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need for fully humanized vascular systems within organoids their potential in neurodevelopmental research by
to ensure their relevance to human physiology and disease simulating the role of the in vivo vascular system in brain
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modeling. While murine vasculature may provide a development. Shi et al. developed vascularized human
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temporary solution, future work must focus on developing COs by integrating ECs, which formed a functional
techniques that promote the formation of human-specific vascular network within the organoids. Vascularization
vascular networks, allowing for more accurate modeling of played a critical role in promoting neural differentiation
neurodevelopmental processes, neurovascular interactions, and accelerating the maturation of neural circuits, closely
and neurological diseases. The integration of emerging mimicking in vivo cortical development. Similar to the
technologies, such as gene editing and biomaterials, holds natural process of brain development, where blood vessels
promise for addressing these challenges, potentially leading regulate the proliferation of NSCs and their differentiation
to more sophisticated organoid models that closely mimic into neurons and glial cells, the presence of a vascular
in vivo brain environments. These advancements will not system in V-Organoids enhanced neurogenesis and
only enhance our understanding of brain development and provided an environment that supported more efficient
disease but also pave the way for innovative therapeutic neuronal maturation (Figure 6A).
approaches, including drug screening and regenerative Another research direction has involved using
medicine applications. vascularized BOs to explore the intricate relationship
4. The application of vascularized BO between brain vasculature development and neural
network formation (Figure 6B). During development,
Vascularization is essential for replicating the complex the vascular and nervous systems may collectively
relationship between neurons, blood vessels, and the immune influence neuronal migration, axonal guidance, and the
system within the brain. Compared to conventional BOs construction of neural circuits. Salmon et al. constructed
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that lack this critical component, vascularized BOs enhance vascularized COs by utilizing microfluidic technology
both their physiological relevance and research applications. to co-culture hPSC-derived pericytes and ECs. Vascular
This advancement has opened new avenues for studying networks were established through microfluidic perfusion,
neurodevelopment and brain development, providing a enabling the investigation of neurovascular organoid
platform for BBB and disease modeling, as well as offering formation on a 3D-printed microfluidic chip. By day 15,
novel approaches for regenerative applications. The integration co-differentiation of βiii-TUBULIN neurons, CD31 ECs,
+
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of vascularization into BOs represents significant progress in and PDGFRβ pericytes was observed, exhibiting a well-
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understanding the complex dynamics of the brain, developing organized architecture. After 30 days of culture, neuronal
more effective treatments for neurological diseases, and axons aligned with the vascular network, and a complex,
enabling in vivo implantation for brain regeneration. layered structure emerged between the neuronal and ECs’
networks. Furthermore, pericytes and ECs integrated with
4.1. Neurodevelopment and brain development
the organoids, indicating robust cellular interaction. Sun
BOs have become indispensable in vitro models for et al. explored the regulatory role of brain vasculature
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studying neural and brain development. Their 3D in neural stem cell differentiation using vascularized
architecture closely replicates the early phases of brain BOs. Their findings demonstrate that signaling molecules
development, including neuron and glial cell production, secreted by ECs could promote the differentiation of neural
neural progenitor cell differentiation, and the establishment stem cells into mature neurons and astrocytes, highlighting
of organized brain regions. Qian et al. used miniature the importance of blood vessels in brain development.
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5
spinning bioreactor techniques to generate brain-region- In addition, they discovered that only the vasculatures
specific organoids, such as forebrain, midbrain, and connected to or near the BOs expressed TJ markers,
hypothalamic organoids. These organoids recapitulated key including Claudin 5 and ZO-1. These observations reveal
features of region-specific brain development, including that vasculatures could be regulated by neural networks.
the organization of progenitor zones and neurogenesis, Further research by Sun et al. confirmed that ECs could
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offering a rough analysis of neurodevelopment. They also regulate brain vascularization through interactions with
provide an accessible and versatile platform for studying neural progenitor cells and influence neurodevelopment.
neurological diseases, including modeling the effects of This underscores the role of neurovascular interactions
the Zika virus, human immunodeficiency virus, and severe in neurodevelopment and offers novel insights into the
acute respiratory syndrome coronavirus 2 exposure on pathological mechanisms underlying neurodevelopmental
neural progenitors, which resemble microcephaly. 170,171 disorders such as microcephaly and autism. 100,172
The vascular system is crucial for regulating neural Vascularized BOs have offered an invaluable model for
stem cell proliferation, differentiation, and migration. investigating the BBB in the context of neurodevelopment.
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Incorporating vascular networks into BOs may expand Recent advancements in the development of “neurovascular

Volume 1 Issue 2 (2025) 20 doi: 10.36922/or.8162