Human Blood Vessel Organoids Penetrate Human Cerebral Organoids and Form a Vessel-Like System

Abstract

Vascularization of tissues, organoids and organ-on-chip models has been attempted using endothelial cells. However, the cultured endothelial cells lack the capacity to interact with other somatic cell types, which is distinct from developing vascular cells in vivo. Recently, it was demonstrated that blood vessel organoids (BVOs) recreate the structure and functions of developing human blood vessels. However, the tissue-specific adaptability of BVOs had not been assessed in somatic tissues. Herein, we investigated whether BVOs infiltrate human cerebral organoids and form a blood–brain barrier. As a result, vascular cells arising from BVOs penetrated the cerebral organoids and developed a vessel-like architecture composed of CD31+ endothelial tubes coated with SMA+ or PDGFR+ mural cells. Molecular markers of the blood-brain barrier were detected in the vascularized cerebral organoids. We revealed that BVOs can form neural-specific blood-vessel networks that can be maintained for over 50 days.

Fate and state transitions during human blood vessel organoid development

“…Cluster markers were identified using the presto package, requiring multiple criteria including FC > 1.2, AUC > 0.65, BH-corrected P < 0.01, detection rate difference > 20 Transcriptome-based GRN reconstruction using SCENIC. We used SCENIC (Aibar et al, 2017) to infer the GRN controlling the transcriptomic changes during BVO development and upon BVO transplantation. In brief, we considered all genes detected in more than 1% of cells merging the time course hBVO scRNA-seq data and the transplanted BVO scRNA-seq data.…”

“…After mesoderm induction, vessels sprout, networks form, and subsequently develop approximate aspects of human vasculature development in vivo (Wimmer et al, 2019a). The hBVO system offers great promise for modeling human disease (Monteil et al, 2020; Wimmer et al, 2019b), and as a tool for therapy development and more accurate or complex tissue engineering (Ahn et al, 2021; Dailamy et al, 2021). However, we lack a detailed cell state atlas across hBVO development, and we do not yet understand the power and limitations of this system in order to harness its full potential.…”

Modeling PCDH19-CE: From 2D Stem Cell Model to 3D Brain Organoids

“…In order to investigate the ability of a drug treatment to across the BBB, several methods have recently been developed using brain organoids complemented by a vascular system with the characteristics of the BBB [ 99 , 100 ]. Interestingly, Ahn et al [ 101 ] recreated a vascularized brain in vitro, obtaining human cortical organoids penetrated by human blood vessels organoids (BVOs). The BVOs consisted of endothelial cells and mural cells enveloped by a basement membrane, resembling the cytoarchitecture of typical blood vessels.…”

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

“…True vascularization of organoids is clearly a goal of the field, however, this has not yet been fully established in culture and has required transplant of engineered tissues into recipient animal models (Mansour et al, 2018 ). The most recent work in this field, however, has shown that co-culture of blood vessel organoids with neural organoids can create vascularization in vitro (Ahn et al, 2021 ). While an exciting advance, additional work will be needed to determine the functionality and long-term viability of these in vitro vessels.…”