, and cardiac myocyte differentiation from ES cells. This review addresses the current understanding of the role of growth factors in the differentiation of cardiac myocytes from ES-embryoid body cell systems in vitro as well as cardiac regeneration in vivo.     

Hepatocyte growth factor (HGF) promotes cardiac stem cell differentiation after myocardial infarction by increasing mTOR activation in p27<Superscript>kip</Superscript> haploinsufficient mice

Myocardial infarction (MI) is a major cause of death worldwide. The treatment of MI has improved during the last decade; however, the loss of myocytes remains a problem because the cells cannot be renewed. Cardiac stem cells were recently discovered and were thought to represent a promising treatment for MI. However, the efficiency of cardiac stem cell differentiation into myocyte is not sufficient. Hepatocyte growth factor (HGF) is related to the differentiation and proliferation of cardiac stem cells. p27^kip1 is a potent cell cycle inhibitor in most organs, especially the heart. In this study, we investigated the relationship among p27, HGF and cardiac stem cells in post-MI cardiac repair. We found that p27 haploinsufficient mice exhibited preserved cardiac function and improved cardiomyocyte renewal compared with wild-type mice. In addition, p27 haploinsufficiency may not increase cardiac stem cell proliferation but could improve their differentiation by increasing mammalian target of rapamycin expression.     

ABC transporters, neural stem cells and neurogenesis--a different perspective

Stem cells intrigue. They have the ability to divide exponentially, recreate the stem cell compartment, as well as create differentiated cells to generate tissues. Therefore, they should be natural candidates to provide a renewable source of cells for transplantation applied in regenerative medicine. Stem cells have the capacity to generate specific tissues or even whole organs like the blood, heart, or bones. A subgroup of stem cells, the neural stem cells （NSCs）, is characterized as a self-renewing population that generates neurons and glia of the developing brain. They can be isolated, genetically manipulated and differentiated in vitro and reintroduced into a developing, adult or a pathologically altered central nervous system. NSCs have been considered for use in cell replacement therapies in various neurodegenerative diseases such as Parkinson＇s disease and Alzheimer＇s disease. Characterization of genes with tightly controlled expression patterns during differentiation represents an approach to understanding the regulation of stem cell commitment. The regulation of stem cell biology by the ATP-binding cassette （ABC） transporters has emerged as an important new field of investigation. As a major focus of stem cell research is in the manipulation of cells to enable differentiation into a targeted cell population; in this review, we discuss recent literatures on ABC transporters and stem cells, and propose an integrated view on the role of the ABC transporters, especially ABCA2, ABCA3, ABCB 1 and ABCG2, in NSCs＇ proliferation, differentiation and regulation, along with comparisons to that in hematopoietic and other stem cells.