Induced pluripotent stem cell-derived cardiac progenitors differentiate to cardiomyocytes and form biosynthetic tissues.
Induced pluripotent stem cell-derived cardiac progenitors differentiate to cardiomyocytes and form biosynthetic tissues.
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DOI：
10.1371/journal.pone.0065963
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Leong KW
中科院分区：
文献类型：
--
作者：
Christoforou N;Liau B;Chakraborty S;Chellapan M;Bursac N;Leong KW
哺乳动物的心脏几乎没有再生能力，并且在损伤后，心肌被非收缩性瘢痕组织所取代。因此，剩余心肌上增加的壁应力和工作负荷导致腔室扩张、功能障碍和心力衰竭。利用自体的、表观遗传重编程的和心脏定向祖细胞来源的基于细胞的治疗可以通过用功能组织替换受损的心肌来潜在地逆转这一过程。然而，目前尚不清楚心脏祖细胞衍生的心肌细胞是否能够达到与终末心肌细胞相当的结构和功能成熟水平。在这里，我们首先描述了小鼠诱导多能干细胞（iPS）的衍生，一旦分化允许富集Nkx 2 -5（+）心脏祖细胞，和心肌细胞特异性表达的红色荧光蛋白。我们发现，心脏祖细胞是多能的，能够分化为内皮细胞，平滑肌细胞和心肌细胞。此外，心脏祖细胞选择对应于cKit（+）细胞富集，而心肌细胞谱系定型伴随着cKit/Flk 1或cKit/Sca-1的双重表达。我们继续表明，心脏祖细胞衍生的心肌细胞能够形成具有成熟电生理特性的电和机械耦合的大规模2D细胞培养物。最后，我们使用生理学相关的3D培养模型检查了细胞祖细胞形成机电相干宏观组织的能力，并证明了在长期培养后，心肌细胞对齐，并在整个生物合成组织构建体的体积中形成稳健的机电连接。我们的结论是，iPS细胞衍生的心脏祖细胞是一个强大的细胞来源的组织工程应用和3D培养平台的药理学筛选和药物开发研究。
The mammalian heart has little capacity to regenerate, and following injury the myocardium is replaced by non-contractile scar tissue. Consequently, increased wall stress and workload on the remaining myocardium leads to chamber dilation, dysfunction, and heart failure. Cell-based therapy with an autologous, epigenetically reprogrammed, and cardiac-committed progenitor cell source could potentially reverse this process by replacing the damaged myocardium with functional tissue. However, it is unclear whether cardiac progenitor cell-derived cardiomyocytes are capable of attaining levels of structural and functional maturity comparable to that of terminally-fated cardiomyocytes. Here, we first describe the derivation of mouse induced pluripotent stem (iPS) cells, which once differentiated allow for the enrichment of Nkx2-5(+) cardiac progenitors, and the cardiomyocyte-specific expression of the red fluorescent protein. We show that the cardiac progenitors are multipotent and capable of differentiating into endothelial cells, smooth muscle cells and cardiomyocytes. Moreover, cardiac progenitor selection corresponds to cKit(+) cell enrichment, while cardiomyocyte cell-lineage commitment is concomitant with dual expression of either cKit/Flk1 or cKit/Sca-1. We proceed to show that the cardiac progenitor-derived cardiomyocytes are capable of forming electrically and mechanically coupled large-scale 2D cell cultures with mature electrophysiological properties. Finally, we examine the cell progenitors’ ability to form electromechanically coherent macroscopic tissues, using a physiologically relevant 3D culture model and demonstrate that following long-term culture the cardiomyocytes align, and form robust electromechanical connections throughout the volume of the biosynthetic tissue construct. We conclude that the iPS cell-derived cardiac progenitors are a robust cell source for tissue engineering applications and a 3D culture platform for pharmacological screening and drug development studies.
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DOI：
10.1126/science.1177350
发表时间：
2009-10-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Domian IJ;Chiravuri M;van der Meer P;Feinberg AW;Shi X;Shao Y;Wu SM;Parker KK;Chien KR
通讯作者：
Chien KR
影响因子：
4.8
作者：
Hong, YK;Lange-Asschenfeldt, B;Detmar, M
通讯作者：
Detmar, M
影响因子：
4.5
作者：
Kamkin, A;Kiseleva, I;Isenberg, G
通讯作者：
Isenberg, G
影响因子：
5.2
作者：
Gepstein, Lior;Ding, Chunhua;Olgin, Jeffery E.
通讯作者：
Olgin, Jeffery E.
影响因子：
15.9
作者：
Klug, MG;Soonpaa, MH;Field, LJ
通讯作者：
Field, LJ