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

• DOI: 10.1016/j.stem.2024.04.019
• Publication Date: 2024-05-15T14:41:53Z
• Authors: Lan Dao; Zhen You; Lu Lu; Tianyang Xu; Avijite Kumer Sarkar; Hui Zhu; Miao Liu; Riccardo Calandrelli; George Yoshida; Pei Lin; Yifei Miao; Sarah Mierke; Srijan Kalva; Haining Zhu; Mingxia Gu; Sudhakar Vadivelu; Sheng Zhong; L. Frank Huang; Ziyuan Guo
• Keywords: Organoids; Pluripotent Stem Cells; Hemangioma, Cavernous, Central Nervous System; Blood-Brain Barrier; Humans; Models, Biological

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.