Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids

The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and central nervous system (CNS) compartments. Despite its critical physiological role, there are no reliable in vitro models that can mimic hBBB development and function. Here, we constructed...

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Veröffentlicht in:Cell stem cell 2024-06, Vol.31 (6), p.818-833.e11
Hauptverfasser: Dao, Lan, You, Zhen, Lu, Lu, Xu, Tianyang, Sarkar, Avijite Kumer, Zhu, Hui, Liu, Miao, Calandrelli, Riccardo, Yoshida, George, Lin, Pei, Miao, Yifei, Mierke, Sarah, Kalva, Srijan, Zhu, Haining, Gu, Mingxia, Vadivelu, Sudhakar, Zhong, Sheng, Huang, L. Frank, Guo, Ziyuan
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Sprache:eng
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Zusammenfassung:The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and central nervous system (CNS) compartments. Despite its critical physiological role, there are no reliable in vitro models that can mimic hBBB development and function. Here, we constructed hBBB assembloids from brain and blood vessel organoids derived from human pluripotent stem cells. We validated the acquisition of blood-brain barrier (BBB)-specific molecular, cellular, transcriptomic, and functional characteristics and uncovered an extensive neuro-vascular crosstalk with a spatial pattern within hBBB assembloids. When we used patient-derived hBBB assembloids to model cerebral cavernous malformations (CCMs), we found that these assembloids recapitulated the cavernoma anatomy and BBB breakdown observed in patients. Upon comparison of phenotypes and transcriptome between patient-derived hBBB assembloids and primary human cavernoma tissues, we uncovered CCM-related molecular and cellular alterations. Taken together, we report hBBB assembloids that mimic the core properties of the hBBB and identify a potentially underlying cause of CCMs. [Display omitted] •Blood-brain barrier (BBB) assembloids resemble key features of the human BBB•Neuro-vascular crosstalk plays a pivotal role in the formation of BBB•Patient-derived BBB assembloids effectively model in vivo cavernoma phenotypes•BBB assembloids reveal SMC loss and disrupted neuro-vascular interactions in CCMs Guo and colleagues created human blood-brain barrier (hBBB) assembloids using stem cell-derived brain and blood vessel organoids. These models mimic key blood-brain barrier (BBB) characteristics and reveal neuro-vascular interactions. Patient-derived assembloids replicated cerebral cavernous malformation (CCM) features, aiding in understanding CCM pathogenesis. This work advances BBB research and illuminates CCM mechanisms.
ISSN:1934-5909
1875-9777
1875-9777
DOI:10.1016/j.stem.2024.04.019