Traktuev Dmitry O, Prater Daniel N, Merfeld-Clauss Stephanie, Sanjeevaiah Aravind Raj, Saadatzadeh M Reza, Murphy Michael, Johnstone Brian H, Ingram David A, March Keith L
Indiana Center for Vascular Biology, Indiana University, School of Medicine, 975 W Walnut St, IB441, Indianapolis, IN 46202, USA.
Circ Res. 2009 Jun 19;104(12):1410-20. doi: 10.1161/CIRCRESAHA.108.190926. Epub 2009 May 14.
Rapid induction and maintenance of blood flow through new vascular networks is essential for successfully treating ischemic tissues and maintaining function of engineered neo-organs. We have previously shown that human endothelial progenitor cells (EPCs) form functioning vessels in mice, but these are limited in number and persistence; and also that human adipose stromal cells (ASCs) are multipotent cells with pericytic properties which can stabilize vascular assembly in vitro. In this study, we tested whether ASCs would cooperate with EPCs to coassemble vessels in in vivo implants. Collagen implants containing EPCs, ASCs, or a 4:1 mixture of both were placed subcutaneously into NOD/SCID mice. After a range of time periods, constructs were explanted and evaluated with regard to vascular network assembly and cell fate; and heterotypic cell interactions were explored by targeted molecular perturbations. The density and complexity of vascular networks formed by the synergistic dual-cell system was many-fold higher than found in implants containing either ASCs or EPCs alone. Coimplantation of ASCs and EPCs with either pancreatic islets or adipocytes produced neoorgans populated by these parenchymal cells, as well as by chimeric human vessels conducting flow. This study is the first to demonstrate prompt and consistent assembly of a vascular network by human ASCs and endothelial cells and vascularization by these cells of parenchymal cells in implants. Mixture of these 2 readily available, nontransformed human cell types provides a practical approach to tissue engineering, therapeutic revascularization, and in vivo studies of human vasculogenesis.
通过新的血管网络快速诱导并维持血流，对于成功治疗缺血组织和维持工程化新器官的功能至关重要。我们之前已经表明，人内皮祖细胞（EPC）可在小鼠体内形成有功能的血管，但数量有限且持久性不足；同时还表明，人脂肪基质细胞（ASC）是具有周细胞特性的多能细胞，可在体外稳定血管组装。在本研究中，我们测试了ASC是否会与EPC合作，在体内植入物中共同组装血管。将含有EPC、ASC或两者4:1混合物的胶原蛋白植入物皮下植入NOD/SCID小鼠体内。在一系列时间段后，取出构建物并评估血管网络组装和细胞命运；通过靶向分子扰动探索异型细胞相互作用。由协同双细胞系统形成的血管网络的密度和复杂性比单独含有ASC或EPC的植入物中高出许多倍。将ASC和EPC与胰岛或脂肪细胞共同植入可产生由这些实质细胞以及有血流的嵌合人血管组成的新器官。本研究首次证明人ASC和内皮细胞能迅速且一致地组装血管网络，并使这些细胞在植入物中对实质细胞进行血管化。这两种易于获得的未转化人细胞类型的混合，为组织工程、治疗性血管再生以及人血管生成的体内研究提供了一种实用方法。
