Comprehensive Single-cell Analysis of the Human Brain Vasculature Across Development, Adulthood, and Pathological Conditions

מושגי ליבה

The human brain vasculature exhibits extensive molecular heterogeneity across development, adulthood, and various vascular-dependent central nervous system pathologies.

תקציר

The study performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells, and other tissue-derived cells from 117 samples, including 68 human fetuses and adult patients. This allowed the researchers to construct a comprehensive molecular atlas of the developing fetal, adult control, and diseased human brain vasculature.

Key insights:

• Identified extensive molecular heterogeneity of the vasculature in healthy fetal and adult human brains, as well as across five vascular-dependent central nervous system (CNS) pathologies, including brain tumors and brain vascular malformations.
• Observed alterations in arteriovenous differentiation and reactivation of fetal genes and pathways in the diseased vasculature.
• Pathological endothelial cells displayed a loss of CNS-specific properties and an upregulation of MHC class II molecules, indicating atypical features.
• Cell-cell interaction analyses revealed substantial endothelial-to-perivascular cell signaling, including immune-related and angiogenic pathways, highlighting the central role of the endothelium within the brain neurovascular unit.
• The single-cell brain atlas provides valuable insights into the molecular architecture and heterogeneity of the developing, adult/control, and diseased human brain vasculature, serving as a powerful reference for future studies.

סטטיסטיקה

606,380 freshly isolated endothelial cells, perivascular cells, and other tissue-derived cells were analyzed from 117 samples, including 68 human fetuses and adult patients.

ציטוטים

"We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations."
"Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells."

תובנות מפתח מזוקקות מ:

Single-cell atlas of the human brain vasculature across development, adulthood and disease - Nature

by Thom... ב- www.nature.com 07-10-2024

https://www.nature.com/articles/s41586-024-07493-y

שאלות מעמיקות

How do the identified molecular alterations in the diseased brain vasculature contribute to the pathogenesis and progression of various CNS disorders?

The molecular alterations identified in the diseased brain vasculature play a crucial role in the pathogenesis and progression of various CNS disorders. For instance, the alteration of arteriovenous differentiation observed in the diseased vasculature can lead to abnormal blood flow patterns, which may contribute to conditions such as brain tumors and vascular malformations. Additionally, the reactivated fetal genes and dysregulated pathways in the diseased vasculature indicate a loss of normal regulatory mechanisms, potentially leading to uncontrolled cell growth or impaired vascular function. The upregulation of MHC class II molecules on pathological endothelial cells suggests an immune response activation within the CNS, which could further exacerbate inflammation and tissue damage in conditions like neuroinflammatory diseases. Overall, these molecular alterations can disrupt the delicate balance of the neurovascular unit, leading to compromised blood-brain barrier integrity, altered signaling pathways, and ultimately contributing to the pathogenesis and progression of CNS disorders.

What are the potential therapeutic implications of targeting the specific pathways and cell-cell interactions observed in the diseased brain vasculature?

Targeting the specific pathways and cell-cell interactions identified in the diseased brain vasculature holds significant therapeutic implications for the treatment of CNS disorders. By focusing on the dysregulated genes and pathways, such as those involved in arteriovenous differentiation or immune-related signaling, novel therapeutic strategies can be developed to restore normal vascular function and mitigate disease progression. For example, targeting the aberrant expression of genes associated with angiogenesis in brain tumors could help inhibit tumor growth and improve patient outcomes. Similarly, modulating the immune response by targeting MHC class II molecules on pathological endothelial cells may help reduce inflammation and tissue damage in neuroinflammatory conditions. Furthermore, leveraging the insights from cell-cell interaction analyses to disrupt or enhance specific ligand-receptor interactions between endothelial and perivascular cells could offer new avenues for therapeutic intervention. Overall, targeting these specific pathways and cell-cell interactions in the diseased brain vasculature has the potential to lead to more effective and targeted treatments for a wide range of CNS disorders.

What are the developmental origins and regulatory mechanisms underlying the extensive molecular heterogeneity of the human brain vasculature?

The extensive molecular heterogeneity of the human brain vasculature has its developmental origins in the intricate processes of vascular development and maturation. During embryonic development, vasculature formation is tightly regulated by a complex interplay of genetic and environmental factors that dictate the differentiation of endothelial cells and perivascular cells. This developmental program establishes the initial molecular landscape of the brain vasculature, which continues to evolve throughout adulthood under the influence of various regulatory mechanisms. These regulatory mechanisms include epigenetic modifications, transcriptional regulation, and signaling pathways that control the expression of genes involved in vascular function, permeability, and maintenance. Additionally, environmental cues and cellular interactions within the neurovascular unit further shape the molecular heterogeneity of the brain vasculature over time. The combination of developmental origins and regulatory mechanisms results in the diverse molecular profiles observed in healthy fetal and adult brain vasculature, as well as in the context of CNS disorders. Understanding these developmental origins and regulatory mechanisms is essential for deciphering the molecular architecture of the human brain vasculature and exploring potential therapeutic targets for vascular-related CNS pathologies.