PDF(Pubmed)
Abstract：
The cellular and molecular mechanisms that are responsible for the poor regenerative capacity of the adult heart after myocardial infarction (MI) are still unclear and their understanding is crucial to develop novel regenerative therapies. Considering the lack of reliable in vitro tissue-like models to evaluate the molecular mechanisms of cardiac regeneration, we used cryoinjury on rat Engineered Heart Tissues (rEHTs) as a new model which recapitulates in part the in vivo response after myocardial injury of neonatal and adult heart. When we subjected to cryoinjury immature and mature rEHTs, we observed a significant increase in cardiomyocyte (CM) DNA synthesis when compared to the controls. As expected, the number of mitotic CMs significantly increases in immature rEHTs when compared to mature rEHTs, suggesting that the extent of CM maturation plays a crucial role in their proliferative response after cryoinjury. Moreover, we show that cryoinjury induces a temporary activation of fibroblast response in mature EHTs, similar to the early response after MI, that is however incomplete in immature EHTs. Our results support the hypothesis that the endogenous maturation program in cardiac myocytes plays a major role in determining the proliferative response to injury. Therefore, we propose rEHTs as a robust, novel tool to in vitro investigate critical aspects of cardiac regeneration in a tissue-like asset free from confounding factors in response to injury, such as the immune system response or circulating inflammatory cytokines.
摘要：
导致心肌梗死（MI）后成年心脏再生能力差的细胞和分子机制尚不清楚，他们的理解对于开发新的再生疗法至关重要。考虑到缺乏可靠的体外组织样模型来评估心脏再生的分子机制，我们使用大鼠工程化心脏组织（rEHTs）的冷冻损伤作为一种新模型，该模型部分概括了新生儿和成人心脏心肌损伤后的体内反应。当我们遭受不成熟和成熟的冷冻损伤时，与对照组相比，我们观察到心肌细胞（CM）DNA合成显着增加。不出所料,与成熟的rEHTs相比，未成熟的rEHTs中有丝分裂CM的数量显着增加，表明CM的成熟程度在冷冻损伤后的增殖反应中起着至关重要的作用。此外，我们表明，冷冻损伤诱导成熟EHTs中的成纤维细胞反应的暂时激活，类似于MI后的早期反应，然而，这在不成熟的EHTs中是不完整的。我们的结果支持以下假设：心肌细胞中的内源性成熟程序在确定对损伤的增殖反应中起主要作用。因此,我们建议REHTs作为一个强大的，新的工具，在体外研究心脏再生的关键方面的组织样资产没有混杂因素的响应损伤，如免疫系统反应或循环炎症细胞因子。
