Department of Internal Medicine, McGovern School of Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States of America; Chair of Cardiology, Department of Surgical, Medical and Molecular Pathology, University of Pisa, Pisa, Italy.
Center of Aging Sciences and Translational Medicine - CESI-Met and Institute of Cardiology, "G. D'Annunzio" University, Chieti-Pescara, Chieti, Italy; Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy.
Vascul Pharmacol. 2020 Dec;135:106807. doi: 10.1016/j.vph.2020.106807. Epub 2020 Oct 31.
Cell therapies are hampered by poor survival and growth of grafts. We tested whether forced co-expression of telomerase reverse transcriptase (TERT) and myocardin (MYOCD) improves post-infarct revascularization and tissue repair by adipose tissue-derived mesenchymal stromal cells (AT-MSCs).
We transplanted AT-MSCs overexpressing MYOCD and TERT in a murine model of acute myocardial infarction (AMI). We characterized paracrine effects of AT-MSCs. When transplanted into infarcted hearts of C57BL/6 mice, AT-MSCs overexpressing TERT and MYOCD decreased scar tissue and the intra-scar CD3 and B220 lymphocyte infiltration; and increased arteriolar density as well as ejection fraction compared with saline or mock-transduced AT-MSCs. These effects were accompanied by higher persistence of the injected cells in the heart, increased numbers of Ki-67 and CD117 cells, and the expression of cardiac actin and β-myosin heavy chain. Intramyocardial delivery of the secretome and its extracellular vesicle (EV)-enriched fraction also decreased scar tissue formation and increased arteriolar density in the murine AMI model. Proteomic analysis of AT-MSCs-EV-enriched fraction predicted the activation of vascular development and the inhibition of immune cell trafficking. Elevated concentrations of miR-320a, miR-150-5p and miR-126-3p associated with regulation of apoptosis and vasculogenesis were confirmed in the AT-MSCs-EV-enriched fraction.
AT-MSCs overexpressing TERT and MYOCD promote persistence of transplanted aged AT-MSCs and enhance arteriolar density in a murine model of AMI. EV-enriched fraction is the component of the paracrine secretion by AT-MSCs with pro-angiogenic and anti-fibrotic activities.
细胞疗法受到移植物存活和生长不良的阻碍。我们测试了端粒酶逆转录酶（TERT）和心肌营养素（MYOCD）的强制共表达是否通过脂肪组织源性间充质基质细胞（AT-MSCs）改善梗死后再血管化和组织修复。
我们在急性心肌梗死（AMI）的小鼠模型中移植了过表达 MYOCD 和 TERT 的 AT-MSCs。我们对 AT-MSCs 的旁分泌作用进行了表征。当移植到 C57BL/6 小鼠梗死的心脏中时，与盐水或 mock 转导的 AT-MSCs 相比，过表达 TERT 和 MYOCD 的 AT-MSCs 减少了疤痕组织和疤痕内 CD3 和 B220 淋巴细胞浸润；增加了小动脉密度和射血分数。这些作用伴随着注入细胞在心脏中的更高持久性，Ki-67 和 CD117 细胞数量增加，以及心脏肌动蛋白和β-肌球蛋白重链的表达增加。心肌内递送分泌组及其富含细胞外囊泡（EV）的部分也减少了小鼠 AMI 模型中的疤痕组织形成和小动脉密度。AT-MSCs-EV 富集部分的蛋白质组学分析预测了血管发育的激活和免疫细胞迁移的抑制。在 AT-MSCs-EV 富集部分中，与凋亡和血管生成调节相关的 miR-320a、miR-150-5p 和 miR-126-3p 的浓度升高得到了证实。
过表达 TERT 和 MYOCD 的 AT-MSCs 促进了移植的老年 AT-MSCs 的存活，并增强了 AMI 小鼠模型中小动脉密度。EV 富集部分是 AT-MSCs 旁分泌的组成部分，具有促血管生成和抗纤维化活性。
