Mlc1-Expressing Perivascular Astrocytes Promote Blood-Brain Barrier Integrity.
John E MoralesArpan DeAlexandra A MillerZhihua ChenJoseph H McCartyPublished in: The Journal of neuroscience : the official journal of the Society for Neuroscience (2021)
In the mammalian brain, perivascular astrocytes (PAs) closely juxtapose blood vessels and are postulated to have important roles in the control of vascular physiology, including regulation of the blood-brain barrier (BBB). Deciphering specific functions for PAs in BBB biology, however, has been limited by the ability to distinguish these cells from other astrocyte populations. In order to characterize selective roles for PAs in vivo , a new mouse model has been generated in which the endogenous megalencephalic leukoencephalopathy with subcortical cysts 1 (Mlc1) gene drives expression of Cre fused to a mutated estrogen ligand-binding domain (Mlc1-T2A-CreERT2). This knock-in mouse model, which we term MLCT, allows for selective identification and tracking of PAs in the postnatal brain. We also demonstrate that MLCT-mediated ablation of PAs causes severe defects in BBB integrity, resulting in premature death. PA loss results in aberrant localization of Claudin 5 and -VE-Cadherin in endothelial cell junctions as well as robust microgliosis. Collectively, these data reveal essential functions for Mlc1-expressing PAs in regulating endothelial barrier integrity in mice and indicate that primary defects in astrocytes that cause BBB breakdown may contribute to human neurologic disorders. SIGNIFICANCE STATEMENT Interlaced among the billions of neurons and glia in the mammalian brain is an elaborate network of blood vessels. Signals from the brain parenchyma control the unique permeability properties of cerebral blood vessels known as the blood-brain barrier (BBB). However, we understand very little about the relative contributions of different neural cell types in the regulation of BBB functions. Here, we show that a specific subpopulation of astrocyte is essential for control of BBB integrity, with ablation of these cells leading to defects in endothelial cell junctions, BBB breakdown, and resulting neurologic deficits.
Keyphrases
- blood brain barrier
- cerebral ischemia
- endothelial cells
- mouse model
- white matter
- resting state
- functional connectivity
- preterm infants
- genome wide
- poor prognosis
- single cell
- gene expression
- type diabetes
- traumatic brain injury
- spinal cord injury
- stem cells
- subarachnoid hemorrhage
- copy number
- signaling pathway
- bone marrow
- multiple sclerosis
- atrial fibrillation
- cell proliferation
- wild type
- cell cycle arrest
- deep learning
- skeletal muscle
- endoplasmic reticulum stress
- brain injury
- metabolic syndrome
- big data
- artificial intelligence
- drug induced
- binding protein