PMID- 37361999
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240214
IS  - 1662-5102 (Print)
IS  - 1662-5102 (Electronic)
IS  - 1662-5102 (Linking)
VI  - 17
DP  - 2023
TI  - Induced pluripotent stem cell model revealed impaired neurovascular interaction 
      in genetic small vessel disease Cerebral Autosomal Dominant Arteriopathy with 
      Subcortical Infarcts and Leukoencephalopathy.
PG  - 1195470
LID - 10.3389/fncel.2023.1195470 [doi]
LID - 1195470
AB  - INTRODUCTION: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts 
      and Leukoencephalopathy (CADASIL) is the most common genetic small vessel disease 
      caused by variants in the NOTCH3 gene. Patients with CADASIL experience recurrent 
      strokes, developing into cognitive defect and vascular dementia. CADASIL is a 
      late-onset vascular condition, but migraine and brain MRI lesions appear in 
      CADASIL patients as early as their teens and twenties, suggesting an abnormal 
      neurovascular interaction at the neurovascular unit (NVU) where microvessels meet 
      the brain parenchyma. METHODS: To understand the molecular mechanisms of CADASIL, 
      we established induced pluripotent stem cell (iPSC) models from CADASIL patients 
      and differentiated the iPSCs into the major NVU cell types including brain 
      microvascular endothelial-like cells (BMECs), vascular mural cells (MCs), 
      astrocytes and cortical projection neurons. We then built an in vitro NVU model 
      by co-culturing different neurovascular cell types in Transwells and evaluated 
      the blood brain barrier (BBB) function by measuring transendothelial electrical 
      resistance (TEER). RESULTS: Results showed that, while the wild-type MCs, 
      astrocytes and neurons could all independently and significantly enhance TEER of 
      the iPSC-BMECs, such capability of MCs from iPSCs of CADASIL patients was 
      significantly impaired. Additionally, the barrier function of the BMECs from 
      CADASIL iPSCs was significantly decreased, accompanied with disorganized tight 
      junctions in iPSC-BMECs, which could not be rescued by the wild-type MCs or 
      sufficiently rescued by the wild-type astrocytes and neurons. DISCUSSION: Our 
      findings provide new insight into early disease pathologies on the neurovascular 
      interaction and BBB function at the molecular and cellular levels for CADASIL, 
      which helps inform future therapeutic development.
CI  - Copyright (c) 2023 Zhang, Zhao, Qi, Kimber, Hooper and Wang.
FAU - Zhang, Wenjun
AU  - Zhang W
AD  - Division of Evolution, Infection and Genomic Sciences, School of Biological 
      Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, 
      Manchester, United Kingdom.
FAU - Zhao, Xiangjun
AU  - Zhao X
AD  - Division of Evolution, Infection and Genomic Sciences, School of Biological 
      Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, 
      Manchester, United Kingdom.
FAU - Qi, Xuewei
AU  - Qi X
AD  - Division of Evolution, Infection and Genomic Sciences, School of Biological 
      Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, 
      Manchester, United Kingdom.
FAU - Kimber, Susan J
AU  - Kimber SJ
AD  - Division of Cell Matrix Biology and Regenerative Medicine, School of Biological 
      Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, 
      Manchester, United Kingdom.
FAU - Hooper, Nigel M
AU  - Hooper NM
AD  - Division of Neuroscience, School of Biological Sciences, Faculty of Biology, 
      Medicine, and Health, The University of Manchester, Manchester, United Kingdom.
AD  - Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science 
      Centre, Northern Care Alliance NHS Group, The University of Manchester, 
      Manchester, United Kingdom.
FAU - Wang, Tao
AU  - Wang T
AD  - Division of Evolution, Infection and Genomic Sciences, School of Biological 
      Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, 
      Manchester, United Kingdom.
AD  - Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science 
      Centre, Northern Care Alliance NHS Group, The University of Manchester, 
      Manchester, United Kingdom.
AD  - Manchester Centre for Genomic Medicine, Manchester University NHS Foundation 
      Trust, Manchester, United Kingdom.
LA  - eng
GR  - MC_PC_16033/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
DEP - 20230608
PL  - Switzerland
TA  - Front Cell Neurosci
JT  - Frontiers in cellular neuroscience
JID - 101477935
PMC - PMC10285224
OTO - NOTNLM
OT  - CADASIL
OT  - blood-brain barrier
OT  - genetic small vessel disease
OT  - neurovascular interaction
OT  - neurovascular unit
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/06/26 19:07
MHDA- 2023/06/26 19:08
PMCR- 2023/01/01
CRDT- 2023/06/26 12:59
PHST- 2023/03/28 00:00 [received]
PHST- 2023/05/16 00:00 [accepted]
PHST- 2023/06/26 19:08 [medline]
PHST- 2023/06/26 19:07 [pubmed]
PHST- 2023/06/26 12:59 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fncel.2023.1195470 [doi]
PST - epublish
SO  - Front Cell Neurosci. 2023 Jun 8;17:1195470. doi: 10.3389/fncel.2023.1195470. 
      eCollection 2023.