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Role of Stromal Cell Population in Myocardial Remodelling

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 17974

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Dr. Gabriela Kania

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Guest Editor

Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland
Interests: mechanism of multiorgan remodeling; heart pathogenesis; fibrosis; fibroblast; arrhythmia; conduction system; 3D cardiac models; systemic sclerosis; heart dysfunction
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Dr. Przemyslaw Blyszczuk

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Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland
Interests: myocarditis; inflammatory dilated cardiomyopathy; innate and adaptive immunity; mouse models of heart failure; myocardial inflammation; Wnt signaling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Stromal cells represent a heterogeneous cell population with connective tissue characteristics, displaying diverse differentiation potentials depending on the tissue and organ localization and playing a specific role in tissue homeostasis and remodeling. Cardiac stromal cells create the appropriate architecture for cardiomyocytes that ensures suitable cardiomyocyte alignment and function in homeostasis. During myocardial remodeling, stromal cells contribute to inflammatory and pro-fibrotic responses closely cross-talking with inflammatory and endothelial cells, indicating stromal cell populations as key objectives in targeted therapies. Nevertheless, the precise role of distinct cardiac stromal cell populations still remains not completely understood. Therefore, in this Special Issue, we encourage submission of manuscripts describing the subpopulations of cardiac stromal cells, their characteristic, function and role in homeostasis and remodeling mainly in cardiovascular and rheumatic diseases in in vitro or ex vivo setups including 3D culture models and in vivo models. We are highly interested in manuscripts reporting application of preclinical and clinical strategies targeting stromal cell activation or function. Likewise, studies on the specific signaling pathways responsible for activation and differentiation of cardiac stromal cells in these diseases and manuscripts describing cardiac immune cell–stromal cell cross-talk are within the scope of this Special Issue.

Dr. Przemyslaw Blyszczuk
Dr. Gabriela Kania
Guest Editors

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Keywords

Stromal cells, fibroblasts
Heart failure in rheumatic diseases
Cardiovascular diseases
Myocardial inflammation
Myocardial fibrosis
Myocardial remodeling
Animal models of heart failure
3D cardiac models

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Published Papers (5 papers)

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Research

17 pages, 4757 KiB

Open AccessArticle

Cytokine-Mediated Alterations of Human Cardiac Fibroblast’s Secretome

by Hanna Bräuninger, Tilo Thottakara, Jacob Schön, Svenja Voss, Vishnu Dhople, Svenja Warnke, Katharina Scherschel, Benedikt Schrage, Paulus Kirchhof, Stefan Blankenberg, Uwe Völker, Dirk Westermann, Elke Hammer and Diana Lindner

Int. J. Mol. Sci. 2021, 22(22), 12262; https://doi.org/10.3390/ijms222212262 - 12 Nov 2021

Cited by 10 | Viewed by 2859

Abstract

Fibroblasts contribute to approximately 20% of the non-cardiomyocytic cells in the heart. They play important roles in the myocardial adaption to stretch, inflammation, and other pathophysiological conditions. Fibroblasts are a major source of extracellular matrix (ECM) proteins whose production is regulated by cytokines, such as TNF-α or TGF-β. The resulting myocardial fibrosis is a hallmark of pathological remodeling in dilated cardiomyopathy (DCM). Therefore, in the present study, the secretome and corresponding transcriptome of human cardiac fibroblasts from patients with DCM was investigated under normal conditions and after TNF-α or TGF-β stimulation. Secreted proteins were quantified via mass spectrometry and expression of genes coding for secreted proteins was analyzed via Affymetrix Transcriptome Profiling. Thus, we provide comprehensive proteome and transcriptome data on the human cardiac fibroblast’s secretome. In the secretome of quiescent fibroblasts, 58% of the protein amount belonged to the ECM fraction. Interestingly, cytokines were responsible for 5% of the total protein amount in the secretome and up to 10% in the corresponding transcriptome. Furthermore, cytokine gene expression and secretion were upregulated upon TNF-α stimulation, while collagen secretion levels were elevated after TGF-β treatment. These results suggest that myocardial fibroblasts contribute to pro-fibrotic and to inflammatory processes in response to extracellular stimuli. Full article

(This article belongs to the Special Issue Role of Stromal Cell Population in Myocardial Remodelling)

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16 pages, 2438 KiB

Open AccessArticle

WNT/β-Catenin Signaling Promotes TGF-β-Mediated Activation of Human Cardiac Fibroblasts by Enhancing IL-11 Production

by Edyta Działo, Marcin Czepiel, Karolina Tkacz, Maciej Siedlar, Gabriela Kania and Przemysław Błyszczuk

Int. J. Mol. Sci. 2021, 22(18), 10072; https://doi.org/10.3390/ijms221810072 - 17 Sep 2021

Cited by 38 | Viewed by 5131

Abstract

Cardiac fibrosis is a pathological process associated with the development of heart failure. TGF-β and WNT signaling have been implicated in pathogenesis of cardiac fibrosis, however, little is known about molecular cross-talk between these two pathways. The aim of this study was to examine the effect of exogenous canonical WNT3a and non-canonical WNT5a in TGF-β-activated human cardiac fibroblasts. We found that WNT3a and TGF-β induced a β-catenin-dependent response, whereas WNT5a prompted AP-1 activity. TGF-β triggered profibrotic signatures in cardiac fibroblasts, and co-stimulation with WNT3a or co-activation of the β-catenin pathway with the GSK3β inhibitor CHIR99021 enhanced collagen I and fibronectin production and development of active contractile stress fibers. In the absence of TGF-β, neither WNT3a nor CHIR99021 exerted profibrotic responses. On a molecular level, in TGF-β-activated fibroblasts, WNT3a enhanced phosphorylation of TAK1 and production and secretion of IL-11 but showed no effect on the Smad pathway. Neutralization of IL-11 activity with the blocking anti-IL-11 antibody effectively reduced the profibrotic response of cardiac fibroblasts activated with TGF-β and WNT3a. In contrast to canonical WNT3a, co-activation with non-canonical WNT5a suppressed TGF-β-induced production of collagen I. In conclusion, WNT/β-catenin signaling promotes TGF-β-mediated fibroblast-to-myofibroblast transition by enhancing IL-11 production. Thus, the uncovered mechanism broadens our knowledge on a molecular basis of cardiac fibrogenesis and defines novel therapeutic targets for fibrotic heart diseases. Full article

