Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed 'mechanoreciprocity'. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.

/pdf/a-tense-situation-forcing-tumour-progression-4myf9i89al.pdf

A Tense Situation: Forcing Tumour Progression

Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.

/pdf/remodeling-and-homeostasis-of-the-extracellular-matrix-5bwgfdcscl.pdf

Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer

Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation.

Cardiac fibroblasts: at the heart of myocardial remodeling.

ST2 is an IL-1 receptor family member with transmembrane (ST2L) and soluble (sST2) isoforms. sST2 is a mechanically induced cardiomyocyte protein, and serum sST2 levels predict outcome in patients with acute myocardial infarction or chronic heart failure. Recently, IL-33 was identified as a functional ligand of ST2L, allowing exploration of the role of ST2 in myocardium. We found that IL-33 was a biomechanically induced protein predominantly synthesized by cardiac fibroblasts. IL-33 markedly antagonized angiotensin II- and phenylephrine-induced cardiomyocyte hypertrophy. Although IL-33 activated NF-kappaB, it inhibited angiotensin II- and phenylephrine-induced phosphorylation of inhibitor of NF-kappa B alpha (I kappa B alpha) and NF-kappaB nuclear binding activity. sST2 blocked antihypertrophic effects of IL-33, indicating that sST2 functions in myocardium as a soluble decoy receptor. Following pressure overload by transverse aortic constriction (TAC), ST2(-/-) mice had more left ventricular hypertrophy, more chamber dilation, reduced fractional shortening, more fibrosis, and impaired survival compared with WT littermates. Furthermore, recombinant IL-33 treatment reduced hypertrophy and fibrosis and improved survival after TAC in WT mice, but not in ST2(-/-) littermates. Thus, IL-33/ST2 signaling is a mechanically activated, cardioprotective fibroblast-cardiomyocyte paracrine system, which we believe to be novel. IL-33 may have therapeutic potential for beneficially regulating the myocardial response to overload.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/30000/30634/JCI0730634.pdf

IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system

Objective Dilated cardiomyopathy (DCM) represents a large subset of patients with congestive heart failure (HF), and myocardial fibrosis has been shown to be associated with this process. Lysyl oxidase (LOX), a key enzyme, plays a potential role in the biogenesis of connective tissue matrices by catalyzing crosslinks in collagen and elastin. However, the mechanisms involved in the remodeling process during HF are not clearly understood. The present work was aimed to determine the changes in collagen phenotypes, MMPs, TIMPs, and LOX, in DCM and non-failing human hearts. Moreover, the role of TGFβ in the induction of type III collagen in cardiac fibroblast is determined. Method Protein and RNA expression were quantified by Western and RT-PCR analysis; collagen phenotypes were determined by SDS-PAGE. Results Our data demonstrated that in all DCM hearts, the collagen concentration was significantly elevated compared to that of the NF hearts associated with an increase in Type I (18%) and Type III (33%) collagen. The content of MMP-2 and MMP-9 were increased significantly in all DCM hearts compared to NF hearts. Transcriptional level of LOX, TIMP 1, and 2 were significantly upregulated in DCM hearts. In addition, a significant increase in the transcript levels of cytokines, notably IFN, IL-6, TNF-α, and TGF-β superfamily was observed in all DCM hearts. Addition of TGFβ to cardiac fibroblasts caused a dose dependent increase in type III collagen. Conclusion Altogether, our data suggest an alteration of collagen, MMPs, various cytokines and particularly, LOX participates, in part, in the remodeling of the heart leading to cardiac dysfunction and HF.

Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy

Abnormal stiffness and altered cardiac function arising from abnormal collagen deposition occur in hypertrophy and heart failure. ANG II has been shown to play a role in this process. To evaluate t...

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00763.2003

Influence of cytokines and growth factors in ANG II-mediated collagen upregulation by fibroblasts in rats: role of myocytes.

Excessive collagen deposition may cause abnormal stiffness of the heart during hypertrophy and heart failure. The potent vasoconstrictor angiotensin II seems, via an unknown mechanism, to stimulate collagen production. This study describes the in vitro and ex vivo effects of [Sar(1)]Ang II on collagen production by fibroblasts in culture and in beating, nonworking heart preparations. The effects of [Sar(1)]Ang II on isolated rat hearts or rat heart fibroblasts were determined by quantifying transcript levels of collagen phenotypes I and III through videodensitometry after Northern blot analysis with specific cDNA probes (collagen [P alpha( 2)r(2)] rat alpha( 2)[I] probe for type I and human skin fibroblast alpha(1)[III] probe for type III). When [Sar(1)]Ang II was added in vitro to neonatal or adult 28-week-old Wistar-Kyoto rat heart fibroblasts, questionable stimulation in the mRNAs of types I and III occurred. In contrast, when 10(-8) mol/L [Sar(1)]Ang II was added to beating, nonworking Wistar-Kyoto rat heart preparation ex vivo, a 1.5- to 2.5-fold stimulation of collagen mRNAs of phenotypes I and III was observed. When neonatal fibroblasts were cocultured with neonatal myocytes in vitro, with 10(-10) mol/L [Sar(1)]Ang II added, there was no stimulation of either phenotype. However, significant stimulation of both collagen transcripts was recorded when 10(-10) mol/L [Sar(1)]Ang II was added to adult fibroblasts cocultured with either neonatal or adult myocytes. Our data suggest that factors produced by myocytes are necessary for upregulation of collagen genes in vitro and demonstrate that fibroblast-myocyte cross-talk is required for Ang II-induced collagen upregulation.

Sagartirtha Sarkar

Papers

Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy

Influence of cytokines and growth factors in ANG II-mediated collagen upregulation by fibroblasts in rats: role of myocytes.

Role of Myocytes in Myocardial Collagen Production

Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice

Myocardial Cell Death and Regeneration during Progression of Cardiac Hypertrophy to Heart Failure