Zhao Yimu, Khosravi Ramak, Cheung Krisco, Shen Karen, Wang Ying, Landau Shira, Okhovatian Sargol, Wu Qinghua, Lu Rick Xing Ze, Wagner Karl T, Bodenstein David F, Shawky Sarah A, Vosoughi Daniel, Beroncal Erika Leigh, Yeager Keith, Cummins Carolyn L, Andreazza Ana C, Vunjak-Novakovic Gordana, Radisic Milica
Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3E3, Canada.
Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
Cell Biomater. 2025 May 27;1(4). doi: 10.1016/j.celbio.2025.100075. Epub 2025 Apr 29.
Cardiac tissue engineering faces challenges due to inadequate vascularization, poor engraftment, and ineffective strategies to control inflammation. This study explores the benefits of geometrically controlled cardiac microtissues over-dispersed cells. Microtissues derived from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and affixed between two polydimethylsiloxane (PDMS) pillars exhibited cellular alignment and contractile function and were necessary to serve as suitable building blocks for assembling larger tissues. Following implantation into the omentum in nude rats, these tissues exhibited robust engraftment, contractility, and vascularization, with significantly reduced inflammation. Compared to dispersed cells, microtissues demonstrated enhanced vessel network formation, reduced cell death (lower lactate dehydrogenase [LDH]), decreased cytotoxicity (lower cell-free mitochondrial DNA [mtDNA]), and decreased Yes-associated protein (YAP) activation in cardiomyocytes and associated non-cardiomyocyte populations. Cytokine analysis revealed elevated pro-angiogenic factors (placenta growth factor [PIGF], endocan, and angiopoietin-2) and reduced inflammatory markers (interleukin-31 receptor A [IL-31 RA], interleukin [IL]-2 R beta, and OX40 ligand) in microtissues compared with dispersed cells, offering a promising approach for cardiac repair and regeneration.
由于血管化不足、植入效果不佳以及控制炎症的策略无效,心脏组织工程面临着挑战。本研究探讨了几何形状可控的心脏微组织相对于分散细胞的优势。源自人诱导多能干细胞衍生心肌细胞(hiPSC-CMs)并固定在两个聚二甲基硅氧烷(PDMS)柱之间的微组织表现出细胞排列和收缩功能,并且是组装更大组织的合适构建块所必需的。将这些组织植入裸鼠大网膜后,它们表现出强大的植入、收缩和血管化能力,炎症明显减轻。与分散细胞相比,微组织显示出增强的血管网络形成、减少的细胞死亡(较低的乳酸脱氢酶[LDH])、降低的细胞毒性(较低的无细胞线粒体DNA[mtDNA])以及心肌细胞和相关非心肌细胞群体中Yes相关蛋白(YAP)激活的减少。细胞因子分析显示,与分散细胞相比,微组织中促血管生成因子(胎盘生长因子[PIGF]、内皮糖蛋白和血管生成素-2)升高,炎症标志物(白细胞介素-31受体A[IL-31 RA]、白细胞介素[IL]-2 Rβ和OX40配体)减少,为心脏修复和再生提供了一种有前景的方法。
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