Nör J E, Peters M C, Christensen J B, Sutorik M M, Linn S, Khan M K, Addison C L, Mooney D J, Polverini P J
Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, USA.
Lab Invest. 2001 Apr;81(4):453-63. doi: 10.1038/labinvest.3780253.
Current model systems used to investigate angiogenesis in vivo rely on the interpretation of results obtained with nonhuman endothelial cells. Recent advances in tissue engineering and molecular biology suggest the possibility of engineering human microvessels in vivo. Here we show that human dermal microvascular endothelial cells (HDMEC) transplanted into severe combined immunodeficient (SCID) mice on biodegradable polymer matrices differentiate into functional human microvessels that anastomose with the mouse vasculature. HDMEC were stably transduced with Flag epitope or alkaline phosphatase to confirm the human origin of the microvessels. Endothelial cells appeared dispersed throughout the sponge 1 day after transplantation, became organized into empty tubular structures by Day 5, and differentiated into functional microvessels within 7 to 10 days. Human microvessels in SCID mice expressed the physiological markers of angiogenesis: CD31, CD34, vascular cellular adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). Human endothelial cells became invested by perivascular smooth muscle alpha-actin-expressing mouse cells 21 days after implantation. This model was used previously to demonstrate that overexpression of the antiapoptotic protein Bcl-2 in HDMEC enhances neovascularization, and that apoptotic disruption of tumor microvessels is associated with apoptosis of surrounding tumor cells. The proposed SCID mouse model of human angiogenesis is ideally suited for the study of the physiology of microvessel development, pathologic neovascular responses such as tumor angiogenesis, and for the development and investigation of strategies designed to enhance the neovascularization of engineered human tissues and organs.
目前用于体内研究血管生成的模型系统依赖于对非人类内皮细胞所获结果的解读。组织工程学和分子生物学的最新进展表明了在体内构建人类微血管的可能性。在此我们展示，移植到严重联合免疫缺陷（SCID）小鼠体内、置于可生物降解聚合物基质上的人类真皮微血管内皮细胞（HDMEC）可分化为功能性人类微血管，并与小鼠脉管系统吻合。用Flag表位或碱性磷酸酶稳定转导HDMEC，以确认微血管的人类来源。移植后1天，内皮细胞似乎分散在整个海绵中，到第5天组织成空的管状结构，并在7至10天内分化为功能性微血管。SCID小鼠体内的人类微血管表达血管生成的生理标志物：CD31、CD34、血管细胞黏附分子1（VCAM - 1）和细胞间黏附分子1（ICAM - 1）。植入后21天，人类内皮细胞被表达血管周围平滑肌α - 肌动蛋白的小鼠细胞所包裹。该模型先前被用于证明HDMEC中抗凋亡蛋白Bcl - 2的过表达可增强新血管形成，以及肿瘤微血管的凋亡破坏与周围肿瘤细胞的凋亡相关。所提出的人类血管生成的SCID小鼠模型非常适合用于研究微血管发育的生理学、病理性新生血管反应如肿瘤血管生成，以及用于开发和研究旨在增强工程化人类组织和器官新血管形成的策略。
