Mapping the cardiac vascular niche in heart failure

Peisker, Fabian; Halder, Maurice; Nagai, James Shiniti; Ziegler, Susanne; Kaesler, Nadine; Hoeft, Konrad; Li, Ronghui; Bindels, Eric M.; Kuppe, Christoph; Moellmann, Julia; Lehrke, Michael; Stoppe, Christian; Schneider, Rebekka K.; Costa, Ivan G.; Kramann, Rafael

doi:10.1038/s41467-022-30682-0

Cited by 55 publications

(71 citation statements)

References 132 publications

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“…The synthesis of structural collagens, such as collagen I and collagen III, is a hallmark of fibroblasts in the healthy and remodeling heart, and Col1a1-GFP reporter mice have been a robust tool for general fibroblast identification in many organs, including the heart [ 23 ]. The indirect Cre-loxP system has also been described for the detection of collagen-producing cells in the heart [ 30 ], as well as in other organs [ 25 ]. However, we failed to detect ZsGreen reporter expression in the hearts of our Col1a1-CreERT2 animal model, either in the control or in MI hearts.…”

Section: Discussionmentioning

confidence: 99%

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Comparative Evaluation of Inducible Cre Mouse Models for Fibroblast Targeting in the Healthy and Infarcted Myocardium

et al. 2022

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Several Cre recombinase transgenic mouse models have been generated for cardiac fibroblast (CF) tracking and heart regulation. However, there is still no consensus on the ideal mouse model to optimally identify and/or regulate these cells. Here, a comparative evaluation of the efficiency and specificity of the indirect reporter Cre-loxP system was carried out in three of the most commonly used fibroblast reporter transgenic mice (Pdgfra-CreERT2, Col1a1-CreERT2 and PostnMCM) under healthy and ischemic conditions, to determine their suitability in in vivo studies of cardiac fibrosis. We demonstrate optimal Cre recombinase activity in CF (but also, although moderate, in endothelial cells (ECs)) derived from healthy and infarcted hearts in the PDGFRa-creERT2 mouse strain. In contrast, no positive reporter signal was found in CF derived from the Col1a1-CreERT2 mice. Finally, in the PostnMCM line, fluorescent reporter expression was specifically detected in activated CF but not in EC, which leads us to conclude that it may be the most reliable model for future studies on cardiovascular disease. Importantly, no lethality or cardiac fibrosis were induced after tamoxifen administration at the established doses, either in healthy or infarcted mice of the three fibroblast reporter lineages. This study lays the groundwork for future efficient in vivo CF tracking and functional analyses.

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Section: Discussionmentioning

confidence: 99%

“…Healthy and MI mice were sacrificed one week after the last tamoxifen injection. The tamoxifen treatment procedure was followed as described in the Jax Cre Repository and as previously described in the literature [ 29 , 30 ]. Cardiotoxicity was not found at the administered doses of tamoxifen.…”

Section: Methodsmentioning

confidence: 99%

Comparative Evaluation of Inducible Cre Mouse Models for Fibroblast Targeting in the Healthy and Infarcted Myocardium

et al. 2022

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“…Additionally, other fibroblast-related genes, including those that define alternative fibroblast populations identified in single-cell RNAseq studies ( Skelly et al, 2018 ; Farbehi et al, 2019 ) were also reduced ( Figure 1I ). As PDGFRβ expressing cells are suggested to adopt fibroblast characteristics after injury ( Peisker et al, 2022 ; Henderson et al, 2013 ), we determined if the remaining collagen expressing cells were derived from a PDGFRβ population. We found that in ablated hearts PDGFRβ + cells maintained a vascular distribution similar to control hearts ( Figure 1—figure supplement 3 ) and that there was no significant increase in PDGFRβ + cells in the Col1a1- GFP + population ( Supplementary file 1a ).…”

Section: Resultsmentioning

confidence: 99%

Consequences of PDGFRα+ fibroblast reduction in adult murine hearts

Kuwabara

Hara

Bhutada

et al. 2022

eLife

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Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, a microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.

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“…Fibroblasts infiltrating from blood-derived progenitors, originating from pericytes, or from the endothelium through endothelial-to-mesenchymal transition have previously been reported to also contribute to cardiac myofibroblasts [ 13 , 14 , 15 ]. However, recent lineage tracing work has demonstrated that nearly all myofibroblasts post-infarction and in pressure overload arise from resident fibroblasts [ 16 , 17 , 18 ]. Myofibroblasts are the primary cells responsible for matrix synthesis in the injured heart.…”

Section: Fibroblasts Myofibroblasts and Fibrosismentioning

confidence: 99%

Canadian Contributions in Fibroblast Biology

Al‐Hattab

Chattopadhyaya

Czubryt

2022

Cells

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Fibroblasts are stromal cells found in virtually every tissue and organ of the body. For many years, these cells were often considered to be secondary in functional importance to parenchymal cells. Over the past 2 decades, focused research into the roles of fibroblasts has revealed important roles for these cells in the homeostasis of healthy tissue, and has demonstrated that activation of fibroblasts to myofibroblasts is a key step in disease initiation and progression in many tissues, with fibrosis now recognized as not only an outcome of disease, but also a central contributor to tissue dysfunction, particularly in the heart and lungs. With a growing understanding of both fibroblast and myofibroblast heterogeneity, and the deciphering of the humoral and mechanical cues that impact the phenotype of these cells, fibroblast biology is rapidly becoming a major focus in biomedical research. In this review, we provide an overview of fibroblast and myofibroblast biology, particularly in the heart, and including a discussion of pathophysiological processes such as fibrosis and scarring. We then discuss the central role of Canadian researchers in moving this field forwards, particularly in cardiac fibrosis, and highlight some of the major contributions of these individuals to our understanding of fibroblast and myofibroblast biology in health and disease.

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Mapping the cardiac vascular niche in heart failure

Cited by 55 publications

References 132 publications

Comparative Evaluation of Inducible Cre Mouse Models for Fibroblast Targeting in the Healthy and Infarcted Myocardium

Comparative Evaluation of Inducible Cre Mouse Models for Fibroblast Targeting in the Healthy and Infarcted Myocardium

Consequences of PDGFRα+ fibroblast reduction in adult murine hearts

Canadian Contributions in Fibroblast Biology

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