Generation of vascularized brain organoids to study neurovascular interactions

  1. Xin-Yao Sun
  2. Xiang-Chun Ju
  3. Yang Li
  4. Peng-Ming Zeng
  5. Jian Wu
  6. Ying-Ying Zhou
  7. Li-Bing Shen
  8. Jian Dong
  9. Yue-Jun Chen
  10. Zhen-Ge Luo

  • Curated by eLife

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    Evaluation Summary:

    This paper puts forward a new approach to generate vascularized brain organoids to copy in vivo structures, which will be of interest to neurobiologists working in both basic and disease-related areas of neuroscience. The novelty of their approach lies in the simultaneous production of vessel-like networks and brain-resident microglia immune cells in a single organoid. The fusion of brain and vessel organoids (fVBOrs) resulted in robust engraftment of vessel-like structures and microglia around ventricular zone (VZ)-like structures, correlating with increased neuronal progenitors. The conclusions are mostly well supported by the data, but a few points need to be clarified and some conclusions would benefit from further experimental support.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Abstract

Brain organoids have been used to recapitulate the processes of brain development and related diseases. However, the lack of vasculatures, which regulate neurogenesis and brain disorders, limits the utility of brain organoids. In this study, we induced vessel and brain organoids, respectively, and then fused two types of organoids together to obtain vascularized brain organoids. The fused brain organoids were engrafted with robust vascular network-like structures and exhibited increased number of neural progenitors, in line with the possibility that vessels regulate neural development. Fusion organoids also contained functional blood–brain barrier-like structures, as well as microglial cells, a specific population of immune cells in the brain. The incorporated microglia responded actively to immune stimuli to the fused brain organoids and showed ability of engulfing synapses. Thus, the fusion organoids established in this study allow modeling interactions between the neuronal and non-neuronal components in vitro, particularly the vasculature and microglia niche.

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  1. Version published to 10.7554/elife.76707 on eLife
  2. eLife

    Evaluation Summary:

    This paper puts forward a new approach to generate vascularized brain organoids to copy in vivo structures, which will be of interest to neurobiologists working in both basic and disease-related areas of neuroscience. The novelty of their approach lies in the simultaneous production of vessel-like networks and brain-resident microglia immune cells in a single organoid. The fusion of brain and vessel organoids (fVBOrs) resulted in robust engraftment of vessel-like structures and microglia around ventricular zone (VZ)-like structures, correlating with increased neuronal progenitors. The conclusions are mostly well supported by the data, but a few points need to be clarified and some conclusions would benefit from further experimental support.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  3. eLife

    Review #1 (Public Review):

    In this paper, Sun et al. established a new approach to generate vascularized brain organoids through side by side generation of brain organoids (BOrs) and vessel organoids (VOrs) that contains vessel-like structures and microglia. The fusion of brain and vessel organoids (fVBOrs) resulted in robust engraftment of vessel-like structures and microglia around ventricular zone (VZ)-like structures in the brain organoids suggesting cellular and functional integration of vessels and microglia with neurons. Importantly, the presence of vascular network and microglia increased the number of neuronal progenitors possibly due to a marked decrease in apoptotic cell number. By simultaneously inducing the inflammatory response by lipopolysaccharide (LPS) treatment and microglia ablation by PLX5622 treatment, authors also demonstrated the ability of microglia to respond immune stimuli in fVBOrs. Overall, the approach they took to generate vascularized brain organoids is a valuable addition to the previously published methods with a strength of simultaneous production of vessel-like structures and microglia in a single organoid. The conclusions in the paper are mostly well supported by the data, but a few points need to be clarified and some conclusions need further experimental supports.

  4. eLife

    Review #2 (Public Review):

    The authors were attempting to introduce blood vessels with a competent blood brain barrier into cerebral brain organoids. The strength of the manuscript is that they were able to show that they are able to introduce all cellular components of a blood brain barrier (including microglia) into the cerebral organoid using their method. They were even able to show functional components of a competent blood brain barrier such as ZO-1 and CLDN5. The quality of the pictures is high. The weakness of the manuscript is that no in vivo perfusion is shown of the capillaries, so it is not clear whether blood vessels are truly competent. Dil staining in vitro is not enough to show competent perfusion.

  5. Version published to 10.1101/2022.01.04.474960v1 on bioRxiv