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

Kelleher, Joseph F.; Dickinson, Adam; Cain, Stuart A.; Hu, Yanhua; Bates, Nicola; Harvey, Adam; Ren, Jianzhen; Zhang, Wenjun; Moreton, Fiona; Muir, Keith W.; Ward, Christopher M.; Touyz, Rhian M.; Sharma, Pankaj; Xu, Qingbo; Kimber, Susan J.; Wang, Tao

doi:10.1016/j.stemcr.2019.10.004

Cited by 49 publications

(55 citation statements)

References 44 publications

(60 reference statements)

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“…The current study showed that increased PDGFRβ in CADASIL MCs resulted in cellular proliferation at significantly lower PDGF-BB concentration. However, a recent study by Kelleher et al [37] reported decreased PDGFRβ in CADASIL iPSC (p.Arg153Cys and p.Cys224Tyr)-derived MCs. Although our study used CADASIL iPSCs with different NOTCH3 mutations from theirs, they are all located in exon3/4.…”

Section: Discussionmentioning

confidence: 92%

Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease

et al. 2020

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common forms of hereditary cerebral small vessel diseases and is caused by mutations in NOTCH3. Our group has previously reported incorporation of NOTCH3 extracellular domain (N3ECD) in the CADASIL-specific granular osmiophilic materials and increase of PDGFRβ immunoreactivity in CADASIL postmortem brains. Here, we aimed to establish an in vitro model of CADASIL, which can recapitulate those CADASIL phenotypes, using induced pluripotent stem cells (iPSCs). We have refined a differentiation protocol of endothelial cells to obtain mature mural cells (MCs) with their characteristic properties. iPSCs from three CADASIL patients with p.Arg182Cys, p.Arg141Cys and p.Cys106Arg mutations were differentiated into MCs and their functional and molecular profiles were compared. The differentiated CADASIL MCs recapitulated pathogenic changes reported previously: increased PDGFRβ and abnormal structure/distribution of filamentous actin network, as well as N3ECD/LTBP-1/HtrA1immunopositive deposits. Migration rate of CADASIL MCs was enhanced but suppressed by knockdown of NOTCH3 or PDGFRB. CADASIL MCs showed altered reactivity to PDGF-BB. Patient-derived MCs can recapitulate CADASIL pathology and are therefore useful in understanding the pathogenesis and developing potential treatment strategies.

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Section: Discussionmentioning

confidence: 92%

Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease

et al. 2020

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“…The upregulated expression of genes linked to the NF-kB pathway was identified, indicating that an inflammatory response may be involved. Another recent study using patient-derived iPSCs showed that CADASIL mutant Notch3 mural cells failed to stabilise endothelial networks (also iPSC-derived) in a co-culture model, unlike wild-type VSMCs [107]. The CADASIL VSMCs were also more prone to apoptosis.…”

Section: Notch3 and Cerebral Autosomal Dominant Arteriopathy With Submentioning

confidence: 98%

Notch3 in Development, Health and Disease

Hosseini-Alghaderi

Baron

2020

Biomolecules

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Notch3 is one of four mammalian Notch proteins, which act as signalling receptors to control cell fate in many developmental and adult tissue contexts. Notch signalling continues to be important in the adult organism for tissue maintenance and renewal and mis-regulation of Notch is involved in many diseases. Genetic studies have shown that Notch3 gene knockouts are viable and have limited developmental defects, focussed mostly on defects in the arterial smooth muscle cell lineage. Additional studies have revealed overlapping roles for Notch3 with other Notch proteins, which widen the range of developmental functions. In the adult, Notch3, in collaboration with other Notch proteins, is involved in stem cell regulation in different tissues in stem cell regulation in different tissues, and it also controls the plasticity of the vascular smooth muscle phenotype involved in arterial vessel remodelling. Overexpression, gene amplification and mis-activation of Notch3 are associated with different cancers, in particular triple negative breast cancer and ovarian cancer. Mutations of Notch3 are associated with a dominantly inherited disease CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and there is further evidence linking Notch3 misregulation to hypertensive disease. Here we discuss the distinctive roles of Notch3 in development, health and disease, different views as to the underlying mechanisms of its activation and misregulation in different contexts and potential for therapeutic intervention.

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“…Clear phenotypes are restricted to the brain, but several studies suggested cardiovascular (van den Boom et al, 2003;Rufa et al, 2007) and renal (Kusaba et al, 2007;Guerrot et al, 2008;Ragno et al, 2012) involvement, though their causal relationship is still unclear. A recent article by Kelleher et al (2019) showed that CADASIL iPSC-derived mural cells, including VSMCs and pericytes were susceptible to apoptotic stress. This may explain why major symptoms are restricted to the brain, because the blood-brain barrier, the crucial structure to maintain brain homeostasis, consists of astrocytes and pericytes (Ihara and Yamamoto, 2016).…”

Section: Why Clinical Symptoms Occur Only In the Brainmentioning

confidence: 99%

Clinical and Genetic Aspects of CADASIL

Mizuno

Mizuta

Watanabe-Hosomi

et al. 2020

Front. Aging Neurosci.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease caused by mutations in NOTCH3, is characterized by recurrent stroke without vascular risk factors, mood disturbances, and dementia. MRI imaging shows cerebral white matter (WM) hyperintensity, particularly in the external capsule and temporal pole. Missense mutations related to a cysteine residue in the 34 EGFr on the NOTCH3 extracellular domain (N3ECD) are a typical mutation of CADASIL. On the other hand, atypical mutations including cysteine sparing mutation, null mutation, homozygous mutation, and other associate genes are also reported. From the viewpoint of gain of function apart from Notch signaling or loss of function of Notch signaling, we review the research article about CADASIL and summarized the pathogenesis of small vessel, stroke, and dementia in this disease.

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

Cited by 49 publications

References 44 publications

Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease

Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease

Notch3 in Development, Health and Disease

Clinical and Genetic Aspects of CADASIL

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