Three-Dimensional Vascular Network Assembly From Diabetic Patient-Derived Induced Pluripotent Stem Cells.
Three-Dimensional Vascular Network Assembly From Diabetic Patient-Derived Induced Pluripotent Stem Cells.
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DOI：
10.1161/atvbaha.115.306362
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Gerecht S
中科院分区：
文献类型：
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作者：
Chan XY;Black R;Dickerman K;Federico J;Lévesque M;Mumm J;Gerecht S
在糖尿病患者中，高血糖会导致内皮祖细胞和细胞缺陷，从而导致心血管并发症。我们的目标是在来自 1 型糖尿病 (T1D) 患者的人类诱导多能干细胞 (hiPSC) 的合成水凝胶中设计三维 (3D) 血管网络，作为糖尿病患者的变革性自体血管疗法。我们验证并优化了贴壁、无饲养层分化程序，以从 hiPSC 中衍生出具有高比例 VEcad+ 细胞的早期血管细胞 (EVC)。我们证明来自健康供体和 T1D 患者的 hiPSC 的分化效率相似。 T1D-hiPSC 衍生的 VEcad+ 细胞可以成熟为表达成熟标志物的功能性内皮细胞 (EC)：冯·维勒布兰德因子和 eNOS，能够结合凝集素并摄取乙酰化低密度脂蛋白，在基质胶中形成索状并对肿瘤坏死因子 α 做出反应。当嵌入工程透明质酸 (HA) 水凝胶中时，T1D-EVC 会发生形态发生并组装成 3D 网络。当封装在新型缺氧诱导 (HI) 水凝胶中时，T1D-EVC 会对低氧做出反应并形成 3D 网络。作为异种移植物，T1D-EVC 融入正在发育的斑马鱼脉管系统中。使用我们强大的协议，我们可以将 T1D-hiPSC 有效分化为 EVC。源自 T1D-hiPSC 的早期 EC 在成熟时具有功能。当嵌入 HA 和 HI 水凝胶中时，T1D-EVC 自组装成 3D 网络。 T1D-EVC 在工程基质中组装成 3D 网络并对缺氧微环境做出反应的能力是糖尿病患者自体血管治疗的重大进步，并且对于组织工程具有广泛的重要性。
In diabetics, hyperglycemia results in deficient endothelial progenitors and cells, leading to cardiovascular complications. We aim to engineer three-dimensional (3D) vascular networks in synthetic hydrogels from type-1 diabetes (T1D) patient-derived human induced pluripotent stem cells (hiPSCs), to serve as a transformative autologous vascular therapy for diabetic patients. We validated and optimized an adherent, feeder free differentiation procedure to derive early vascular cells (EVCs) with high portions of VEcad+ cells from hiPSCs. We demonstrate similar differentiation efficiency from hiPSCs derived from healthy donor and T1D patients. T1D-hiPSC-derived VEcad+ cells can mature to functional endothelial cells (ECs) expressing mature markers: von Willebrand factor and eNOS, are capable of lectin binding and acetylated low density lipoprotein uptake, form cords in Matrigel and respond to tumor necrosis factor alpha. When embedded in engineered hyaluronic acid (HA) hydrogels, T1D-EVCs undergo morphogenesis and assemble into 3D networks. When encapsulated in a novel hypoxia-inducible (HI) hydrogel, T1D-EVCs respond to low oxygen and form 3D networks. As xenografts, T1D-EVCs incorporate into developing zebrafish vasculature. Using our robust protocol, we can direct efficient differentiation of T1D-hiPSC to EVCs. Early ECs derived from T1D-hiPSC are functional when mature. T1D-EVCs self-assembled into 3D networks when embedded in HA and HI hydrogels. The capability of T1D-EVCs to assemble into 3D networks in engineered matrices and to respond to a hypoxic microenvironment is a significant advancement for autologous vascular therapy in diabetic patients and has broad importance for tissue engineering.