Fluctuation-driven mechanotransduction regulates mitochondrial-network structure and function

Bartolák‐Suki, Erzsébet; Imsirovic, Jasmin; Parameswaran, Harikrishnan; Wellman, Tyler J.; Martínez, Núria; Allen, Philip G.; Frey, Urs; Suki, Bélâ

doi:10.1038/nmat4358

Cited by 63 publications

(102 citation statements)

References 44 publications

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“…A possible explanation is via extracellular ATP which is a known surfactagogue (Rooney, 2001). We reason that cycle-by-cycle variations in stretch upregulates intracellular ATP production by doubling its level through a microtubule- and non-muscle myosin-dependent pathway compared to monotonous stretch, in a similar manner to our observation in vascular smooth muscle cells both in culture and intact tissue (Bartolak-Suki et al, 2015). Consequently, extracellular ATP concentration may increase following VV.…”

Section: Discussionsupporting

confidence: 89%

Optimization of Variable Ventilation for Physiology, Immune Response and Surfactant Enhancement in Preterm Lambs

et al. 2017

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Preterm infants often require mechanical ventilation due to lung immaturity including reduced or abnormal surfactant. Since cyclic stretch with cycle-by-cycle variability is known to augment surfactant release by epithelial cells, we hypothesized that such in vivo mechanotransduction improves surfactant maturation and hence lung physiology in preterm subjects. We thus tested whether breath-by-breath variability in tidal volume (VT) in variable ventilation (VV) can be tuned for optimal performance in a preterm lamb model. Preterm lambs were ventilated for 3 h with conventional ventilation (CV) or two variants of VV that used a maximum VT of 1.5 (VV1) or 2.25 (VV2) times the mean VT. VT was adjusted during ventilation to a permissive pCO2 target range. Respiratory mechanics were monitored continuously using the forced oscillation technique, followed by postmortem bronchoalveolar lavage and tissue collection. Both VVs outperformed CV in blood gas parameters (pH, SaO2, cerebral O2 saturation). However, only VV2 lowered PaCO2 and had a higher specific respiratory compliance than CV. VV2 also increased surfactant protein (SP)-B release compared to VV1 and stimulated its production compared to CV. The production and release of proSP-C however, was increased with CV compared to both VVs. There was more SP-A in both VVs than CV in the lung, but VV2 downregulated SP-A in the lavage, whereas SP-D significantly increased in CV in both the lavage and lung. Compared to CV, the cytokines IL-1β, and TNFα decreased with both VVs with less inflammation during VV2. Additionally, VV2 lungs showed the most homogeneous alveolar structure and least inflammatory cell infiltration assessed by histology. CV lungs exhibited over-distension mixed with collapsed and interstitial edematous regions with occasional hemorrhage. Following VV1, some lambs had normal alveolar structure while others were similar to CV. The IgG serum proteins in the lavage, a marker of leakage, were the highest in CV. An overall combined index of performance that included physiological, biochemical and histological markers was the best in VV2 followed by VV1. Thus, VV2 outperformed VV1 by enhancing SP-B metabolism resulting in open alveolar airspaces, less leakage and inflammation and hence better respiratory mechanics.

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Section: Discussionsupporting

confidence: 89%

Optimization of Variable Ventilation for Physiology, Immune Response and Surfactant Enhancement in Preterm Lambs

et al. 2017

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“…Vascular smooth muscle cells were isolated from bovine aortae using the explant method as previously described 36 and experiments were performed at the first passage. Cells were seeded in the middle section of collagen type I coated cover slips immersed in cell culture media and were allowed to attach for 24 h and subsequently labeled with beads described below.…”

Section: Methodsmentioning

confidence: 99%

“…Larger gel blocks prepared similarly as above were cut into pieces of 4 × 8 × 0.5 mm in dimension and assembled into a vertical uniaxial stretcher device 36 . Briefly, small metal plates were glued to the edges of the PAA sample with rigid wires.…”

Section: Methodsmentioning

confidence: 99%

A microfluidic chamber-based approach to map the shear moduli of vascular cells and other soft materials

Suki

Murata

et al. 2017

Sci Rep

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There is growing interest in quantifying vascular cell and tissue stiffness. Most measurement approaches, however, are incapable of assessing stiffness in the presence of physiological flows. We developed a microfluidic approach which allows measurement of shear modulus (G) during flow. The design included a chamber with glass windows allowing imaging with upright or inverted microscopes. Flow was controlled gravitationally to push culture media through the chamber. Fluorescent beads were conjugated to the sample surface and imaged before and during flow. Bead displacements were calculated from images and G was computed as the ratio of imposed shear stress to measured shear strain. Fluid-structure simulations showed that shear stress on the surface did not depend on sample stiffness. Our approach was verified by measuring the moduli of polyacrylamide gels of known stiffness. In human pulmonary microvascular endothelial cells, G was 20.4 ± 12 Pa and decreased by 20% and 22% with increasing shear stress and inhibition of non-muscle myosin II motors, respectively. The G showed a larger intra- than inter-cellular variability and it was mostly determined by the cytosol. Our shear modulus microscopy can thus map the spatial distribution of G of soft materials including gels, cells and tissues while allowing the visualization of microscopic structures such as the cytoskeleleton.

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“…Rats ( n = 3) were sacrificed and the thoracic aorta was isolated as described previously36. Samples were fixed in a mixture of 3% glutaraldehyd 3% paraformaldehyde in 0.1 M cacodylate buffer, pH 7.4 at 4 °C for 24 hours, washed 6x in 0.1 M cacodylate buffer pH 7.4, then gradually dehydrated in an ethanol series (1 × 10 min.…”

Section: Methodsmentioning

confidence: 99%

Homeostatic maintenance via degradation and repair of elastic fibers under tension

Alves

Araújo

Oliveira

et al. 2016

Sci Rep

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Cellular maintenance of the extracellular matrix requires an effective regulation that balances enzymatic degradation with the repair of collagen fibrils and fibers. Here, we investigate the long-term maintenance of elastic fibers under tension combined with diffusion of general degradative and regenerative particles associated with digestion and repair processes. Computational results show that homeostatic fiber stiffness can be achieved by assuming that cells periodically probe fiber stiffness to adjust the production and release of degradative and regenerative particles. However, this mechanism is unable to maintain a homogeneous fiber. To account for axial homogeneity, we introduce a robust control mechanism that is locally governed by how the binding affinity of particles is modulated by mechanical forces applied to the ends of the fiber. This model predicts diameter variations along the fiber that are in agreement with the axial distribution of collagen fibril diameters obtained from scanning electron microscopic images of normal rat thoracic aorta. The model predictions match the experiments only when the applied force on the fiber is in the range where the variance of local stiffness along the fiber takes a minimum value. Our model thus predicts that the biophysical properties of the fibers play an important role in the long-term regulatory maintenance of these fibers.

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Fluctuation-driven mechanotransduction regulates mitochondrial-network structure and function

Cited by 63 publications

References 44 publications

Optimization of Variable Ventilation for Physiology, Immune Response and Surfactant Enhancement in Preterm Lambs

Optimization of Variable Ventilation for Physiology, Immune Response and Surfactant Enhancement in Preterm Lambs

A microfluidic chamber-based approach to map the shear moduli of vascular cells and other soft materials

Homeostatic maintenance via degradation and repair of elastic fibers under tension

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