| Endothelial type I interferon signaling modulates the vascular response to ischemic brain injury |
Kavli Affiliate: Arnold R. Kriegstein and Edward Chang
| Authors: Shubhang Bhalla, Belda Gulsuyu, Damian Sanchez, Jayden M Ross, Santhosh Arul, Adnan Gopinadhan, Muhammet Ozturk, Tanzila Mukhtar, Jonathan J Augustin, Jerry C Wang, Joseph Kim, Chang N Kim, Sena Oten, Yohei Rosen, John M Barnabei, Vijay Letchuman, Shantel Weinsheimer, Helen Kim, Elizabeth E Crouch, Edward F Chang, David Haussler, Mircea Teodorescu, Arnold R Kriegstein, Tomasz J Nowakowski and Ethan A Winkler
| Summary:
Human cortical development involves the coupling of neurogenesis and cerebrovascular growth. However, interactions between neural and vascular cells are largely missing in most brain organoids, which are crucial models for studying neurodevelopment and disease. Here, we establish vascularized cortical assembloids (vCAs) by fusing mesoderm-derived vascular organoids (VOs) with cortical organoids (COs). vCAs self-assemble lumenized networks of endothelial cells, pericytes, and perivascular fibroblasts that acquire blood-brain barrier (BBB) specialization and arteriovenous specification in vitro. Single-cell RNA-sequencing and immunofluorescence imaging revealed that vascularization improves neuroepithelial architecture, reduces hypoxia and apoptosis, expands cortical progenitor pools, and enhances neuronal maturation and connectivity compared with COs. Moreover, atlas-level integration with human neurodevelopmental tissue and cross-protocol benchmarking demonstrate superior transcriptional concordance, especially for vascular cell and glial populations, relative to existing approaches. This scalable and reproducible platform improves fidelity and throughput for modeling human neurovascular co-development and enables systematic studies across brain regions and diseases using engineered or patient-derived iPSCs.