(This article belongs to the Special Issue Role of Stromal Cell Population in Myocardial Remodelling)

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14 pages, 4415 KiB

Open AccessArticle

Long-Term Severe In Vitro Hypoxia Exposure Enhances the Vascularization Potential of Human Adipose Tissue-Derived Stromal Vascular Fraction Cell Engineered Tissues

by Myroslava Mytsyk, Giulia Cerino, Gregory Reid, Laia Gili Sole, Friedrich S. Eckstein, David Santer and Anna Marsano

Int. J. Mol. Sci. 2021, 22(15), 7920; https://doi.org/10.3390/ijms22157920 - 24 Jul 2021

Cited by 7 | Viewed by 2247

Abstract

The therapeutic potential of mesenchymal stromal/stem cells (MSC) for treating cardiac ischemia strongly depends on their paracrine-mediated effects and their engraftment capacity in a hostile environment such as the infarcted myocardium. Adipose tissue-derived stromal vascular fraction (SVF) cells are a mixed population composed mainly of MSC and vascular cells, well known for their high angiogenic potential. A previous study showed that the angiogenic potential of SVF cells was further increased following their in vitro organization in an engineered tissue (patch) after perfusion-based bioreactor culture. This study aimed to investigate the possible changes in the cellular SVF composition, in vivo angiogenic potential, as well as engraftment capability upon in vitro culture in harsh hypoxia conditions. This mimics the possible delayed vascularization of the patch upon implantation in a low perfused myocardium. To this purpose, human SVF cells were seeded on a collagen sponge, cultured for 5 days in a perfusion-based bioreactor under normoxia or hypoxia (21% and <1% of oxygen tension, respectively) and subcutaneously implanted in nude rats for 3 and 28 days. Compared to ambient condition culture, hypoxic tension did not alter the SVF composition in vitro, showing similar numbers of MSC as well as endothelial and mural cells. Nevertheless, in vitro hypoxic culture significantly increased the release of vascular endothelial growth factor (p < 0.001) and the number of proliferating cells (p < 0.00001). Moreover, compared to ambient oxygen culture, exposure to hypoxia significantly enhanced the vessel length density in the engineered tissues following 28 days of implantation. The number of human cells and human proliferating cells in hypoxia-cultured constructs was also significantly increased after 3 and 28 days in vivo, compared to normoxia. These findings show that a possible in vivo delay in oxygen supply might not impair the vascularization potential of SVF- patches, which qualifies them for evaluation in a myocardial ischemia model. Full article

(This article belongs to the Special Issue Role of Stromal Cell Population in Myocardial Remodelling)

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15 pages, 3799 KiB

Open AccessArticle

Selective Cardiomyocyte Oxidative Stress Leads to Bystander Senescence of Cardiac Stromal Cells

by Hélène Martini, Lise Lefevre, Sylvain Sayir, Romain Itier, Damien Maggiorani, Marianne Dutaur, Dimitri J. Marsal, Jérôme Roncalli, Nathalie Pizzinat, Daniel Cussac, Angelo Parini, Jeanne Mialet-Perez and Victorine Douin-Echinard

Int. J. Mol. Sci. 2021, 22(5), 2245; https://doi.org/10.3390/ijms22052245 - 24 Feb 2021

Cited by 10 | Viewed by 3057

Abstract

Accumulation of senescent cells in tissues during normal or accelerated aging has been shown to be detrimental and to favor the outcomes of age-related diseases such as heart failure (HF). We have previously shown that oxidative stress dependent on monoamine oxidase A (MAOA) activity in cardiomyocytes promotes mitochondrial damage, the formation of telomere-associated foci, senescence markers, and triggers systolic cardiac dysfunction in a model of transgenic mice overexpressing MAOA in cardiomyocytes (Tg MAOA). However, the impact of cardiomyocyte oxidative stress on the cardiac microenvironment in vivo is still unclear. Our results showed that systolic cardiac dysfunction in Tg MAOA mice was strongly correlated with oxidative stress induced premature senescence of cardiac stromal cells favoring the recruitment of CCR2⁺ monocytes and the installation of cardiac inflammation. Understanding the interplay between oxidative stress induced premature senescence and accelerated cardiac dysfunction will help to define new molecular pathways at the crossroad between cardiac dysfunction and accelerated aging, which could contribute to the increased susceptibility of the elderly to HF. Full article

(This article belongs to the Special Issue Role of Stromal Cell Population in Myocardial Remodelling)

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19 pages, 4475 KiB

Open AccessArticle

The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis

by Jemima Seidenberg, Mara Stellato, Amela Hukara, Burkhard Ludewig, Karin Klingel, Oliver Distler, Przemysław Błyszczuk and Gabriela Kania

Int. J. Mol. Sci. 2021, 22(4), 1861; https://doi.org/10.3390/ijms22041861 - 13 Feb 2021

Cited by 19 | Viewed by 3502

Abstract

Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis. Full article

(This article belongs to the Special Issue Role of Stromal Cell Population in Myocardial Remodelling)

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