TY - JOUR
T1 - Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids
AU - Dao, Lan
AU - You, Zhen
AU - Lu, Lu
AU - Xu, Tianyang
AU - Sarkar, Avijite Kumer
AU - Zhu, Hui
AU - Liu, Miao
AU - Calandrelli, Riccardo
AU - Yoshida, George
AU - Lin, Pei
AU - Miao, Yifei
AU - Mierke, Sarah
AU - Kalva, Srijan
AU - Zhu, Haining
AU - Gu, Mingxia
AU - Vadivelu, Sudhakar
AU - Zhong, Sheng
AU - Huang, L. Frank
AU - Guo, Ziyuan
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2024/6/6
Y1 - 2024/6/6
N2 - 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.
AB - 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.
KW - assembloids
KW - cerebral cavernous malformations
KW - human PSC-derived organoids
KW - human blood-brain barrier
KW - neuro-vascular development
KW - neuro-vascular interactions
KW - single-cell transcriptomics
KW - spatial transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85193409609&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85193409609&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2024.04.019
DO - 10.1016/j.stem.2024.04.019
M3 - Article
C2 - 38754427
AN - SCOPUS:85193409609
SN - 1934-5909
VL - 31
SP - 818-833.e11
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 6
ER -