Endothelial extracellular vesicles enhance vascular self-assembly in engineered human cardiac tissues.

IF 8.2 2区 医学 Q1 ENGINEERING, BIOMEDICAL Biofabrication Pub Date : 2024-09-18 DOI:10.1088/1758-5090/ad76d9
Karl T Wagner, Rick X Z Lu, Shira Landau, Sarah A Shawky, Yimu Zhao, David F Bodenstein, Luis Felipe Jiménez Vargas, Richard Jiang, Sargol Okhovatian, Ying Wang, Chuan Liu, Daniel Vosoughi, Dakota Gustafson, Jason E Fish, Carolyn L Cummins, Milica Radisic
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Abstract

The fabrication of complex and stable vasculature in engineered cardiac tissues represents a significant hurdle towards building physiologically relevant models of the heart. Here, we implemented a 3D model of cardiac vasculogenesis, incorporating endothelial cells (EC), stromal cells, and human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) in a fibrin hydrogel. The presence of CMs disrupted vessel formation in 3D tissues, resulting in the upregulation of endothelial activation markers and altered extracellular vesicle (EV) signaling in engineered tissues as determined by the proteomic analysis of culture supernatant. miRNA sequencing of CM- and EC-secreted EVs highlighted key EV-miRNAs that were postulated to play differing roles in cardiac vasculogenesis, including the let-7 family and miR-126-3p in EC-EVs. In the absence of CMs, the supplementation of CM-EVs to EC monolayers attenuated EC migration and proliferation and resulted in shorter and more discontinuous self-assembling vessels when applied to 3D vascular tissues. In contrast, supplementation of EC-EVs to the tissue culture media of 3D vascularized cardiac tissues mitigated some of the deleterious effects of CMs on vascular self-assembly, enhancing the average length and continuity of vessel tubes that formed in the presence of CMs. Direct transfection validated the effects of the key EC-EV miRNAs let-7b-5p and miR-126-3p in improving the maintenance of continuous vascular networks. EC-EV supplementation to biofabricated cardiac tissues and microfluidic devices resulted in tissue vascularization, illustrating the use of this approach in the engineering of enhanced, perfusable, microfluidic models of the myocardium.

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内皮细胞外囊泡增强了工程人体心脏组织的血管自组装能力。
在工程心脏组织中制造复杂而稳定的血管是建立与生理相关的心脏模型的一大障碍。在这里,我们在纤维蛋白水凝胶中加入了内皮细胞(EC)、基质细胞和人类 iPSC 衍生心肌细胞(CM),实现了心脏血管生成的三维模型。CM的存在破坏了三维组织中的血管形成,导致内皮活化标志物上调,并改变了工程组织中的细胞外囊泡(EV)信号,这是由培养上清液的蛋白质组分析确定的。在没有CMs的情况下,将CM-EVs补充到EC单层中会减少EC的迁移和增殖,并在应用于三维血管组织时导致更短和更不连续的自组装血管。与此相反,在三维血管化心脏组织的组织培养基中添加 EC-EVs 可减轻 CMs 对血管自组装的一些有害影响,增强在 CMs 存在下形成的血管管的平均长度和连续性。直接转染验证了关键的 EC-EV miRNA let-7b-5p 和 miR-126-3p 在改善连续血管网络的维持方面的作用。向生物制造的心脏组织和微流控装置补充 EC-EV 可实现组织血管化,这说明这种方法可用于制造增强的、可灌注的心肌微流控模型。
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来源期刊
Biofabrication
Biofabrication ENGINEERING, BIOMEDICAL-MATERIALS SCIENCE, BIOMATERIALS
CiteScore
17.40
自引率
3.30%
发文量
118
审稿时长
2 months
期刊介绍: Biofabrication is dedicated to advancing cutting-edge research on the utilization of cells, proteins, biological materials, and biomaterials as fundamental components for the construction of biological systems and/or therapeutic products. Additionally, it proudly serves as the official journal of the International Society for Biofabrication (ISBF).
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