Abstract
Organoids derived from human pluripotent stem cells are interesting models to study mechanisms of morphogenesis and promising platforms for disease modeling and drug screening. However, they mostly remain incomplete as they lack stroma, tissue resident immune cells and in particular vasculature, which create important niches during development and disease. We propose, that the directed incorporation of mesodermal progenitor cells (MPCs) into organoids will overcome the aforementioned limitations. In order to demonstrate the feasibility of the method, we generated complex human tumor as well as neural organoids. We show that the formed blood vessels display a hierarchic organization and mural cells are assembled into the vessel wall. Moreover, we demonstrate a typical blood vessel ultrastructure including endothelial cell-cell junctions, a basement membrane as well as luminal caveolae and microvesicles. We observe a high plasticity in the endothelial network, which expands, while the organoids grow and is responsive to anti-angiogenic compounds and pro-angiogenic conditions such as hypoxia. We show that vessels within tumor organoids connect to host vessels following transplantation. Remarkably, MPCs also deliver Iba1+ cells that infiltrate the neural tissue in a microglia-like manner.
Highlights
Organoids derived from human pluripotent stem cells are interesting models to study mechanisms of morphogenesis and promising platforms for disease modeling and drug screening
During the initial 3 day-induction phase, human induced pluripotent stem cells (hiPSCs) completely lose pluripotency marker expression (Fig. 1A–D) and approximately 80% of the cells become positive for Brachyury at day 2 of differentiation (Figs 1E–H, S1)
When mesodermal progenitor cells (MPCs) are treated with either PDGF or VEGF, these cells differentiate into smooth muscle cells or endothelial cells, respectively (Fig. 1I,J), underscoring their mesodermal identity and their potential to produce the two major cell types of the blood vessel wall
Summary
Organoids derived from human pluripotent stem cells are interesting models to study mechanisms of morphogenesis and promising platforms for disease modeling and drug screening They mostly remain incomplete as they lack stroma, tissue resident immune cells and in particular vasculature, which create important niches during development and disease. These organoids recapitulate the development of epithelial structures in a fascinating manner They remain incomplete as vasculature, stromal components and tissue resident immune cells are mostly lacking. All these cell types derive from mesenchymal tissue and it is well known that epithelial-mesenchymal interactions play a fundamental role during tissue development[8,9]. Besides providing a functional vasculature, we create mesenchymal-epithelial interfaces, an important developmental component during organogenesis
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