Functional crosstalk between cardiac fibroblasts and adult cardiomyocytes by soluble mediators

Cartledge, James; Kane, Christopher; Dias, Priyanthi; Tesfom, Meron; Clarke, Lucy; Mckee, Benjamin; Ayoubi, Samha Al; Chester, Adrian H.; Yacoub, Magdi H.; Camelliti, Patrizia; Terracciano, Cesare M.

doi:10.1093/cvr/cvu264

Cited by 128 publications

(123 citation statements)

References 44 publications

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“…Medium conditioned with cardiac fibroblasts isolated from pressure-overloaded rat hearts increased cardiomyocyte size, which was inhibited by transforming growth factor-β (TGF-β) type 1 receptor antagonist. 39 These results suggest that cardiac fibroblasts and adult cardiomyocytes communicate via paracrine networks (Figure ; Table).…”

Section: Cardiac Fibroblast-cardiomyocyte Paracrine Communications Inmentioning

confidence: 85%

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Kamo

Akazawa

Komuro

2015

Circulation Research

140

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Section: Cardiac Fibroblast-cardiomyocyte Paracrine Communications Inmentioning

confidence: 85%

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Kamo

Akazawa

Komuro

2015

Circulation Research

140

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“…Interstitial fibroblasts contribute to the biochemical, structural, and electromechanical properties of the myocardium, and are therefore are of particular interest for their major role in the development of cardiac fibrosis following their transdifferentiation into myofibroblasts [Brown et al, 2005;Camelliti et al, 2005;Weber et al, 2013;Travers et al, 2016]. TGFβ1 plays a critical role in myofibroblast transdifferentiation via Smad3 signaling [Bujak et al, 2007, Dobaczewski et al, 2010 and the upregulation of CTGF, FN, and collagen levels [Lijnen et al, 2000, Bujak et al, 2007 as well in directing CM hypertrophy and the cross-talk between CMs and CFs [Cartledge et al, 2015]. A limitation of this study is that we have not yet tested the effect of known antifibrotic agents on TGFβ1-stimulated fibrosis in VCSs.…”

Section: Discussionmentioning

confidence: 99%

Vascularized Cardiac Spheroids as Novel 3D in vitro Models to Study Cardiac Fibrosis

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Tang

et al. 2017

Cells Tissues Organs

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Spheroid cultures are among the most explored cellular biomaterials used in cardiovascular research, due to their improved integration of biochemical and physiological features of the heart in a defined architectural three-dimensional microenvironment when compared to monolayer cultures. To further explore the potential use of spheroid cultures for research, we engineered a novel in vitro model of the heart with vascularized cardiac spheroids (VCSs), by coculturing cardiac myocytes, endothelial cells, and fibroblasts isolated from dissociated rat neonatal hearts (aged 1-3 days) in hanging drop cultures. To evaluate the validity of VCSs in recapitulating pathophysiological processes typical of the in vivo heart, such as cardiac fibrosis, we then treated VCSs with transforming growth factor beta 1 (TGFβ1), a known profibrotic agent. Our mRNA analysis demonstrated that TGFβ1-treated VCSs present elevated levels of expression of connective tissue growth factor, fibronectin, and TGFβ1 when compared to control cultures. We demonstrated a dramatic increase in collagen deposition following TGFβ1 treatment in VCSs in the PicroSirius Red-stained sections. Doxorubicin, a renowned cardiotoxic and profibrotic agent, triggered apoptosis and disrupted vascular networks in VCSs. Taken together, our findings demonstrate that VCSs are a valid model for the study of the mechanisms involved in cardiac fibrosis, with the potential to be used to investigate novel mechanisms and therapeutics for treating and preventing cardiac fibrosis in vitro.

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“…In another study on the effects of fibroblast on cardiomyocytes, cardiomyocyte hypertrophy was observed. In that study it was demonstrated that transforming growth factor beta (TGFβ) had an bidirectional regulatory signaling role between the fibroblasts and cardiomyocytes[39]. Factors such as TGFβ are involved or expressed in response to hypertrophy and loss of adhesions.…”

Section: Discussionmentioning

confidence: 99%

Recombinant human collagen-based microspheres mitigate cardiac conduction slowing induced by adipose tissue-derived stromal cells

et al. 2017

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BackgroundStem cell therapy to improve cardiac function after myocardial infarction is hampered by poor cell retention, while it may also increase the risk of arrhythmias by providing an arrhythmogenic substrate. We previously showed that porcine adipose tissue-derived-stromal cells (pASC) induce conduction slowing through paracrine actions, whereas rat ASC (rASC) and human ASC (hASC) induce conduction slowing by direct coupling. We postulate that biomaterial microspheres mitigate the conduction slowing influence of pASC by interacting with paracrine signaling.AimTo investigate the modulation of ASC-loaded recombinant human collagen-based microspheres, on the electrophysiological behavior of neonatal rat ventricular myocytes (NRVM).MethodUnipolar extracellular electrograms, derived from microelectrode arrays (8x8 electrodes) containing NRVM, co-cultured with ASC or ASC loaded microspheres, were used to determine conduction velocity (CV) and conduction heterogeneity. Conditioned medium (Cme) of (co)cultures was used to assess paracrine mechanisms.ResultsMicrospheres did not affect CV in control (NRVM) monolayers. In co-cultures of NRVM and rASC, hASC or pASC, CV was lower than in controls (14.4±1.0, 13.0±0.6 and 9.0± 1.0 vs. 19.5±0.5 cm/s respectively, p<0.001). Microspheres loaded with either rASC or hASC still induced conduction slowing compared to controls (13.5±0.4 and 12.6±0.5 cm/s respectively, p<0.001). However, pASC loaded microspheres increased CV of NRVM compared to pASC and NRMV co-cultures (16.3±1.3 cm/s, p< 0.001) and did not differ from controls (p = NS). Cme of pASC reduced CV in control monolayers of NRVM (10.3±1.1 cm/s, p<0.001), similar to Cme derived from pASC-loaded microspheres (11.1±1.7 cm/s, p = 1.0). The presence of microspheres in monolayers of NRVM abolished the CV slowing influence of Cme pASC (15.9±1.0 cm/s, p = NS vs. control).ConclusionThe application of recombinant human collagen-based microspheres mitigates indirect paracrine conduction slowing through interference with a secondary autocrine myocardial factor.

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Functional crosstalk between cardiac fibroblasts and adult cardiomyocytes by soluble mediators

Abstract: Fibroblasts have different roles during physiology and disease in regulating myocardial function via soluble mediators. A crosstalk between fibroblasts and cardiomyocytes, controlled by TGF-β, is crucial in this interaction.

Cited by 128 publications

References 44 publications

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Vascularized Cardiac Spheroids as Novel 3D in vitro Models to Study Cardiac Fibrosis

Recombinant human collagen-based microspheres mitigate cardiac conduction slowing induced by adipose tissue-derived stromal cells

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