Engineering stem cell cardiac patch with microvascular features representative of native myocardium
Engineering stem cell cardiac patch with microvascular features representative of native myocardium
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DOI：
10.7150/thno.29552
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhao, Feng
中科院分区：
文献类型：
--
作者：
Qian, Zichen;Sharma, Dhavan;Zhao, Feng
天然心肌是一种高度排列的组织，具有定向的血管系统。其特有的细胞和纳米级细胞外基质(ECM)组织以及定向的血管网络确保了适当的血液供应和功能表现。虽然各向异性心脏结构的研究已经取得了很大的进展，但目前还没有一种理想的生物材料或有效的血管化策略来工程定向和高密度的毛细血管样微血管用于临床心血管治疗。一种天然的定向ECM纳米纤维支架模拟组织ECM的生理结构和成分，并引导新生血管网络的形成。本研究的目的是构建具有生理性心肌微血管特征的定向致密的微血管网络。方法：以高排列的脱细胞人真皮成纤维细胞作为ECM支架，通过人间充质干细胞(HMSCs)和内皮细胞(ECs)的共培养来调节微血管网络的生理排列。结果：细胞外基质可通过CD166轨道转化为内皮细胞，显著改善hMSC-EC的串扰和血管网络的形成。与随机排列的纳米纤维ECM相比，排列整齐的ECM纳米纤维增强了微血管网络的结构、长度和密度。此外，hMSC-EC共培养可促进促血管生长因子的分泌，并通过金属蛋白酶-2的激活促进基质重塑，形成高度致密的血管网络，其毛细血管间距(20微米)与天然心肌相似。结论：hMSC-EC在高度排列的ECM上共培养可形成具有生理性定向致密的微血管网络，具有较大的心脏组织工程应用潜力。
The natural myocardium is a highly aligned tissue with an oriented vasculature. Its characteristic cellular as well as nanoscale extracellular matrix (ECM) organization along with an oriented vascular network ensures appropriate blood supply and functional performance. Although significant efforts have been made to develop anisotropic cardiac structure, currently neither an ideal biomaterial nor an effective vascularization strategy to engineer oriented and high-density capillary-like microvessels has been achieved for clinical cardiovascular therapies. A naturally derived oriented ECM nanofibrous scaffold mimics the physiological structure and components of tissue ECM and guides neovascular network formation. The objective of this study was to create an oriented and dense microvessel network with physiological myocardial microvascular features.Methods: Highly aligned decellularized human dermal fibroblast sheets were used as ECM scaffold to regulate physiological alignment of microvascular networks by co-culturing human mesenchymal stem cells (hMSCs) and endothelial cells (ECs). The influence of topographical features on hMSC and EC interaction was investigated to understand underlying mechanisms of neovasculature formation.Results: Results demonstrate that the ECM topography can be translated to ECs via CD166 tracks and significantly improved hMSC-EC crosstalk and vascular network formation. The aligned ECM nanofibers enhanced structure, length, and density of microvascular networks compared to randomly organized nanofibrous ECM. Moreover, hMSC-EC co-culture promoted secretion of pro-angiogenic growth factors and matrix remodeling via metalloprotease-2 (MMP-2) activation, which resulted in highly dense vascular network formation with intercapillary distance (20 mu m) similar to the native myocardium.Conclusion: HMSC-EC co-culture on the highly aligned ECM generates physiologically oriented and dense microvascular network, which holds great potential for cardiac tissue engineering.