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Rinkevich Y.,Stanford University | Mori T.,Stanford University | Mori T.,National Cancer Research Institute | Sahoo D.,Stanford University | And 3 more authors.
Nature Cell Biology | Year: 2012

Fibroblasts and smooth muscle cells (FSMCs) are principal cell types of connective and adventitial tissues that participate in the development, physiology and pathology of internal organs, with incompletely defined cellular origins. Here, we identify and prospectively isolate from the mesothelium a mouse cell lineage that is committed to FSMCs. The mesothelium is an epithelial monolayer covering the vertebrate thoracic and abdominal cavities and internal organs. Time-lapse imaging and transplantation experiments reveal robust generation of FSMCs from the mesothelium. By targeting mesothelin (MSLN), a surface marker expressed on mesothelial cells, we identify and isolate precursors capable of clonally generating FSMCs. Using a genetic lineage tracing approach, we show that embryonic and adult mesothelium represents a common lineage to trunk FSMCs, and trunk vasculature, with minimal contributions from neural crest, or circulating cells. The isolation of FSMC precursors enables the examination of multiple aspects of smooth muscle and fibroblast biology as well as the prospective isolation of these precursors for potential regenerative medicine purposes. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Kegel L.,Erasmus Medical Center | Aunin E.,Erasmus Medical Center | Meijer D.,Erasmus Medical Center | Bermingham Jr. J.R.,Erasmus Medical Center | And 2 more authors.
ASN Neuro | Year: 2013

The development and function of the vertebrate nervous system depend on specific interactions between different cell types. Two examples of such interactions are synaptic transmission and myelination. LGI1-4 (leucine-rich glioma inactivated proteins) play important roles in these processes. They are secreted proteins consisting of an LRR (leucinerich repeat) domain and a so-called epilepsy-associated or EPTP (epitempin) domain. Both domains are thought to function in protein-protein interactions. The first LGI gene to be identified, LGI1, was found at a chromosomal translocation breakpoint in a glioma cell line. It was subsequently found mutated in ADLTE (autosomal dominant lateral temporal (lobe) epilepsy) also referred to as ADPEAF (autosomal dominant partial epilepsy with auditory features). LGI1 protein appears to act at synapses and antibodies against LGI1 may cause the autoimmune disorder limbic encephalitis. A similar function in synaptic remodelling has been suggested for LGI2, which is mutated in canine Benign Familial Juvenile Epilepsy. LGI4 is required for proliferation of glia in the peripheral nervous system and binds to a neuronal receptor, ADAM22, to foster ensheathment and myelination of axons by Schwann cells. Thus, LGI proteins play crucial roles in nervous system development and function and their study is highly important, both to understand their biological functions and for their therapeutic potential. Here, we review our current knowledge about this important family of proteins, and the progress made towards understanding their functions. © 2013 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC-BY). Source


Gunn T.M.,McLaughlin Research Institute
BMC Research Notes | Year: 2012

Functional annotation of every gene in the mouse genome is a herculean task that requires a multifaceted approach. Many large-scale initiatives are contributing to this undertaking. The International Knockout Mouse Consortium (IKMC) plans to mutate every protein-coding gene, using a combination of gene trapping and gene targeting in embryonic stem cells. Many other groups are performing using the chemical mutagen ethylnitrosourea (ENU) or transpon-based systems to induce mutations, screening offspring for phenovariants and identifying the causative mutations. A recent paper in BMC Research Notes by Arnold et al. presents data from an ENU-based mutagenesis project that provides not only some of the first phenotype-genotype information for a large number of genes, but also a trove of information, all publicly available, that demonstrates the specificity and efficiency of ENU mutagenesis. © 2012 Gunn; licensee BioMed Central Ltd. Source


Park L.,New York Medical College | Zhou P.,New York Medical College | Koizumi K.,New York Medical College | El Jamal S.,New York Medical College | And 4 more authors.
Stroke | Year: 2013

Background and Purpose-: Amyloid-β (Aβ), a peptide that accumulates in the brain and circulates in the blood of patients with Alzheimer disease, alters the regulation of cerebral blood flow and may contribute to the brain dysfunction underlying the dementia. However, the contributions of brain and circulating Aβ1-40 to the vascular dysfunction have not been elucidated. Methods-: We used transgenic mice overexpressing mutated forms of the amyloid precursor protein in which Aβ1-40 is elevated in blood and brain (Tg-2576) or only in brain (Tg-SwDI). Mice were equipped with a cranial window, and the increase in cerebral blood flow induced by neural activity (whisker stimulation), or by topical application of endothelium-dependent vasodilators, was assessed by laser-Doppler flowmetry. Results-: The cerebrovascular dysfunction was observed also in Tg-SwDI mice, but despite ≈40% higher levels of brain Aβ1-40, the effect was less marked than in Tg-2576 mice. Intravascular administration of Aβ1-40 elevated plasma Aβ1-40 and enhanced the dysfunction in Tg-SwDI mice, but not in Tg-2576 mice. Conclusions-: The results provide evidence that Aβ1-40 acts on distinct luminal and abluminal vascular targets, the deleterious cerebrovascular effects of which are additive. Furthermore, the findings highlight the importance of circulating Aβ1-40 in the cerebrovascular dysfunction and may provide insight into the cerebrovascular alterations in conditions in which elevations in plasma Aβ1-40 occur. © 2012 American Heart Association, Inc. Source


Park L.,New York Medical College | Koizumi K.,New York Medical College | El Jamal S.,New York Medical College | Zhou P.,New York Medical College | And 4 more authors.
Stroke | Year: 2014

Background and Purpose: Accumulation of amyloid-β in cerebral blood vessels occurs in familial and sporadic forms of cerebral amyloid angiopathy and is a prominent feature of Alzheimer disease. However, the functional correlates of the vascular pathology induced by cerebral amyloid angiopathy and the mechanisms involved have not been fully established. METHODS-: We used male transgenic mice expressing the Swedish, Iowa, and Dutch mutations of the amyloid precursor protein (Tg-SwDI) to examine the effect of cerebral amyloid angiopathy on cerebrovascular structure and function. Somatosensory cortex cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized Tg-SwDI mice and wild-type littermates equipped with a cranial window. RESULTS-: Tg-SwDI mice exhibited reductions in cerebral blood flow responses to whisker stimulation, endothelium-dependent vasodilators, or hypercapnia at 3 months when compared with wild-type mice, whereas the response to adenosine was not attenuated. However, at 18 and 24 months, all cerebrovascular responses were markedly reduced. At this time, there was evidence of cerebrovascular amyloid deposition, smooth muscle fragmentation, and pericyte loss. Neocortical superfusion with the free radical scavenger manganic(I-II)meso-tetrakis(4- benzoic acid) porphyrin rescued endothelium-dependent responses and functional hyperemia completely at 3 months but only partially at 18 months. CONCLUSIONS-: Tg-SwDI mice exhibit a profound age-dependent cerebrovascular dysfunction, involving multiple regulatory mechanisms. Early in the disease process, oxidative stress is responsible for most of the vascular dysfunction, but with advancing disease structural alterations of the vasomotor apparatus also play a role. Early therapeutic interventions are likely to have the best chance to counteract the deleterious vascular effects of cerebral amyloid angiopathy. © 2014 American Heart Association, Inc. Source

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