Balanced Wnt/Dickkopf1 signaling by mesenchymal vascular progenitor cells in the microvascular niche maintains distal lung structure and function

Summers, Megan; Richmond, Bradley W.; Kropski, Jonathan A.; Majka, Sarah A; Bastarache, Julie A.; Hatzopoulos, Antonis K.; Bylund, Jeffery B.; Ghosh, Moumita; Petrache, Irina; Foronjy, Robert; Geraghty, Patrick; Majka, Susan M.

doi:10.1152/ajpcell.00277.2020

Cited by 9 publications

(9 citation statements)

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“…The most downregulated gene following ZNF827 knockdown is CKAP4 , which encodes the Cytoskeleton-associated protein 4. CKAP4, also known as cytoplasmic protein 63, is a transmembrane and endoplasmic reticulum protein acting as a receptor to several proteins such as tissue plasminogen activator 44 , Wnt inhibitor Dickkopf-1 45 or nexin 17 46 , with major implications in angiogenesis and SMC function. CKAP4 was recently found to regulate vascular SMC survival in the context of abdominal aortic aneurysm 34 .…”

Section: Discussionmentioning

confidence: 99%

ZNF827pleiotropic cardiovascular risk locus involves regulation by Nuclear factor-1

Liu,

Esmael

et al. 2024

Preprint

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IntroductionSCAD (spontaneous coronary artery dissection) is a form of myocardial infarction that disproportionately affects young women. SCAD is caused by the formation of a hematoma within coronary artery wall, resulting in its blockage. Sixteen SCAD susceptibility loci are currently known, includingZNF827gene locus on chromosome 4. Several common genetic variations withinZNF827are also linked to coronary artery disease (CAD), systolic blood pressure (SBP), and ascending aortic diameter. The molecular processes driving these genetic connections, however, are unknown.MethodsWe performed fine-mapping and genetic colocalization analysis atZNF827locus on multiple GWAS signals and quantitative expression traits. We explored the regulatory function of sequences of interest using a luciferase reporter system in rat smooth muscle cells. We used siRNA to knockdown the expression of gene and assessed transcriptomic changes through bulk RNA-Seq.ResultsThe genetic association signals for SCAD, CAD, blood pressure, and aorta dimensions could all be explained by a single causal variant. We identified rs13128814 as the most likely causative variant. This variant overlaps epigenetic regulatory markers specifically active in vascular SMCs and fibroblasts. A 1kb region containing the SCAD-risk allele (A) of rs13128814 variant had a transcriptional activation impact, while the protective allele (G) had no effect. In silico predictions found nuclear factor 1 (NF1) transcription factors preferentially bind to the A allele of rs13128814. We found that overexpressing NFIA (Nuclear Factor 1 A-Type) activated transcription in this area. SCAD association andZNF827eQTL colocalization in various vascular tissues suggested the latter as a plausible target gene in this locus. Knockdown ofZNF827in iPSC-derived SMCs and fibroblasts, followed by RNA-seq, identified a large number of dysregulated genes, including multiple genes involved in cardiovascular disease.ConclusionOur findings inZNF827locus support the hypothesis that the rs13128814 variant, which may affect the binding of NF1 family transcription factors and causeZNF827expression to be deregulated, is the molecular mechanism underpinning the relationship of theZNF827locus with numerous cardiovascular disorders.ZNF827acts as a regulator of gene expression in vascular SMCs and fibroblasts. Further investigation ofZNF827function in vascular tissue will be required to understand the implications of its dysregulation on cardiovascular physiopathology.

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Section: Discussionmentioning

confidence: 99%

ZNF827pleiotropic cardiovascular risk locus involves regulation by Nuclear factor-1

Liu,

Esmael

et al. 2024

Preprint

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“…The main manifestations of the microvascular disease related to T2DM are diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy [24] (Figure 2). The mechanisms that lead to vascular damage are multiple and involve various alterations in signaling pathways, including the Wnt pathway [13,25]. Table 1 shows some components of the Wnt pathway that are altered in the microvascular diseases in T2DM patients.…”

