Shortened ALK1 regulatory fragment maintains a specific activity in arteries feeding ischemic tissues

Li, X; Yonenaga, Yoshikuni; Seki, Tsugio

doi:10.1038/gt.2009.53

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…To begin to address this question, we employed a transgenic approach to identify flow-controlled regulatory elements in zebrafish acvrl1 intron 1. We chose this region because mouse acvrl1 intron 2, which is homologous to zebrafish and human intron 1, is required to drive arterial-specific transgene expression [18,19]. Additionally, compared to downstream introns, first introns are generally more conserved across species and harbor a relative abundance of cis regulatory elements and active chromatin marks [49].…”

Section: Discussionmentioning

confidence: 99%

“…The human ACVRL1 promoter contains validated Sp1 and Kruppel-like factor 6 (KLF6) binding sites, which are required for basal and/or injury-induced ACVRL1 transcription in ECs [15,16], and UBR5, a nuclear E3 ubiquitin ligase, may be involved in negative regulation by antagonizing Sp1 binding [17]. In addition, functional binding sites for the ETS family transcription factors (ETS1, FLI1) and FOXF1 have been identified in the mouse Acvrl1 promoter, and a 2.2 kb element in mouse Acvrl1 intron 2 (which is equivalent to human and zebrafish intron 1) is required for arterial EC-localized Acvrl1 expression [18][19][20][21]. However, how this intronic fragment directs arterial expression is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Blood flow regulatesacvrl1transcription via ligand-dependent Alk1 activity

Anzell,

Kunz,

Donovan

et al. 2024

Preprint

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Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by the development of arteriovenous malformations (AVMs) that can result in significant morbidity and mortality. HHT is caused primarily by mutations in bone morphogenetic protein receptors ACVRL1/ALK1, a signaling receptor, or endoglin (ENG), an accessory receptor. Because overexpression of Acvrl1 prevents AVM development in both Acvrl1 and Eng null mice, enhancing ACVRL1 expression may be a promising approach to development of targeted therapies for HHT. Therefore, we sought to understand the molecular mechanism of ACVRL1 regulation. We previously demonstrated in zebrafish embryos that acvrl1 is predominantly expressed in arterial endothelial cells and that expression requires blood flow. Here, we document that flow dependence exhibits regional heterogeneity and that acvrl1 expression is rapidly restored after reinitiation of flow. Furthermore, we find that acvrl1 expression is significantly decreased in mutants that lack the circulating Alk1 ligand, Bmp10, and that BMP10 microinjection into the vasculature in the absence of flow enhances acvrl1 expression in an Alk1-dependent manner. Using a transgenic acvrl1:egfp reporter line, we find that flow and Bmp10 regulate acvrl1 at the level of transcription. Finally, we observe similar ALK1 ligand-dependent increases in ACVRL1 in human endothelial cells subjected to shear stress. These data suggest that Bmp10 acts downstream of blood flow to maintain or enhance acvrl1 expression via a positive feedback mechanism, and that ALK1 activating therapeutics may have dual functionality by increasing both ALK1 signaling flux and ACVRL1 expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blood flow regulatesacvrl1transcription via ligand-dependent Alk1 activity

Anzell,

Kunz,

Donovan

et al. 2024

Preprint

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“…Stem cell-based cell therapy has been linked to the prevention or delay host cell death and restore injured tissue (Blurton-Jones et al, 2009; Goldman, 2005; Kim and de Vellis, 2009; Lindvall and Kokaia, 2006). Previous studies have shown the preservation of host neurons and recovery of function through the transplantation of human NSCs expressing diverse functional genes, especially growth factors, in animal models of PD, ALS, stroke and spinal cord injury (Hwang et al, 2009; Lee et al, 2007, 2008, 2009a,2009b, 2010; Yasuhara et al, 2006). Due to their high survival rate and ability to differentiate into both neurons and glial cells following transplantation into damaged tissue, human NSCs have emerged as highly-effective source of cells for genetic manipulation and gene transfer into the CNS ex vivo (Kim, 2004; Kim and de Vellis, 2009).…”

