The effect of biophysical attributes of the ocular trabecular meshwork associated with glaucoma on the cell response to therapeutic agents

Abstract

Glaucoma is a devastating neurodegenerative disease, which can lead to vision loss and is associated with irreversible damage to retinal ganglion cells. Although the mechanism of disease onset remains unknown, we have recently demonstrated that the stiffness of the ocular trabecular meshwork (HTM) increases dramatically in human donor eyes with a history of glaucoma. Here we report that polyacrylamide hydrogels, which mimic the compliant conditions of normal and glaucomatous HTM, profoundly modulate cytoskeletal dynamics and the elastic modulus of the overlying HTM cells. Substratum compliance also modulates HTM cell response to Latrunculin-B, a cytoskeletal disrupting agent currently in human clinical trials for the treatment of glaucoma. Additionally, we observed a compliance-dependent rebound effect of Latrunculin-B with an unexpected increase in HTM cell elastic modulus being observed upon withdrawal of the drug. The results predict that cytoskeletal disrupting drugs may be more potent in advanced stages of glaucoma.

Altered mechanobiology of Schlemm’s canal endothelial cells in glaucoma

“…Published protocols were followed to make polyacrylamide gels composed of 8% (wt/vol) acrylamide, 3% (wt/vol) (3-acrylamidepropyl) trimethylammonium chloride (API), and a variable percentage of bisacrylamide (0.04, 0.1, 0.2, 0.5, and 1.3%; wt/vol) (18,(35)(36)(37). These API gels were positively charged and electrostatically absorb ECM proteins, including collagen 1 (36).…”

Indentation Versus Tensile Measurements of Young's Modulus for Soft Biological Tissues

“…At the micro-to nanoscopic level, bulk and local compliance influence a wide menu of fundamental cell behaviors, including cell morphology, [14][15][16][17] proliferation, 16,[18][19][20] motility, 15,[21][22][23][24][25] differentiation, 18,[26][27][28][29] and response to therapeutic agents. 30 It is therefore important to properly characterize the compliant biophysical state of tissues to understand how this biophysical attribute relates to proper function. However, a cursory review of the literature quickly reveals significant differences in reported values of the compliance of soft tissues.…”

Role of Substratum Stiffness in Modulating Genes Associated with Extracellular Matrix and Mechanotransducers YAP and TAZ

“…Numerous studies from our laboratory [8][9][10][11] and others [12][13][14][15][16][17][18][19] have demonstrated that modulation of substratum stiffness can alter phenotypic characteristics of cells, gene expression, or response to drugs. However, the primary molecular mechanisms by which the biophysical attributes influence cell behaviors remain unknown.…”