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

  1. Giovanni Stefano Ugolini
  2. Andrea Pavesi
  3. Marco Rasponi
  4. Gianfranco Beniamino Fiore
  5. Roger Kamm
  6. Monica Soncini  Is a corresponding author
  1. Politecnico di Milano, Italy
  2. Agency for Science, Technology and Research, Singapore
  3. Massachusetts Institute of Technology, United States
Research Article
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Cite this article as: eLife 2017;6:e22847 doi: 10.7554/eLife.22847

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.

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Author details

  1. Giovanni Stefano Ugolini

    Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  2. Andrea Pavesi

    Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2777-1043
  3. Marco Rasponi

    Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Gianfranco Beniamino Fiore

    Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Roger Kamm

    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Monica Soncini

    Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
    For correspondence
    monica.soncini@polimi.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8607-7196

Funding

No external funding was received for this work.

Reviewing Editor

  1. Gordana Vunjak-Novakovic, Columbia University, United States

Publication history

  1. Received: November 8, 2016
  2. Accepted: March 17, 2017
  3. Accepted Manuscript published: March 18, 2017 (version 1)
  4. Accepted Manuscript updated: March 22, 2017 (version 2)
  5. Version of Record published: April 27, 2017 (version 3)

Copyright

© 2017, Ugolini et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

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    Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified.

    Methods:

    A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta smooth muscle-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs).

    Results:

    Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients.

    Conclusions:

    The aorta smooth muscle-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta smooth muscle-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.

    Funding:

    National Key R and D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.

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    Elisabeth Gludovacz et al.
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    Background:

    Excessive plasma histamine concentrations cause symptoms in mast cell activation syndrome, mastocytosis, or anaphylaxis. Anti-histamines are often insufficiently efficacious. Human diamine oxidase (hDAO) can rapidly degrade histamine and therefore represents a promising new treatment strategy for conditions with pathological histamine concentrations.

    Methods:

    Positively charged amino acids of the heparin-binding motif of hDAO were replaced with polar serine or threonine residues. Binding to heparin and heparan sulfate, cellular internalization and clearance in rodents were examined.

    Results:

    Recombinant hDAO is rapidly cleared from the circulation in rats and mice. After mutation of the heparin-binding motif, binding to heparin and heparan sulfate was strongly reduced. The double mutant rhDAO-R568S/R571T showed minimal cellular uptake. The short α-distribution half-life of the wildtype protein was eliminated, and the clearance was significantly reduced in rodents.

    Conclusions:

    The successful decrease in plasma clearance of rhDAO by mutations of the heparin-binding motif with unchanged histamine-degrading activity represents the first step towards the development of rhDAO as a first-in-class biopharmaceutical to effectively treat diseases characterized by excessive histamine concentrations in plasma and tissues.

    Funding:

    Austrian Science Fund (FWF) Hertha Firnberg program grant T1135 (EG); Sigrid Juselius Foundation, Medicinska Understödsförening Liv och Hälsa rft (TAS and SeV).