Over the last 4 decades, cell culture techniques have evolved towards the creation of in vitro multicellular entities that incorporate the three-dimensional complexity of in vivo tissues and organs. As a result, stem cells and adult progenitor cells have been used to derive self-organized 3D cell aggregates that mimic the morphological and functional traits of organs in vitro. These so-called organoids were first generated from primary animal and human tissues, then human pluripotent stem cells (hPSCs) arose as a new tool for organoid generation. Due to their self-renewal capacity and differentiation potential, hPSCs are an unlimited source of cells used for organoids. Today, hPSC-derived small intestinal, kidney, brain, liver, and pancreas organoids, among others, have been produced and are promising in vitro human models for diverse applications, including fundamental research, drug development and regenerative medicine. However, achieving in vivo-like organ complexity and maturation in vitro remains a challenge. Current hPSC-derived organoids are often limited in size and developmental state, resembling embryonic or fetal organs rather than adult organs. The use of endothelial cells to vascularize hPSC-derived organoids may represent a key to ensuring oxygen and nutrient distribution in large organoids, thus contributing to the maturation of adult-like organoids through paracrine signaling. Here, we review the current state of the art regarding vascularized hPSC-derived organoids (vhPSC-Orgs). We analyze the progress achieved in the generation of organoids derived from the three primary germ layers (endoderm, mesoderm and ectoderm) exemplified by the pancreas, liver, kidneys and brain. Special attention will be given to the role of the endothelium in the organogenesis of the aforementioned organs, the sources of endothelial cells employed in vhPSC-Org protocols and the remaining challenges preventing the creation of ex vivo functional and vascularized organs.

中文翻译：

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内皮是器官发育和hPSC衍生的类器官血管形成的关键因素

在过去的四十年中，细胞培养技术已朝着创建体外多细胞实体发展，该多细胞实体结合了体内组织和器官的三维复杂性。结果，干细胞和成年祖细胞已被用于衍生自组织的3D细胞聚集体，这些聚集体在体外模拟器官的形态和功能特征。这些所谓的类器官首先从原始动物和人类组织中产生，然后人类多能干细胞（hPSC）出现，成为产生类器官的新工具。由于它们的自我更新能力和分化潜能，hPSC是用于类器官的细胞的无限来源。如今，已经产生了hPSC衍生的小肠，肾脏，脑，肝脏和胰腺类器官，它们有望在体外人类模型中得到广泛应用，包括基础研究，药物开发和再生医学。然而，实现类似体内的器官复杂性和体外成熟仍然是一个挑战。目前，hPSC衍生的类器官通常在大小和发育状态上受到限制，类似于胚胎或胎儿器官，而不是成人器官。使用内皮细胞血管化hPSC衍生的类器官可能是确保大型类器官中氧气和营养物质分布的关键，从而通过旁分泌信号促成成人类类器官的成熟。在这里，我们回顾了有关血管化hPSC衍生的类器官（vhPSC-Orgs）的当前技术水平。我们分析了从三个主要的细菌层（内胚层，中胚层和外胚层）衍生的类器官的产生过程中取得的进展，这三个层是胰腺，肝脏，肾脏和大脑。