Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior

Vijay Krishna Raghunathan, Julia Benoit, Ramesh Kasetti, Gulab Zode, Michelle Salemi, Brett S. Phinney, Kate E. Keller, Julia A. Staverosky, Christopher J Murphy, Ted Acott, Janice Vranka

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Ocular hypertension is a causal risk-factor to developing glaucoma. This is associated with stiffening of the trabecular meshwork (TM), the primary site of resistance to aqueous-humor-outflow. The mechanisms underlying this stiffening or how pathologic extracellular matrix (ECM) affects cell function are poorly understood. It is recognized that mechanotransduction systems allow cells to sense and translate the intrinsic biophysical properties of ECM into intracellular signals to control gene transcription, protein expression, and cell behavior. Using an anterior segment perfusion model, we document that there are significantly more low flow regions that are much stiffer, and fewer high flow regions that are less stiff in glaucomatous TM (GTM) when compared to non-glaucomatous TMs (NTM). GTM tissue also has fewer cells overall when compared with NTM tissue. In order to study the role of pathologic ECM in glaucoma disease progression, we conducted studies using cell derived matrices (CDM). First, we characterized the mechanics, composition and organization of fibronectin in ECM deposited by GTM and NTM cells treated with glucocorticosteroids. Then, we determined that these GTM-derived ECM are able to induce stiffening of normal NTM cells, and alter their gene/protein expression to resemble that of a glaucomatous phenotype. Further, we demonstrate that GTM-derived ECM causes endoplasmic reticular stress in NTM. They also became resistant to being reorganized by these NTM cells. These phenomena were exacerbated by ECMs obtained from steroid treated glaucoma model groups. Collectively, our data demonstrates that CDMs represent a novel tool for the study of bidirectional interactions between TM cells and their immediate microenvironment. Statement of Significance: Extracellular matrix (ECM) changes are prevalent in a number of diseases. The precise mechanisms by which changes in the ECM contribute to disease progression is unclear, primarily due to absence of appropriate models. Here, using glaucoma as a disease model, we document changes in cell derived matrix (CDM) and tissue mechanics that contribute to the pathology. Subsequently, we determine the effect that ECMs from diseased and healthy individuals have on healthy cell behaviors. Data emanating from this study demonstrate that CDMs are a potent tool for the study of cell-ECM interactions.

Original languageEnglish (US)
JournalActa Biomaterialia
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Trabecular Meshwork
Extracellular Matrix
Military electronic countermeasures
Glaucoma
Tissue
Mechanics
Genes
Proteins
Disease Progression
Pathology
Transcription
Fibronectins
Ocular Hypertension
Aqueous Humor
Steroids
Cells

Keywords

  • Atomic force microscopy
  • Biomechanics
  • Cell derived matrices
  • Extracellular matrix
  • Glaucoma
  • Mechanotransduction
  • Trabecular meshwork

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Biochemistry
  • Biomedical Engineering
  • Molecular Biology

Cite this

Raghunathan, V. K., Benoit, J., Kasetti, R., Zode, G., Salemi, M., Phinney, B. S., ... Vranka, J. (Accepted/In press). Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior. Acta Biomaterialia. https://doi.org/10.1016/j.actbio.2018.02.037

Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior. / Raghunathan, Vijay Krishna; Benoit, Julia; Kasetti, Ramesh; Zode, Gulab; Salemi, Michelle; Phinney, Brett S.; Keller, Kate E.; Staverosky, Julia A.; Murphy, Christopher J; Acott, Ted; Vranka, Janice.

In: Acta Biomaterialia, 01.01.2018.

Research output: Contribution to journalArticle

Raghunathan, VK, Benoit, J, Kasetti, R, Zode, G, Salemi, M, Phinney, BS, Keller, KE, Staverosky, JA, Murphy, CJ, Acott, T & Vranka, J 2018, 'Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior', Acta Biomaterialia. https://doi.org/10.1016/j.actbio.2018.02.037
Raghunathan, Vijay Krishna ; Benoit, Julia ; Kasetti, Ramesh ; Zode, Gulab ; Salemi, Michelle ; Phinney, Brett S. ; Keller, Kate E. ; Staverosky, Julia A. ; Murphy, Christopher J ; Acott, Ted ; Vranka, Janice. / Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior. In: Acta Biomaterialia. 2018.
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