Topological Arrangement of Cardiac Fibroblasts Regulates Cellular Plasticity

Yu, Jingyi; Seldin, Marcus M.; Fu, Kai; Shen, Li; Lam, Larry; Wang, Ping; Wang, Yijie; Huang, Dian; Nguyen, Thang L.; Wei, Bowen; Kulkarni, Rajan P.; Carlo, Dino Di; Teitell, Michael A.; Pellegrini, Matteo; Lusis, Aldons J.; Deb, Arjun

doi:10.1161/circresaha.118.312589

Cited by 47 publications

(42 citation statements)

References 41 publications

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“…Unfortunately, homogeneous cardiac fibroblast tissues has received less attention, although they could serve as simple test beds to specifically address cardiac fibrosis mechanisms. We introduced a ring-shaped engineered connective tissue (ECT) model composed of cardiac fibroblasts and collagen I, which offers several advantages compared to other models like floating discs, aggregates with or without collagen, and sheet-like tissues [24][25][26][27][28]. In the ring-shaped model, the cells compress the matrix against a central stiff rod, which does not allow them to contract the tissue into an undefined ball-like structure.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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Cardiac fibrosis is a hallmark of heart failure for which there is no effective pharmacological therapy. By genetic modification and in vivo inhibitor approaches it was suggested that the Rho-associated kinases (ROCK1 and ROCK2) are involved in pro-fibrotic signalling in cardiac fibroblasts and that they may serve as targets for anti-fibrotic therapies. We demonstrate that simultaneous inhibition of ROCK1 and ROCK2 strongly interfered with tissue formation and their biomechanical properties in a model of engineered connective tissue (ECT), comprised of cardiac fibroblasts and collagen. These effects were observed with both rat and human ECT. Inhibitors of different chemistries, including the isoquinoline inhibitors Fasudil and H1152P as well as the pyrazol-phenyl inhibitor SR-3677, showed comparable effects. By combined treatment of ECT with TGF-β and H1152P, we could identify ROCK as a mediator of TGF-β-dependent tissue stiffening. Moreover, expression analyses suggested that lysyl oxidase (LOX) is a downstream target of the ROCK-actin-MRTF/SRF pathway and inhibition of this pathway by Latrunculin A and CCG-203971 showed similar anti-fibrotic effects in the ECT model as ROCK inhibitors. In line with the collagen crosslinking function of LOX, its inhibition by βaminopropionitrile resulted in reduced ECT stiffness, but let tissue compaction unaffected. Finally, we show that ROCK inhibition also reduced the compaction and stiffness of engineered heart muscle tissues. Our results indicate that pharmacological inhibition of ROCK has a strong anti-fibrotic potential which is in part due to a decrease in the expression of the collagen crosslinking enzyme lysyl oxidase.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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“…The optimized protocol of Sung and colleagues, termed simplified CLARITY method (SCM), allows to achieve full transparency of hearts within 2–3 weeks (Figure d) and preserves signal from genetically encoded GFP. As such, SCM was already applied to study cardiac lineage and protein distribution in the whole adult mouse heart (Figure h) and spatial rearrangement of fibroblasts after myocardial infarction . Notably, to successfully assess spatial distribution of kidney specific renal outer medullary potassium (ROMK) channels in adult mice, the authors developed dual‐sided illumination cardiac LSFM setup .…”

Section: Application Of Toc For Particular Peripheral Organsmentioning

confidence: 99%

Advances in Ex Situ Tissue Optical Clearing

Matryba

Kaczmarek

Gołąb

2019

Laser & Photonics Reviews

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Examination of whole organs with subcellular resolution in health, disease, and during development is necessary to decipher their biological complexity. However, until recently, this has been virtually impossible due to the natural opacity of organ tissue. Recent progress in tissue optical clearing (TOC) has overcome this limitation by turning organs into transparent, light-permitting specimens. At least 20 original TOC methods have been developed in less than a decade, which were followed by hundreds of attempts that were aimed at their optimization and practical application. The majority of proof-of-concept studies have focused on the brain. However, it is apparent that TOC might be equally valuable when applied to peripheral organs or even the whole body. The progress in TOC for peripheral organs is delineated in an organ-by-organ fashion and whole-body clearing approaches are discussed. Additionally, physical and optical approaches for TOC affecting the optical properties of the samples and image quality are discussed to explore their advantages, limitations, and future possibilities.

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“…Acute myocardial infarction (MI) is a leading cause of global mortality, accounting for nearly three million deaths worldwide per annum [1]. Although conventional therapies (antiplatelet agents and percutaneous coronary intervention) improve in-hospital mortality, nearly 30% of patients suffer heart failure as a result of continued loss of functional cardiomyocytes [2,3]. To save a damaged heart, scientists have developed pharmacological and mechanical support therapies to improve blood supply and to salvage the injured myocardia [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor-II overexpression accelerates parthenogenetic stem cell differentiation into cardiomyocytes and improves cardiac function after acute myocardial infarction in mice

et al. 2020

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Background: Parthenogenetic stem cells (PSCs) are a promising source of regenerated cardiomyocytes; however, their application may be limited without a paternal genome. Insulin-like growth factor-II (IGF-II), a paternally expressed growth hormone, is critical in embryonic differentiation. This study investigated whether forced expression of IGF-II in PSCs can accelerate their differentiation. Methods: Overexpression and re-knockdown of IGF-II in PSCs were performed to investigate the role of IGF-II in PSC differentiation. The derivatives of PSCs with different IGF-II manipulations were transplanted into infarcted murine hearts to investigate the role of IGF-II in cardiomyocyte differentiation in vivo. Results: Data showed that the expression of cardiac troponin T and troponin I in IGF-II-PSC outgrowths preceded that of parental PSC outgrowths, suggesting that IGF-II can accelerate PSC differentiation into cardiac lineage. Overexpression of IGF-II accelerated PSC differentiation towards cardiomyocytes while inhibiting PSC proliferation via the IGF-II/IGF1R signaling. Similar to that observed in cardiac marker expression, on differentiation day 24, IGF-II-PSCs showed PCNA and cyclin D2 expression comparable to juvenile mouse cardiomyocytes, showing that IGF-II-PSCs at this stage possess differential and proliferative properties similar to those of juvenile cardiomyocytes. Moreover, the expression pattern of cardiac markers in IGF-II-overexpressing PSC derivatives resembled that of juvenile mouse cardiomyocytes. After transplantation into the infarcted mouse hearts, IGF-II-PSC-derived cardiomyocytes displayed significant characteristics of mature cardiomyocytes, and IGF-II-depletion by shRNA significantly reversed these effects, suggesting the critical role of IGF-II in promoting cardiomyocyte maturation in vivo. Furthermore, IGF-II-overexpressing PSC derivatives reduced collagen deposition and mitochondrial damage in the infarcted areas and improved cardiac function. The re-knockdown of IGF-II could counteract these favorable effects of IGF-II.

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Topological Arrangement of Cardiac Fibroblasts Regulates Cellular Plasticity

Abstract: Taken together, these findings demonstrate that simple topological changes in cardiac fibroblast organization are sufficient to induce chromatin remodeling and global changes in gene expression with potential functional consequences for the healing heart.

Cited by 47 publications

References 41 publications

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Advances in Ex Situ Tissue Optical Clearing

Insulin-like growth factor-II overexpression accelerates parthenogenetic stem cell differentiation into cardiomyocytes and improves cardiac function after acute myocardial infarction in mice

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