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

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

doi:10.1016/j.stem.2024.04.019

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

Cell Stem Cell. 2024 May 7:S1934-5909(24)00146-2. doi: 10.1016/j.stem.2024.04.019. Online ahead of print.

Authors

Lan Dao¹, Zhen You², Lu Lu¹, Tianyang Xu³, Avijite Kumer Sarkar¹, Hui Zhu¹, Miao Liu², Riccardo Calandrelli³, George Yoshida¹, Pei Lin³, Yifei Miao⁴, Sarah Mierke⁵, Srijan Kalva¹, Haining Zhu⁶, Mingxia Gu⁴, Sudhakar Vadivelu⁵, Sheng Zhong⁷, L Frank Huang⁸, Ziyuan Guo⁹

Affiliations

¹ Center for Stem Cell and Organoid Medicine, Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
² Department of Pediatric and Adolescent Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
³ Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Center for Stem Cell and Organoid Medicine, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁵ Divisions of Pediatric Neurosurgery and Interventional Neuroradiology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
⁶ Department of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
⁷ Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: szhong@ucsd.edu.
⁸ Department of Pediatric and Adolescent Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA. Electronic address: huang.frank@mayo.edu.
⁹ Center for Stem Cell and Organoid Medicine, Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: ziyuan.guo@cchmc.org.

PMID: 38754427
DOI: 10.1016/j.stem.2024.04.019

Abstract

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.

Keywords: assembloids; cerebral cavernous malformations; human PSC-derived organoids; human blood-brain barrier; neuro-vascular development; neuro-vascular interactions; single-cell transcriptomics; spatial transcriptomics.