Guo Rui, Wan Feng, Morimatsu Masatoshi, Xu Qing, Feng Tian, Yang Hang, Gong Yichen, Ma Shuhong, Chang Yun, Zhang Siyao, Jiang Youxu, Wang Heqing, Chang Dehua, Zhang Hongjia, Ling Yunpeng, Lan Feng
Department of Cardiac Surgery, Peking University Third Hospital, Beijing, 100191, China.
Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8558, Japan.
Bioact Mater. 2021 Mar 5;6(9):2999-3012. doi: 10.1016/j.bioactmat.2021.01.036. eCollection 2021 Sep.
Stem cell-based therapy has been used to treat ischaemic heart diseases for two decades. However, optimal cell types and transplantation methods remain unclear. This study evaluated the therapeutic effects of human umbilical cord mesenchymal stem cell (hUCMSC) sheet on myocardial infarction (MI).
hUCMSCs expressing luciferase were generated by lentiviral transduction for bio-luminescent imaging tracking of cells. We applied a temperature-responsive cell culture surface-based method to form the hUCMSC sheet. Cell retention was evaluated using an bio-luminescent imaging tracking system. Unbiased transcriptional profiling of infarcted hearts and further immunohistochemical assessment of monocyte and macrophage subtypes were used to determine the mechanisms underlying the therapeutic effects of the hUCMSC sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, angiogenesis and left ventricular remodelling.
When transplanted to the infarcted mouse hearts, hUCMSC sheet significantly improved the retention and survival compared with cell suspension. At the early stage of MI, hUCMSC sheet modulated inflammation by decreasing Mcp1-positive monocytes and CD68-positive macrophages and increasing Cx3cr1-positive non-classical macrophages, preserving the cardiomyocytes from acute injury. Moreover, the extracellular matrix produced by hUCMSC sheet then served as bioactive scaffold for the host cells to graft and generate new epicardial tissue, providing mechanical support and routes for revascularsation. These effects of hUCMSC sheet treatment significantly improved the cardiac function at days 7 and 28 post-MI.
hUCMSC sheet formation dramatically improved the biological functions of hUCMSCs, mitigating adverse post-MI remodelling by modulating the inflammatory response and providing bioactive scaffold upon transplantation into the heart.
Due to its excellent availability as well as superior local cellular retention and survival, allogenic transplantation of hUCMSC sheets can more effectively acquire the biological functions of hUCMSCs, such as modulating inflammation and enhancing angiogenesis. Moreover, the hUCMSC sheet method allows the transfer of an intact extracellular matrix without introducing exogenous or synthetic biomaterial, further improving its clinical applicability.
基于干细胞的疗法已用于治疗缺血性心脏病二十年了。然而，最佳的细胞类型和移植方法仍不明确。本研究评估了人脐带间充质干细胞（hUCMSC）片层对心肌梗死（MI）的治疗效果。
通过慢病毒转导产生表达荧光素酶的hUCMSC，用于细胞的生物发光成像追踪。我们应用基于温度响应性细胞培养表面的方法形成hUCMSC片层。使用生物发光成像追踪系统评估细胞滞留情况。对梗死心脏进行无偏转录谱分析，并进一步对单核细胞和巨噬细胞亚型进行免疫组织化学评估，以确定hUCMSC片层治疗效果的潜在机制。进行超声心动图和心脏切片的病理分析，以评估心脏功能、血管生成和左心室重塑。
与细胞悬液相比，当移植到梗死小鼠心脏时，hUCMSC片层显著提高了细胞滞留和存活率。在MI早期，hUCMSC片层通过减少Mcp1阳性单核细胞和CD68阳性巨噬细胞并增加Cx3cr1阳性非经典巨噬细胞来调节炎症，保护心肌细胞免受急性损伤。此外，hUCMSC片层产生的细胞外基质随后作为宿主细胞移植和生成新的心外膜组织的生物活性支架，为血管再生提供机械支持和途径。hUCMSC片层治疗的这些效果在MI后第7天和第28天显著改善了心脏功能。
hUCMSC片层的形成显著改善了hUCMSC的生物学功能，通过调节炎症反应并在移植到心脏时提供生物活性支架来减轻MI后的不良重塑。
由于其良好的可获得性以及优异的局部细胞滞留和存活率异基因移植hUCMSC片层可以更有效地获得hUCMSC的生物学功能，如调节炎症和增强血管生成。此外，hUCMSC片层方法允许完整细胞外基质的转移，而无需引入外源性或合成生物材料，进一步提高了其临床适用性。
