Poster abstracts
Poster number 86 submitted by Gongbo Guo
Dissecting Molecular Mechanisms Underlying Blood-Brain Barrier Deficits in Tuberous Sclerosis Complex
Gongbo Guo (Institute of Genomic Medicine, Nationwide Childrens Hospital), Morgan Moser (Institute of Genomic Medicine, Nationwide Childrens Hospital), Alecia Biel (Institute of Genomic Medicine, Nationwide Childrens Hospital), Sheldon Ding, Ryan Rutherford (Institute of Genomic Medicine, Nationwide Childrens Hospital), Mark E. Hester (Institute of Genomic Medicine, Nationwide Childrens Hospital)
Abstract:
Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder caused by pathogenic variants in TSC1 or TSC2, which encode hamartin and tuberin—key regulators of mammalian target of rapamycin (mTOR) signaling. Dysregulation of this pathway leads to benign tumor formation and significant neurological complications, including refractory epilepsy, autism spectrum disorder, and intellectual disability, which represent the primary clinical burden in pediatric patients. Although mTOR inhibitors offer partial therapeutic benefit, their limited efficacy and adverse effects highlight the need for additional mechanistic insights and treatment strategies. Here, we investigated the role of pericytes, specialized mural cells essential for blood–brain barrier (BBB) integrity and vascular stability, in TSC-associated neurovascular pathology. Human induced pluripotent stem cells (iPSCs) derived from TSC patients harboring TSC2 mutations were differentiated into pericytes and compared with CRISPR-Cas9–corrected isogenic controls, alongside TSC2 knockout models. Functional assays using coculture with human brain microvascular endothelial cells revealed that TSC2-deficient pericytes exhibited impaired support of BBB integrity, resulting in increased vascular leakage. Additionally, these cells showed enhanced calcification potential, implicating mTOR hyperactivation in pathological vascular mineralization. Importantly, genetic correction of TSC2 restored normal pericyte function, directly linking mutation-driven dysfunction to BBB deficits. Collectively, these findings identify pericytes as critical mediators of neurovascular dysfunction in TSC and suggest that targeting pericyte-specific mechanisms may provide novel therapeutic avenues to improve epilepsy control and neurodevelopmental outcomes in affected children.
References:
Brown, J. A., Faley, S. L., Judge, M., Ward, P., Ihrie, R. A., Carson, R., Armstrong, L., Sahin, M., Wikswo, J. P., Ess, K. C., & Neely, M. D. (2024). Rescue of impaired blood–brain barrier in tuberous sclerosis complex patient derived neurovascular unit. Journal of Neurodevelopmental Disorders, 16, 27. https://doi.org/10.1186/s11689-024-09543-y
Guo, D., Zhang, B., Han, L., Rensing, N. R., & Wong, M. (2024). Cerebral vascular and blood–brain barrier abnormalities in a mouse model of epilepsy and tuberous sclerosis complex. Epilepsia, 65(2), 483–496. https://doi.org/10.1111/epi.17848
Fazio, A., Neri, I., Koufi, F. D., Marvi, M. V., Galvani, A., Evangelisti, C., McCubrey, J. A., Cocco, L., Manzoli, L., & Ratti, S. (2024). Signaling role of pericytes in vascular health and tissue homeostasis. International Journal of Molecular Sciences, 25(12), 6592. https://doi.org/10.3390/ijms25126592
Keywords: TSC, BBB, Pericyte