Human cardiac fibroblasts adaptive responses to controlled combined mechanical strain and oxygen changes in vitro
- Politecnico di Milano, Italy
- Agency for Science, Technology and Research, Singapore
- Singapore-MIT Alliance for Research and Technology, Singapore
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.
Article and author information
Author details
Funding
No external funding was received for this work.
Reviewing Editor
- Gordana Vunjak-Novakovic, Columbia University, United States
Version history
- Received: November 8, 2016
- Accepted: March 17, 2017
- Accepted Manuscript published: March 18, 2017 (version 1)
- Accepted Manuscript updated: March 22, 2017 (version 2)
- 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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Human cardiac fibroblasts adaptive responses to controlled combined mechanical strain and oxygen changes in vitro
eLife 6:e22847.
https://doi.org/10.7554/eLife.22847
Further reading
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- Medicine
Rare early-onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the viral genome was detected in pelvic ganglia. Human HPSE2 was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders, whereas bladders were uniformly distended in mutant mice, a defect ameliorated by AAV9/HPSE2 treatment. Therapeutically, AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.
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- Medicine
Background:
Diffuse large B-cell lymphoma (DLBCL) is the predominant type of malignant B-cell lymphoma. Although various treatments have been developed, the limited efficacy calls for more and further exploration of its characteristics.
Methods:
Datasets from the Gene Expression Omnibus (GEO) database were used for identifying the tumor purity of DLBCL. Survival analysis was employed for analyzing the prognosis of DLBCL patients. Immunohistochemistry was conducted to detect the important factors that influenced the prognosis. Drug-sensitive prediction was performed to evaluate the value of the model.
Results:
VCAN, CD3G, and C1QB were identified as three key genes that impacted the outcome of DLBCL patients both in GEO datasets and samples from our center. Among them, VCAN and CD3G+ T cells were correlated with favorable prognosis, and C1QB was correlated with worse prognosis. The ratio of CD68 + macrophages and CD8 + T cells was associated with better prognosis. In addition, CD3G+T cells ratio was significantly correlated with CD68 + macrophages, CD4 + T cells, and CD8 +T cells ratio, indicating it could play an important role in the anti-tumor immunity in DLBCL. The riskScore model constructed based on the RNASeq data of VCAN, C1QB, and CD3G work well in predicting the prognosis and drug sensitivity.
Conclusions:
VCAN, CD3G, and C1QB were three key genes that influenced the tumor purity of DLBCL, and could also exert certain impact on drug sensitivity and prognosis of DLBCL patients.
Funding:
This work is supported by the Shenzhen High-level Hospital Construction Fund and CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&T-B-062).
