Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes

Chang, Alex Chia Yu; Pardon, Gaspard; Chang, Andrew Chia Hao; Wu, Haodi; Ong, Sang-Ging; Eguchi, Asuka; Ancel, Sara; Holbrook, Colin; Ramunas, John; Ribeiro, Alexandre J. S.; LaGory, Edward L.; Wang, Honghui; Koleckar, Kassie; Giaccia, Amato J.; Mack, David L.; Childers, Martin K.; Denning, Chris; Day, John W.; Wu, Joseph C.; Pruitt, Beth L.; Blau, Helen M.

doi:10.1016/j.stemcr.2021.04.018

Cited by 33 publications

(76 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using a tuneable hydrogel and traction force microscopy, DMD cardiomyocytes were demonstrated unable to compensate for dystrophin deficiency when cultured on substrates with fibrotic-like elastic modulus (i.e. 35 kPa), showing impaired functionality while maintaining the features of DMD cardiomyopathy on 10 kPa hydrogels (Chang et al 2021 ). Different approaches aiming at understanding the triggers and mechanisms of cardiac pathologies rely on application of non-physiological stimuli to healthy cardiomyocytes.…”

Section: Pathology and Disease Modelsmentioning

confidence: 99%

Current strategies of mechanical stimulation for maturation of cardiac microtissues

et al. 2021

View full text Add to dashboard Cite

The most advanced in vitro cardiac models are today based on the use of induced pluripotent stem cells (iPSCs); however, the maturation of cardiomyocytes (CMs) has not yet been fully achieved. Therefore, there is a rising need to move towards models capable of promoting an adult-like cardiomyocytes phenotype. Many strategies have been applied such as co-culture of cardiomyocytes, with fibroblasts and endothelial cells, or conditioning them through biochemical factors and physical stimulations. Here, we focus on mechanical stimulation as it aims to mimic the different mechanical forces that heart receives during its development and the post-natal period. We describe the current strategies and the mechanical properties necessary to promote a positive response in cardiac tissues from different cell sources, distinguishing between passive stimulation, which includes stiffness, topography and static stress and active stimulation, encompassing cyclic strain, compression or perfusion. We also highlight how mechanical stimulation is applied in disease modelling.

show abstract

Section: Pathology and Disease Modelsmentioning

confidence: 99%

Current strategies of mechanical stimulation for maturation of cardiac microtissues

et al. 2021

View full text Add to dashboard Cite

show abstract

“…This affects the microenvironment and possibly may contribute to increased substrate stiffness. Since increased substrate stiffness triggers contractile dysfunction associated with telomere shortening one may speculate that changes in the extracellular matrix environment by aged heart fibroblasts may support a phenotype of accelerated aging [105]. Moreover, studies demonstrated that aging of the heart is accompanied by disturbed expression patterns and distribution of Cx43, with age‐dependent decrease of Cx43 [106], which may be linked to increased risk for arrhythmic events [107].…”

Section: Communication Between Fibroblasts and Cardiomyocytesmentioning

confidence: 99%

Fibroblast‐mediated intercellular crosstalk in the healthy and diseased heart

et al. 2021

View full text Add to dashboard Cite

Cardiac fibroblasts constitute a major cell population in the heart. They secrete extracellular matrix components and various other factors shaping the microenvironment of the heart. In silico analysis of intercellular communication based on single‐cell RNA sequencing revealed that fibroblasts are the source of the majority of outgoing signals to other cell types. This observation suggests that fibroblasts play key roles in orchestrating cellular interactions that maintain organ homeostasis but that can also contribute to disease states. Here, we will review the current knowledge of fibroblast interactions in the healthy, diseased, and aging heart. We focus on the interactions that fibroblasts establish with other cells of the heart, specifically cardiomyocytes, endothelial cells and immune cells, and particularly those relying on paracrine, electrical, and exosomal communication modes.

show abstract

“…The deposited TTR system is used again here with the addition of using the normal myocardium stiffness of 10 kPa so that the cells could shorten (Engler et al, 2008). A softer substrate avoids any dysfunctional changes due to higher stiffness (Chang et al, 2021). Stiffness is a major trigger of several mechanosignaling pathways making it a key factor in the regulation of muscle cell size (Russell & Solís, 2021; Solís & Russell, 2019).…”

Section: Discussionmentioning

confidence: 99%

Transthyretin deposition alters cardiomyocyte sarcomeric architecture, calcium transients, and contractile force

Dittloff

Spanghero

Solis-Ocampo

et al. 2022

Physiological Reports

View full text Add to dashboard Cite

Age‐related wild‐type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart, this leads to age‐related heart failure with preserved ejection fraction (HFpEF). The hypothesis tested is that TTR deposited in vitro disrupts cardiac myocyte cell‐to‐cell and cell‐to‐matrix adhesion complexes, resulting in altered calcium handling, force generation, and sarcomeric disorganization. Human iPSC‐derived cardiomyocytes and neonatal rat ventricular myocytes (NRVMs), when grown on TTR‐coated polymeric substrata mimicking the stiffness of the healthy human myocardium (10 kPa), had decreased contraction and relaxation velocities as well as decreased force production measured using traction force microscopy. Both NRVMs and adult mouse atrial cardiomyocytes had altered calcium kinetics with prolonged transients when cultured on TTR fibril‐coated substrates. Furthermore, NRVMs grown on stiff (~GPa), flat or microgrooved substrates coated with TTR fibrils exhibited significantly decreased intercellular electrical coupling as shown by FRAP dynamics of cells loaded with the gap junction‐permeable dye calcein‐AM, along with decreased gap junction content as determined by quantitative connexin 43 staining. Significant sarcomeric disorganization and loss of sarcomere content, with increased ubiquitin localization to the sarcomere, were seen in NRVMs on various TTR fibril‐coated substrata. TTR presence decreased intercellular mechanical junctions as evidenced by quantitative immunofluorescence staining of N‐cadherin and vinculin. Current therapies for wtATTR are cost‐prohibitive and only slow the disease progression; therefore, better understanding of cardiomyocyte maladaptation induced by TTR amyloid may identify novel therapeutic targets.

show abstract

Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes

Cited by 33 publications

References 48 publications

Current strategies of mechanical stimulation for maturation of cardiac microtissues

Current strategies of mechanical stimulation for maturation of cardiac microtissues

Fibroblast‐mediated intercellular crosstalk in the healthy and diseased heart

Transthyretin deposition alters cardiomyocyte sarcomeric architecture, calcium transients, and contractile force

Contact Info

Product

Resources

About