Historical and current perspectives on blood endothelial cell heterogeneity in the brain

Abstract

Dynamic brain activity requires timely communications between the brain parenchyma and circulating blood. Brain–blood communication is facilitated by intricate networks of brain vasculature, which display striking heterogeneity in structure and function. This vascular cell heterogeneity in the brain is fundamental to mediating diverse brain functions and has long been recognized. However, the molecular basis of this biological phenomenon has only recently begun to be elucidated. Over the past century, various animal species and in vitro systems have contributed to the accumulation of our fundamental and phylogenetic knowledge about brain vasculature, collectively advancing this research field. Historically, dye tracer and microscopic observations have provided valuable insights into the anatomical and functional properties of vasculature across the brain, and these techniques remain an important approach. Additionally, recent advances in molecular genetics and omics technologies have revealed significant molecular heterogeneity within brain endothelial and perivascular cell types. The combination of these conventional and modern approaches has enabled us to identify phenotypic differences between healthy and abnormal conditions at the single-cell level. Accordingly, our understanding of brain vascular cell states during physiological, pathological, and aging processes has rapidly expanded. In this review, we summarize major historical advances and current knowledge on blood endothelial cell heterogeneity in the brain, and discuss important unsolved questions in the field.

Promising Strategies for Preserving Adult Endothelium Health and Reversing Its Dysfunction: From Liquid Biopsy to New Omics Technologies and Noninvasive Circulating Biomarkers

“…Additionally, recent advances in molecular genetics and omics technologies also showed significant molecular heterogeneity within brain endothelial and perivascular cell types [ 42 ]. The blend of these conventional and modern approaches has enabled detecting phenotypical variations between healthy and abnormal conditions at the single-cell level.…”

“…The blend of these conventional and modern approaches has enabled detecting phenotypical variations between healthy and abnormal conditions at the single-cell level. Accordingly, a deep understanding of brain vascular cell states during physiological, pathological, and aging processes has rapidly emerged, and therapeutic approaches have been developed, including vascularization models of human brain organoids on a chip (widely quoted in [ 42 ]), self-assembling multicellular blood–brain barrier (BBB) spheroids (widely quoted in [ 42 ]), and improved endothelial BBB differentiation protocols using human pluripotent or induced pluripotent stem cells (widely quoted in [ 8 , 42 ]). Human organoid and cell reprogramming technologies have rapidly improved, allowing the simulation of human brain development and disease modeling with the construction of a functional vasculature.…”

“…These in vitro models will become potent instruments for exploring human-specific vascular traits absent in animal models, for investigating drug delivery across the BBB, and for screening drugs targeting BBB dysfunction in neurological diseases. Consequently, this research recently led our group, along with others, to hypothesize a close relationship between endothelial BBB conditions and neurodegenerative diseases (widely quoted in [ 8 , 42 ]).…”

Promising Strategies for Preserving Adult Endothelium Health and Reversing Its Dysfunction: From the Liquid Biopsy to New Omics Technologies and Non-invasive Circulating Biomarkers

“…Additionally, recent advances in molecular genetics and omics technologies also showed a significant molecular heterogeneity within brain endothelial and perivascular cell types [42]. The blend of these conventional and modern approaches has enabled detecting phenotypical variations between healthy and abnormal conditions at the single-cell level.…”

Local angiogenic interplay of Vegfc/d and Vegfa drives brain region-specific development of fenestrated capillaries

“…The copyright holder for this preprint this version posted December 9, 2022. ; https://doi.org/10.1101/2022.12.08.519692 doi: bioRxiv preprint vascular permeability which serves to maintain fluid balance and also mediate neuroendocrine and neural immune activities 7,11 . Thus, intra-brain vascular heterogeneity is fundamental to brain homeostasis and brain region-specific neural tasks.…”