Department of Bioengineering and Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA.
Department of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA; Institute of Genetics and Biomedical Research (Milan Unit), National Research Council of Italy, 20189 Rozzano, MI, Italy.
Acta Biomater. 2022 Oct 15;152:47-59. doi: 10.1016/j.actbio.2022.08.050. Epub 2022 Aug 27.
As the native regenerative potential of adult cardiac tissue is limited post-injury, stimulating endogenous repair mechanisms in the mammalian myocardium is a potential goal of regenerative medicine therapeutics. Injection of myocardial matrix hydrogels into the heart post-myocardial infarction (MI) has demonstrated increased cardiac muscle and promotion of pathways associated with cardiac development, suggesting potential promotion of cardiomyocyte turnover. In this study, the myocardial matrix hydrogel was shown to have native capability as an effective reactive oxygen species scavenger and protect against oxidative stress induced cell cycle inhibition in vitro. Encapsulation of cardiomyocytes demonstrated an enhanced turnover in in vitro studies, and in vivo assessments of myocardial matrix hydrogel treatment post-MI showed increased thymidine analog uptake in cardiomyocyte nuclei compared to saline controls. Overall, this study provides evidence that properties of the myocardial matrix material provide a microenvironment mitigating oxidative damage and supportive of cardiomyocytes undergoing DNA synthesis, toward possible DNA repair or cell cycle activation. STATEMENT OF SIGNIFICANCE: Loss of adult mammalian cardiomyocyte turnover is influenced by shifts in oxidative damage, which represents a potential mechanism for improving restoration of cardiac muscle after myocardial infarction (MI). Injection of a myocardial matrix hydrogel into the heart post-MI previously demonstrated increased cardiac muscle and promotion of pathways associated with cardiac development, suggesting potential in promoting proliferation of cardiomyocytes. In this study, the myocardial matrix hydrogel was shown to protect cells from oxidative stress and increase proliferation in vitro. In a rat MI model, greater presence of tissue free thiol content spared from oxidative damage, lesser mitochondrial superoxide content, and increased thymidine analog uptake in cardiomyocytes was found in matrix injected animals compared to saline controls. Overall, this study provides evidence that properties of the myocardial matrix material provide a microenvironment supportive of cardiomyocytes undergoing DNA synthesis, toward possible DNA repair or cell cycle activation.
由于成年人心肌组织的固有再生能力有限，因此刺激哺乳动物心肌中的内源性修复机制是再生医学治疗的潜在目标。在心肌梗死后将心肌基质水凝胶注入心脏已被证明可以增加心肌并促进与心脏发育相关的途径，这表明它可能促进心肌细胞更新。在这项研究中，心肌基质水凝胶被证明具有作为有效活性氧物质清除剂的固有能力，并能防止体外氧化应激诱导的细胞周期抑制。在体外研究中，将心肌细胞包封后显示出更高的更新率，并且在心肌梗死后用心肌基质水凝胶治疗的体内评估中，与生理盐水对照组相比，心肌细胞核中的胸苷类似物摄取增加。总的来说，这项研究提供了证据表明，心肌基质材料的特性提供了一个减轻氧化损伤的微环境，并支持正在进行 DNA 合成的心肌细胞，这可能有助于 DNA 修复或细胞周期激活。
成年哺乳动物心肌细胞更新的丧失受氧化损伤的影响，这代表了改善心肌梗死后心肌恢复的潜在机制。心肌梗死后将心肌基质水凝胶注入心脏可增加心肌并促进与心脏发育相关的途径，这表明其具有促进心肌细胞增殖的潜力。在这项研究中，心肌基质水凝胶被证明可以保护细胞免受氧化应激并增加体外增殖。在大鼠心肌梗死模型中，与生理盐水对照组相比，在注射基质的动物中发现组织游离巯基含量更多、线粒体超氧化物含量更少，并且心肌细胞中的胸苷类似物摄取增加，这表明免受氧化损伤的保护。总的来说，这项研究提供了证据表明，心肌基质材料的特性提供了一个支持正在进行 DNA 合成的心肌细胞的微环境，这可能有助于 DNA 修复或细胞周期激活。
