Federal State Budgetary, Institution National Medical Research Center of Cardiology Named after Academician E.I. Chazov, Ministry of Health of the Russian Federation, 121552 Moscow, Russia.
Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 141534 Moscow, Russia.
Int J Mol Sci. 2023 Nov 21;24(23):16575. doi: 10.3390/ijms242316575.
Ischemic heart disease and its complications, such as myocardial infarction and heart failure, are the leading causes of death in modern society. The adult heart innately lacks the capacity to regenerate the damaged myocardium after ischemic injury. Multiple lines of evidence indicated that stem-cell-based transplantation is one of the most promising treatments for damaged myocardial tissue. Different kinds of stem cells have their advantages for treating ischemic heart disease. One facet of their mechanism is the paracrine effect of the transplanted cells. Particularly promising are stem cells derived from cardiac tissue per se, referred to as cardiosphere-derived cells (CDCs), whose therapeutic effect is mediated by the paracrine mechanism through secretion of multiple bioactive molecules providing immunomodulatory, angiogenic, anti-fibrotic, and anti-inflammatory effects. Although secretome-based therapies are increasingly being used to treat various cardiac pathologies, many obstacles remain because of population heterogeneity, insufficient understanding of potential modulating compounds, and the principles of secretome regulation, which greatly limit the feasibility of this technology. In addition, components of the inflammatory microenvironment in ischemic myocardium may influence the secretome content of transplanted CDCs, thus altering the efficacy of cell therapy. In this work, we studied how Tumor necrosis factor alpha (TNFa), as a key component of the pro-inflammatory microenvironment in damaged myocardium from ischemic injury and heart failure, may affect the secretome content of CDCs and their angiogenic properties. We have shown for the first time that TNFa may act as a promising compound modulating the CDC secretome, which induces its profiling to enhance proangiogenic effects on endothelial cells. These results allow us to elucidate the underlying mechanisms of the impact of the inflammatory microenvironment on transplanted CDCs and may contribute to the optimization of CDC efficiency and the development of the technology for producing the CDC secretome with enhanced proangiogenic properties for cell-free therapy.
缺血性心脏病及其并发症，如心肌梗死和心力衰竭，是现代社会的主要死亡原因。成人心脏在缺血性损伤后先天缺乏再生受损心肌的能力。多项研究表明，基于干细胞的移植是治疗受损心肌组织最有前途的方法之一。不同类型的干细胞在治疗缺血性心脏病方面各有优势。其机制之一是移植细胞的旁分泌作用。特别有前途的是源自心脏组织本身的干细胞，称为心脏球源性细胞（cardiosphere-derived cells，CDCs），其治疗效果通过旁分泌机制介导，通过分泌多种具有免疫调节、血管生成、抗纤维化和抗炎作用的生物活性分子。尽管基于分泌组的治疗方法越来越多地用于治疗各种心脏病变，但由于人群异质性、对潜在调节化合物的理解不足以及分泌组调节的原则，该技术的可行性受到了极大限制，仍然存在许多障碍。此外，缺血性心肌炎症微环境中的成分可能影响移植 CDCs 的分泌组内容，从而改变细胞治疗的疗效。在这项工作中，我们研究了肿瘤坏死因子-α（Tumor necrosis factor alpha，TNFa）作为受损心肌中促炎微环境的关键组成部分，如何影响 CDCs 的分泌组内容及其血管生成特性。我们首次表明，TNFa 可能作为一种有前途的调节性化合物，调节 CDC 的分泌组，从而诱导其谱改变，增强对内皮细胞的促血管生成作用。这些结果使我们能够阐明炎症微环境对移植 CDCs 的影响的潜在机制，并可能有助于优化 CDC 的效率，并开发具有增强的促血管生成特性的无细胞治疗用 CDC 分泌组的技术。
