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Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures

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Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures. / Kelleher, Joseph; Dickinson, Adam; Cain, Stuart; Hu, Yanhua; Bates, Nicola; Harvey, Adam; Ren, Jianzhen; Zhang, Wenjun; Moreton, Fiona C.; Muir, Keith W.; Ward, Christopher; Touyz, Rhian M.; Sharma, Pankaj; Xu, Qingbo; Kimber, Susan J.; Wang, Tao.

In: Stem cell reports, Vol. 13, No. 5, 12.11.2019, p. 817-831.

Research output: Contribution to journalArticle

Harvard

Kelleher, J, Dickinson, A, Cain, S, Hu, Y, Bates, N, Harvey, A, Ren, J, Zhang, W, Moreton, FC, Muir, KW, Ward, C, Touyz, RM, Sharma, P, Xu, Q, Kimber, SJ & Wang, T 2019, 'Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures', Stem cell reports, vol. 13, no. 5, pp. 817-831. https://doi.org/10.1016/j.stemcr.2019.10.004

APA

Kelleher, J., Dickinson, A., Cain, S., Hu, Y., Bates, N., Harvey, A., ... Wang, T. (2019). Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures. Stem cell reports, 13(5), 817-831. https://doi.org/10.1016/j.stemcr.2019.10.004

Vancouver

Kelleher J, Dickinson A, Cain S, Hu Y, Bates N, Harvey A et al. Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures. Stem cell reports. 2019 Nov 12;13(5):817-831. https://doi.org/10.1016/j.stemcr.2019.10.004

Author

Kelleher, Joseph ; Dickinson, Adam ; Cain, Stuart ; Hu, Yanhua ; Bates, Nicola ; Harvey, Adam ; Ren, Jianzhen ; Zhang, Wenjun ; Moreton, Fiona C. ; Muir, Keith W. ; Ward, Christopher ; Touyz, Rhian M. ; Sharma, Pankaj ; Xu, Qingbo ; Kimber, Susan J. ; Wang, Tao. / Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures. In: Stem cell reports. 2019 ; Vol. 13, No. 5. pp. 817-831.

Bibtex Download

@article{1da22ce39cde47f6bd2e0d5564f94179,
title = "Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures",
abstract = "CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor β, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets.",
keywords = "angiogenesis, CADASIL, genetic stroke, iPSC, iPSC disease model, notch signaling, NOTCH3, pericytes, small vessel disease, vascular dementia",
author = "Joseph Kelleher and Adam Dickinson and Stuart Cain and Yanhua Hu and Nicola Bates and Adam Harvey and Jianzhen Ren and Wenjun Zhang and Moreton, {Fiona C.} and Muir, {Keith W.} and Christopher Ward and Touyz, {Rhian M.} and Pankaj Sharma and Qingbo Xu and Kimber, {Susan J.} and Tao Wang",
year = "2019",
month = "11",
day = "12",
doi = "10.1016/j.stemcr.2019.10.004",
language = "English",
volume = "13",
pages = "817--831",
journal = "Stem cell reports",
issn = "2213-6711",
number = "5",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures

AU - Kelleher, Joseph

AU - Dickinson, Adam

AU - Cain, Stuart

AU - Hu, Yanhua

AU - Bates, Nicola

AU - Harvey, Adam

AU - Ren, Jianzhen

AU - Zhang, Wenjun

AU - Moreton, Fiona C.

AU - Muir, Keith W.

AU - Ward, Christopher

AU - Touyz, Rhian M.

AU - Sharma, Pankaj

AU - Xu, Qingbo

AU - Kimber, Susan J.

AU - Wang, Tao

PY - 2019/11/12

Y1 - 2019/11/12

N2 - CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor β, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets.

AB - CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor β, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets.

KW - angiogenesis

KW - CADASIL

KW - genetic stroke

KW - iPSC

KW - iPSC disease model

KW - notch signaling

KW - NOTCH3

KW - pericytes

KW - small vessel disease

KW - vascular dementia

UR - http://www.scopus.com/inward/record.url?scp=85074533950&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2019.10.004

DO - 10.1016/j.stemcr.2019.10.004

M3 - Article

C2 - 31680059

AN - SCOPUS:85074533950

VL - 13

SP - 817

EP - 831

JO - Stem cell reports

JF - Stem cell reports

SN - 2213-6711

IS - 5

ER -

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