Human cardiac fibroblasts adaptive responses to controlled combined mechanical strain and oxygen changes in vitro

Abstract

Upon cardiac pathological conditions such as ischemia, microenvironmental changes instruct a series of cellular responses that trigger cardiac fibroblasts-mediated tissue adaptation and inflammation. A comprehensive model of how early environmental changes may induce cardiac fibroblasts (CF) pathological responses is far from being elucidated, partly due to the lack of approaches involving complex and simultaneous environmental stimulation. Here, we provide a first analysis of human primary CF behavior by means of a multi-stimulus microdevice for combined application of cyclic mechanical strain and controlled oxygen tension. Our findings elucidate differential human CFs responses to different combinations of the above stimuli. Individual stimuli cause proliferative effects (PHH3+ mitotic cells, YAP translocation, PDGF secretion) or increase collagen presence. Interestingly, only the combination of hypoxia and a simulated loss of contractility (2% strain) is able to additionally induce increased CF release of inflammatory and pro-fibrotic cytokines and matrix metalloproteinases.DOI: http://dx.doi.org/10.7554/eLife.22847.001

Cardiac Fibrotic Remodeling on a Chip with Dynamic Mechanical Stimulation

“…Various responses of myofibroblast activation to cyclic strains have been reported. In a combined mechanical strain and hypoxia in vitro model, compared with 2% stretching strain (1 Hz), 8% stretching strain attenuated both CFs remodeling and profibrotic responses taking place in hypoxia . Cyclic stretch (4% and 8%, 1 Hz) of fibroblasts on silicone membranes was shown to increase the expression and production of collagen and fibronectin .…”

“…Once the substrate stiffness is lowered to a level matching in vivo tissue, myofibroblast activation can be suppressed or reversed . In the human heart, a mechanical strain is considered to be cyclic at roughly 1 Hz, ranging from 2% (loss of contractility) to 10% (physiological) to 15% (pathological) or even 20% (hyperpathological) depending on pathological states . It has been established that the altered mechanical properties of the myocardium are associated with regulation of the phenotypic remodeling of CFs .…”

“…Similar limitations also exist for other bioreactors . A recently developed bioreactor was able to achieve two magnitudes of stretching strains (2% and 8%) which were exerted on a 2D stretchable polydimethylsiloxane (PDMS) membrane . It is still a challenge to integrate a wide range of mechanical strains due to the limited stretching strain of PDMS membrane, covering physiological, and pathological levels (5–20%), into one bioreactor that could be used to investigate the relationship between strain and myofibroblast activation.…”

Doxorubicin-Induced p53 Interferes with Mitophagy in Cardiac Fibroblasts

“…In addition to myocytes, cardiac fibroblasts are key players in myocardial stress responses, including cardiac extracellular remodeling and wound healing [20][21][22] . Cardiac fibroblasts interact with myocytes through direct connections and paracrine signaling [23][24][25][26] .…”

A Simple Vacuum‐Based Microfluidic Technique to Establish High‐Throughput Organs‐On‐Chip and 3D Cell Cultures at the Microscale

“…In summary, to increase adoption and efficacy of microfluidic organs‐on‐chip an important aspect to address is the limited scale‐up potential of current platforms. While microfluidic organs‐on‐chip based on monolayer cell cultures have been described to achieve some degree of parallelization, they are expected to be surpassed by physiologically relevant 3D cultures where cells can be embedded in controlled ECM and display tissue‐like architecture and properties. However, it is currently impractical to quickly obtain multiple 3D replicates in organs‐on‐chip.…”