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| Status |
Public on May 15, 2024 |
| Title |
Modeling the Blood-Brain Barrier Formation and Cerebral Cavernous Malformations in human PSCs- and primary tissue-derived organoids |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and 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 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 cavernomas tissues, we uncovered CCM-related molecular and cellular alterations. Taken together, we report hBBB assembloids that mimic core properties of the human BBB and identify a potentially underlying cause of CCMs.
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| Overall design |
BBB assembloids was prepared by combining a H9 ESCs derived cerebral organoids, where the astrocytic differentiation is promotated by adding LIF with 15%FBS, with a blood vessel organoid from H9 ESCs indurced mesoderm. Both organoids were developed separately and embedded in a matrigel droplet. We then repurposed the used Illumina Nextseq 2000 sequencing flow cells to a spatial barcoded matrix for RNA hybirdizations. By appling the HIFI-Slide protocol on the assembloid fresh frozen sections for RNA capture and library preparations, we sequencing the extracted library to confirm the cell type and gene expression co-localizations of the BBB assembloids.
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| Contributor(s) |
Dao L, You Z, Lu L, Xu T, Sarkar AK, Zhu H, Liu M, Calandrelli R, Yoshida G, Lin P, Miao Y, Mierke S, Kalva S, Gu M, Vadivelu S, Zhong S, Huang LF, Guo Z |
| Citation(s) |
38754427 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 GM138852 |
Revealing protein-protein interactions and RNA-protein interactions at genome-scale in two weeks |
THE REGENTS OF THE UNIV. OF CALIF., UNIV. OF CALIF., SAN DIEGO |
Sheng Zhong |
| DP1 DK126138 |
Extremely high-throughput mapping of protein, RNA, and chromatin interactions in health and disease |
THE REGENTS OF THE UNIV. OF CALIF., UNIV. OF CALIF., SAN DIEGO |
Sheng Zhong |
| UH3 CA256960 |
Spatial in situ mapping of RNA-chromatin interactions at transcriptome-and-genome scale in human tissues |
THE REGENTS OF THE UNIV. OF CALIF., UNIV. OF CALIF., SAN DIEGO |
Sheng Zhong |
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| Submission date |
Apr 10, 2024 |
| Last update date |
May 28, 2024 |
| Contact name |
Sheng Zhong |
| E-mail(s) |
szhong@ucsd.edu
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| Organization name |
UC San Diego
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| Department |
Shu Chien-Gene Lay Department of Bioengineering
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| Street address |
9500 Gilman Dr, La Jolla
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| City |
San Diego |
| State/province |
California |
| ZIP/Postal code |
92093 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (1) |
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| Relations |
| BioProject |
PRJNA1098726 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE263669_RAW.tar |
19.1 Mb |
(http)(custom) |
TAR (of MTX, SPOT, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
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