Section: Wnt Pathway and Microvascular Disease In Type 2 Diabetes Mel...mentioning

confidence: 99%

The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus

Torre

García-Fontana

González-Salvatierra

et al. 2022

IJMS

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Vascular complications are the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). These vascular abnormalities result in a chronic hyperglycemic state, which influences many signaling molecular pathways that initially lead to increased oxidative stress, increased inflammation, and endothelial dysfunction, leading to both microvascular and macrovascular complications. Endothelial dysfunction represents the initial stage in both types of vascular complications; it represents “mandatory damage” in the development of microvascular complications and only “introductory damage” in the development of macrovascular complications. Increasing scientific evidence has revealed an important role of the Wnt pathway in the pathophysiology of the vascular wall. It is well known that the Wnt pathway is altered in patients with T2DM. This review aims to be an update of the current literature related to the Wnt pathway molecules that are altered in patients with T2DM, which may also be the cause of damage to the vasculature. Both microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) are analyzed. This review aims to concisely concentrate all the evidence to facilitate the view on the vascular involvement of the Wnt pathway and its components by highlighting the importance of exploring possible therapeutic strategy for patients with T2DM who develop vascular pathologies.

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“…According to the most recent publications (Etc 2019; Xie et al, 2016), interstitial lung fibroblasts, pericytes, lipofibroblasts, mesothelial cells and LR-MSCs, whose roles within the alveolar lung niche are list in the legend within the figure, give rise to the myofibroblast population representing the key cells for the onset and progression of fibrosis. activation of Wnt in linage labeled ABCG2 positive pulmonary mesenchymal vascular progenitor cells (MVPC) drive microvascular dysfunction and exacerbated fibrosis (Summers et al, 2021). In 2011 Jun and collaborators demonstrated that treatment of mice with bleomycin led to the decrease of endogenous LR-MSCs population identified as H33342 low CD45 neg by flow cytometry and in vivo by immunostaining to detect the multidrug resistance transporter ATP binding cassette (ABCG2.)…”

Section: The Role Of Lung Resident Mesenchymal Stromal/stem Cells In Lung Homeostasis Injury and Repairmentioning

confidence: 99%

“…Cao et al found that inhibition of the Shh-Wnt pathway in the bleomycin mouse model prevented LR-MSCs from differentiating into myofibroblasts and reduced lung fibrosis ( Cao et al, 2018 ). Summers et al, further report in the same model that genetic activation of Wnt in linage labeled ABCG2 positive pulmonary mesenchymal vascular progenitor cells (MVPC) drive microvascular dysfunction and exacerbated fibrosis ( Summers et al, 2021 ). In 2011 Jun and collaborators demonstrated that treatment of mice with bleomycin led to the decrease of endogenous LR-MSCs population identified as H33342 low CD45 neg by flow cytometry and in vivo by immunostaining to detect the multidrug resistance transporter ATP binding cassette (ABCG2.)…”

Section: The Role Of Lung Resident Mesenchymal Stromal/stem Cells In Lung Homeostasis Injury and Repairmentioning

confidence: 99%

Dissecting the Role of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis: Cause or Solution

et al. 2021

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Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung’s architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associated with disease onset and progression, it has been hypothesized that IPF lungs might be affected either by a regenerative deficit of the alveolar epithelium or by a dysregulation of repair mechanisms in response to alveolar and vascular damage. This latter might be related to the progressive dysfunction and exhaustion of the resident stem cells together with a process of cellular and tissue senescence. The role of endogenous mesenchymal stromal/stem cells (MSCs) resident in the lung in the homeostasis of these mechanisms is still a matter of debate. Although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue ageing processes with loss of lung regenerative potential. In addition, MSCs have immunomodulatory properties and can secrete anti-fibrotic factors. Thus, MSCs obtained from other sources administered systemically or directly into the lung have been investigated for lung epithelial repair and have been explored as a potential therapy for the treatment of lung diseases including IPF. Given these multiple potential roles of MSCs, this review aims both at elucidating the role of resident lung MSCs in IPF pathogenesis and the role of administered MSCs from other sources for potential IPF therapies.

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Balanced Wnt/Dickkopf1 signaling by mesenchymal vascular progenitor cells in the microvascular niche maintains distal lung structure and function

Cited by 9 publications

References 72 publications

ZNF827pleiotropic cardiovascular risk locus involves regulation by Nuclear factor-1

ZNF827pleiotropic cardiovascular risk locus involves regulation by Nuclear factor-1

The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus

Dissecting the Role of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis: Cause or Solution

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