An in vitro model for the assessment of stem cell fate following implantation within the infarct microenvironment identifies ISL-1 expression as the strongest predictor of c-Kit(+) cardiac progenitor cells' therapeutic potential.
An in vitro model for the assessment of stem cell fate following implantation within the infarct microenvironment identifies ISL-1 expression as the strongest predictor of c-Kit(+) cardiac progenitor cells' therapeutic potential.
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DOI：
10.1016/j.yjmcc.2015.09.007
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发表时间：
2015-11
影响因子：
5
通讯作者：
Black LD 3rd
中科院分区：
文献类型：
--
作者：
Sullivan KE;Burns LJ;Black LD 3rd
细胞疗法有可能大大改善美国每年145万心肌梗死（MI）患者的临床结局，然而，与这种治疗相关的局限性-包括植入不良，显著的细胞死亡和分化潜力差-阻碍了其在临床上的广泛应用。为了优化移植细胞提供的功能改善，需要开发增加细胞保留和活力，同时支持分化和促进旁分泌信号传导的方法。目前的体内模型是昂贵的，难以访问和操作，并且是耗时的。我们已经开发了一种体外MI模型，该模型可以直接、一致和相对准确地预测体内注射后的细胞命运。该模型证明了梗死环境如何损害细胞植入和分化，但确定了一种植入策略，增强了体外细胞命运。多元线性回归确定了模型中调节血管分化潜能的变量，包括氧张力、硬度和细胞因子的存在，而通过原始细胞分离物中Isl-1表达比模型系统中存在的任何其他变量更准确地预测心脏分化。该模型强调了细胞对梗死变量的敏感性如何从一行到另一行变化，这强调了模型系统在患者特定基础上预测细胞命运的重要性。该模型系统的进一步开发可以帮助预测患者水平的心脏祖细胞治疗的临床疗效，以及确定细胞递送的最佳策略。
Cell therapy has the potential to drastically improve clinical outcomes for the 1.45 million patients suffering from a myocardial infarction (MI) each year in the U.S. However, the limitations associated with this treatment -including poor engraftment, significant cell death and poor differentiation potential - have prevented its widespread application clinically. To optimize functional improvements provided by transplanted cells, there is a need to develop methods that increase cellular retention and viability, while supporting differentiation and promoting paracrine signaling. Current in vivo models are expensive, difficult to access and manipulate and are time consuming. We have developed an in vitro model of MI which allows for a straightforward, consistent and relatively accurate prediction of cell fate following injection in vivo. The model demonstrated how the infarct environment impairs cellular engraftment and differentiation, but identified an implantation strategy which enhanced cell fate in vitro. Multivariate linear regression identified variables within the model that regulated vascular differentiation potential including oxygen tension, stiffness and cytokine presence, while cardiac differentiation was more accurately predicted by Isl-1 expression in the original cell isolate than any other variable present within the model system. The model highlighted how the cells’ sensitivity to the infarct variables varied from line to line, which emphasizes the importance of the model system for the prediction of cell fate on a patient specific basis. Further development of this model system could help predict the clinical efficacy of cardiac progenitor cell therapy at the patient level as well as identify the optimal strategy for cell delivery.