Generation of vascularized brain organoids to study neurovascular interactions
- ShanghaiTech University, China
- Chinese Academy of Sciences, China
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 (BBB)-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, in particular the vasculature and microglia niche.
Data availability
Single cell RNA sequencing transcriptome data supporting this study have been deposited in NCBI Sequence Read Archive (SRA) repository (https://www.ncbi.nlm.nih.gov/sra) with accession number SRP338043 (VOR: SRR15992286; VOR2:SRR15992285).
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Generation of vascularized brain organoids to study neurovascular interactionsNCBI Sequence Read Archive, SRP338043.
Article and author information
Author details
Funding
National Key Research and Development Program of China (PI,2021ZD0202500)
- Zhen-Ge Luo
National Natural Science Foundation of China (PI,32130035)
- Zhen-Ge Luo
National Natural Science Foundation of China (PI,92168107)
- Zhen-Ge Luo
National Natural Science Foundation of China (PI,31871034)
- Xiang-Chun Ju
Chinese Academy of Sciences Key Project (PI,QYZDJ-SSW-SMC025)
- Zhen-Ge Luo
Shanghai Municipal People's Government (Co-I,2018SHZDZX05)
- Zhen-Ge Luo
Shanghai Municipal People's Government (PI,201409001700)
- Zhen-Ge Luo
National Key Research and Development Program of China (Co-I,2017YFA0700500)
- Xiang-Chun Ju
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States
Version history
- Received: December 30, 2021
- Preprint posted: January 4, 2022 (view preprint)
- Accepted: May 1, 2022
- Accepted Manuscript published: May 4, 2022 (version 1)
- Version of Record published: June 30, 2022 (version 2)
Copyright
© 2022, Sun et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Generation of vascularized brain organoids to study neurovascular interactions
eLife 11:e76707.
https://doi.org/10.7554/eLife.76707
Further reading
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- Neuroscience
The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel ‘shadow’ was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse, and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the plastic entrainment of vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions, and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.
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- Medicine
- Neuroscience
Background:
Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine’s molecular mechanisms connect to its neural and behavioral effects.
Methods:
We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets.
Results:
We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine’s data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level.
Conclusions:
These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry.
Funding:
This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1–190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016–0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 – 2056) (FXV).
Clinical trial number:
