A bioengineering approach to Schlemm's canal-like stem cell differentiation for in vitro glaucoma drug screening

Tian, Yangzi Isabel; Zhang, Xulang; Torrejon, Karen Yud; Danias, John; Gindina, Sofya; Nayyar, Ashima; Du, Yiqin; Xie, Yubing

doi:10.1016/j.actbio.2020.01.033

Cited by 12 publications

(11 citation statements)

References 57 publications

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“…Previous studies have demonstrated that glaucomatous SC cells isolated from POAG eyes exhibited higher levels of filamentous (F)-actin, α-smooth muscle actin (αSMA) and fibronectin, as well as increased cell stiffness compared to normal SC cells 14, 15 . The ocular hypertension-causing steroid dexamethasone was shown to increase F-actin fibers, while the IOP-lowering Rho-associated kinase (ROCK) inhibitor Y27632 decreased F-actin levels 16, 17 ; F-actin is thought to mediate SC cell contractility and stiffness to negatively affect aqueous humor outflow and IOP 18 . Thus, SC cell dysfunction is thought to be a significant contributor to the increased outflow resistance in POAG; however, the mechanistic underpinnings of SC cell pathobiology remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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

Perkumas

Stamer

et al. 2022

Preprint

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Purpose: Elevated transforming growth factor beta2 (TGFβ2) 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 SC cells under glaucomatous conditions are not well understood. Here, we investigate how TGFβ2 regulates YAP/TAZ activity in human SC (HSC) cells using biomimetic extracellular matrix (ECM) hydrogels, and examine whether pharmacologic YAP/TAZ inhibition would attenuate TGFβ2-induced HSC cell dysfunction. Methods: Primary HSC cells were seeded atop photocrosslinked ECM hydrogels, made of collagen type I, elastin-like polypeptide and hyaluronic acid, or encapsulated within the hydrogels. Changes in actin cytoskeleton, YAP/TAZ activity, ECM production, phospho-myosin light chain levels, and hydrogel contraction were assessed. Results: TGFβ2 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 decreased fibronectin expression and reduced actomyosin cytoskeletal rearrangement in HSC cells induced by TGFβ2. Similarly, verteporfin significantly attenuated TGFβ2-induced HSC cell-encapsulated hydrogel contraction. Conclusions: Our 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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Section: Introductionmentioning

confidence: 99%

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

Perkumas

Stamer

et al. 2022

Preprint

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“…SC cells cultured on this surface also exhibited an unusually high transfection efficiency when challenged with exogenous siRNA, suggesting that in vivo SC cells may be similarly susceptible to therapeutic transfection [92]. Intriguingly, Tian et al (2020) recently observed that, when exposed to shear stress and exogenous VEGF-C, SC-like cell monolayers can be differentiated from human adipose-derived stem cells (ADSCs) co-cultured with TM cells on a micropatterned SU-8 scaffold [122]. This finding has the potential to dramatically expand the availability of accurate trabecular outflow models, although the phenotypic characteristics of SC-like cells must be further studied to ensure their analogy to their in vivo counterparts.…”

Section: D Topographical Scaffold Models Of the Tmmentioning

confidence: 99%

Tissue-Engineered Models for Glaucoma Research

Soden

Lee

2020

Micromachines

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Glaucoma is a group of optic neuropathies characterized by the progressive degeneration of retinal ganglion cells (RGCs). Patients with glaucoma generally experience elevations in intraocular pressure (IOP), followed by RGC death, peripheral vision loss and eventually blindness. However, despite the substantial economic and health-related impact of glaucoma-related morbidity worldwide, the surgical and pharmacological management of glaucoma is still limited to maintaining IOP within a normal range. This is in large part because the underlying molecular and biophysical mechanisms by which glaucomatous changes occur are still unclear. In the present review article, we describe current tissue-engineered models of the intraocular space that aim to advance the state of glaucoma research. Specifically, we critically evaluate and compare both 2D and 3D-culture models of the trabecular meshwork and nerve fiber layer, both of which are key players in glaucoma pathophysiology. Finally, we point out the need for novel organ-on-a-chip models of glaucoma that functionally integrate currently available 3D models of the retina and the trabecular outflow pathway.

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“…al using this same scaffold has observed that when subjecting human adipose‐derived cells to exogenous vascular endothelial growth factor C (VEGF‐C), shear stress and coculturing them with HTMC can provide mechanical and cellular cues necessary for human Schlemm's Canal cells (HSC) differentiation. Thus, overcoming the isolation difficulties of primary HSC, is critical for outflow physiology and glaucoma understanding (Tian et al, 2020).…”

Section: Te Approaches To Recreating Tmmentioning

confidence: 99%

Technological advances in ocular trabecular meshwork in vitro models for glaucoma research

Bikuna-Izagirre

Aldazábal

Extramiana

et al. 2022

Biotech & Bioengineering

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Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by the progressive degeneration of the optic nerve. Intraocular pressure (IOP), which is considered to be the main risk factor for glaucoma development, builds up in response to the resistance (resistance to what?) provided by the trabecular meshwork (TM) to aqueous humor (AH) outflow. Although the TM and its relationship to AH outflow have remained at the forefront of scientific interest, researchers remain uncertain regarding which mechanisms drive the deterioration of the TM. Current tissue‐engineering fabrication techniques have come up with promising approaches to successfully recreate the TM. Nonetheless, more accurate models are needed to understand the factors that make glaucoma arise. In this review, we provide a chronological evaluation of the technological milestones that have taken place in the field of glaucoma research, and we conduct a comprehensive comparison of available TM fabrication technologies. Additionally, we also discuss AH perfusion platforms, since they are essential for the validation of these scaffolds, as well as pressure–outflow relationship studies and the discovery of new IOP‐reduction therapies.

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A bioengineering approach to Schlemm's canal-like stem cell differentiation for in vitro glaucoma drug screening

Cited by 12 publications

References 57 publications

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

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

Tissue-Engineered Models for Glaucoma Research

Technological advances in ocular trabecular meshwork in vitro models for glaucoma research

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