YAP/TAZ mediate TGFβ2-induced Schlemm's canal cell dysfunction

Li, H.; Perkumas, K. M.; Stamer, W. D.; Ganapathy, P. S.; Herberg, S.

doi:10.1101/2022.06.06.494681

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bioRxiv · 10.1101/2022.06.06.494681

YAP/TAZ mediate TGFβ2-induced Schlemm's canal cell dysfunction

Li, H.·Perkumas, K. M.·Stamer, W. D.·Ganapathy, P. S.·Herberg, S.

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Abstract

PurposeElevated transforming growth factor beta2 (TGF{beta}2) levels in the aqueous humor have been linked to glaucomatous outflow tissue dysfunction. Potential mediators of dysfunction are the transcriptional co-activators, Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ). However, the molecular underpinnings of YAP/TAZ modulation in Schlemms Canal (SC) cells under glaucomatous conditions are not well understood. Here, we investigate how TGF{beta}2 regulates YAP/TAZ activity in human SC (HSC) cells using biomimetic extracellular matrix (ECM) hydrogels, and examine whether pharmacologic YAP/TAZ inhibition would attenuate TGF{beta}2-induced HSC cell dysfunction. MethodsPrimary HSC cells were seeded atop photocrosslinked ECM hydrogels, made of collagen type I, elastin-like polypeptide and hyaluronic acid, or encapsulated within the hydrogels. HSC cells were induced with TGF{beta}2 in the absence or presence of concurrent actin destabilization or pharmacologic YAP/TAZ inhibition. Changes in actin cytoskeletal organization, YAP/TAZ activity, ECM production, phospho-myosin light chain levels, and hydrogel contraction were assessed. ResultsTGF{beta}2 significantly increased YAP/TAZ nuclear localization in HSC cells, which was prevented by either filamentous (F)-actin relaxation or depolymerization. Pharmacologic YAP/TAZ inhibition using verteporfin without light stimulation decreased fibronectin expression and reduced actomyosin cytoskeletal rearrangement in HSC cells induced by TGF{beta}2. Similarly, verteporfin significantly attenuated TGF{beta}2-induced HSC cell-encapsulated hydrogel contraction. ConclusionsOur data provide evidence for a pathologic role of aberrant YAP/TAZ signaling in HSC cells under simulated glaucomatous conditions, and suggest that pharmacologic YAP/TAZ inhibition has promising potential to improve outflow tissue dysfunction.

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Li, H., Perkumas, K. M., Stamer, W. D., Ganapathy, P. S., Herberg, S.. 2022-06-06. YAP/TAZ mediate TGFβ2-induced Schlemm's canal cell dysfunction. https://doi.org/10.1101/2022.06.06.494681

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