Mechanical response of cardiac microtissues to acute localized injury.
Mechanical response of cardiac microtissues to acute localized injury.
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DOI：
10.1152/ajpheart.00305.2022
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发表时间：
2022-10-01
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心肌梗死（MI）后，心脏发生变化，包括局部重塑，可导致机械和电气特性的局部异常，最终增加心律失常和心力衰竭的风险。虽然这些反应已成功地重现在心肌梗死的动物模型，局部变化的组织和细胞水平的机械引起的心肌梗死仍然难以在体内研究。在这里，我们开发了一种体外心脏微组织（CMT）损伤系统，通过急性局灶性损伤概括了心肌梗死后所见的区域反应。使用脉冲激光，在微组织的中心诱导细胞死亡，导致钙信号传导的损失和损伤区域收缩功能的完全丧失，并导致CMT的总力产生减少39%。7天后，损伤区域仍然没有心肌细胞（CM），并显示波形蛋白和纤连蛋白（纤维化重塑的两个标志物）的表达增加。有趣的是，虽然受伤的区域表现出最小的恢复，在未受伤的区域钙振幅恢复到与对照组相当的水平。此外，尽管受伤区域缺乏收缩功能，但整体力量生产恢复到损伤前水平。相反，未受伤的区域表现出升高的收缩功能，补偿了受伤区域的功能丧失，与体内观察到的组织水平力学变化相似。总之，这项工作提出了一个新的体外模型，研究心脏组织重塑和损伤后的机电变化。我们报告了一种体外心脏损伤模型，该模型使用高功率激光在人类工程心脏微组织内诱导局部细胞死亡和局灶性纤维化反应。该模型捕捉了急性损伤对受损区域和周围健康组织中的组织反应、重塑和机电恢复的影响，模拟了心肌梗死后体内观察到的收缩功能的类似变化。
After a myocardial infarction (MI), the heart undergoes changes including local remodeling that can lead to regional abnormalities in mechanical and electrical properties, ultimately increasing the risk of arrhythmias and heart failure. Although these responses have been successfully recapitulated in animal models of MI, local changes in tissue and cell-level mechanics caused by MI remain difficult to study in vivo. Here, we developed an in vitro cardiac microtissue (CMT) injury system that through acute focal injury recapitulates aspects of the regional responses seen following an MI. With a pulsed laser, cell death was induced in the center of the microtissue causing a loss of calcium signaling and a complete loss of contractile function in the injured region and resulting in a 39% reduction in the CMT’s overall force production. After 7 days, the injured area remained void of cardiomyocytes (CMs) and showed increased expression of vimentin and fibronectin, two markers for fibrotic remodeling. Interestingly, although the injured region showed minimal recovery, calcium amplitudes in uninjured regions returned to levels comparable with control. Furthermore, overall force production returned to preinjury levels despite the lack of contractile function in the injured region. Instead, uninjured regions exhibited elevated contractile function, compensating for the loss of function in the injured region, drawing parallels to changes in tissue-level mechanics seen in vivo. Overall, this work presents a new in vitro model to study cardiac tissue remodeling and electromechanical changes after injury. NEW & NOTEWORTHY We report an in vitro cardiac injury model that uses a high-powered laser to induce regional cell death and a focal fibrotic response within a human-engineered cardiac microtissue. The model captures the effects of acute injury on tissue response, remodeling, and electromechanical recovery in both the damaged region and surrounding healthy tissue, modeling similar changes to contractile function observed in vivo following myocardial infarction.
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64.8
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