Section: Cell Therapy For Neurological Disordersmentioning

confidence: 99%

“…From these studies, it seems that various neurotrophic factors such as NGF and BDNF play important function of neuroprotection and brain repair in AD model animals (Beck et al, 1995; Schäbitz et al, 2000). Previous studies have shown that F3 human NSCs expressing neurotrophic factors, not only BDNF, but also neurotrophin-3, glial cell line-derived growth factor, and vascular endothelial growth factor, protected host neurons in animal models of hemorrhagic stroke (Lee et al, 2007, 2008), PD (Yasuhara et al, 2006) and ALS (Hwang et al, 2009). …”

Section: Cell Therapy For Neurological Disordersmentioning

confidence: 99%

Recent preclinical evidence advancing cell therapy for Alzheimer's disease

Borlongan

2012

Experimental Neurology

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Alzheimer's disease (AD) causes brain degeneration, primarily depleting cholinergic cells, and leading to cognitive and learning dysfunction. Logically, to augment the cholinergic cell loss, a viable treatment for AD has been via drugs boosting brain acetylcholine production. However, this is not a curative measure. To this end, nerve growth factor (NGF) has been examined as a possible preventative treatment against cholinergic neuronal death while enhancing memory capabilities; however, NGF brain bioavailability is challenging as it does not cross the blood–brain barrier. Investigations into stem cell- and gene-based therapy have been explored in order to enhance NGF potency in the brain. Along this line of research, a genetically modified cell line, called HB1.F3 transfected with the cholinergic acetyltransferase or HB1.F3.ChAT cells, has shown safety and efficacy profiles in AD models. This stem cell transplant therapy for AD is an extension of the neural stem cells' use in other neurological treatments, such as Parkinson's disease and stroke, and recently extended to cancer. The HB1 parent cell and its associated cell lines have been used as a vehicle to deliver genes of interest in various neurological models, and are highly effective as they can differentiate into neurons and glial cells. A focus of this mini-review is the recent demonstration that the transplantation of HB1.F3.ChAT cells in an AD animal model increases cognitive function coinciding with upregulation of acetylcholine levels in the cerebrospinal fluid. In addition, there is a large dispersion throughout the brain of the transplanted stem cells which is important to repair the widespread cholinergic cell loss in AD. Some translational caveats that need to be satisfied prior to initiating clinical trials of HB1.F3.ChAT cells in AD include regulating the host immune response and the possible tumorigenesis arising from the transplantation of this genetically modified cell line. Further studies are warranted to test the safety and effectiveness of these cells in AD transgenic animal models. This review highlights the recent progress of stem cell therapy in AD, not only emphasizing the significant basic science strides made in this field, but also providing caution on remaining translational issues necessary to advance this novel treatment to the clinic.

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“…Nonetheless, most studies to date suggest that its major roles are related to the endothelial specific expression pattern. ALK1 is involved in angiogenesis and a regulatory region of ACVRL1 gene is sufficient for endothelial expression in arteries feeding ischemic tissues (Li et al 2009). The characterization of the ACVRL1 promoter and the study of its transcriptional regulation remain largely unknown.…”

Section: Regulated Expression Of Hht Genesmentioning

confidence: 99%

Involvement of the TGF-β superfamily signalling pathway in hereditary haemorrhagic telangiectasia

et al. 2010

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Hereditary haemorrhagic telangiectasia (HHT) is a vascular hereditary autosomic dominant disease associated with epistaxis, telangiectases, gastrointestinal haemorrhages and arteriovenous malformations in lung, liver and brain. It affects 1-2 in 10,000 people. There are at least three different genes mutated in HHT, ENG, ACVRL1 and MADH4 that encode endoglin, activin receptor-like kinase (ALK1) and Smad4 proteins, respectively. These proteins are involved in the transforming growth factor (TGF)-β superfamily signalling pathway of vascular endothelial cells. Mutations in ENG (HHT1) and ACVRL1 (HHT2) account for more than 90% of all HHT mutations. In this article, we review the underlying molecular and cellular bases and the therapeutic approaches that have been addressed in our laboratory in recent years.

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Shortened ALK1 regulatory fragment maintains a specific activity in arteries feeding ischemic tissues

Cited by 6 publications

References 19 publications

Blood flow regulatesacvrl1transcription via ligand-dependent Alk1 activity

Blood flow regulatesacvrl1transcription via ligand-dependent Alk1 activity

Recent preclinical evidence advancing cell therapy for Alzheimer's disease

Involvement of the TGF-β superfamily signalling pathway in hereditary haemorrhagic telangiectasia

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