Mechanosensitive release of adenosine 5′‐triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: A mechanism for purinergic involvement in chronic strain

Beckel, Jonathan M.; Argall, Arthur J.; Lim, Jason; Xia, Jingsheng; Lu, Wennan; Coffey, Erin E.; Macarak, Edward J.; Shahidullah, M; Delamere, Nicholas A.; Zode, Gulab; Sheffield, Val C.; Shestopalov, Valery I.; Laties, Alan M.; Mitchell, Claire H.

doi:10.1002/glia.22695

Cited by 139 publications

(155 citation statements)

References 85 publications

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“…Herein we provide functional data to demonstrate that transplantation of iPSC-TM into a mouse model of glaucoma can restore IOP control and prevent RGC degeneration. These studies were aided by the development of a transgenic mouse model of glaucoma because of expression of human myocilin with the disease causing mutation Y437H (Tg-MYOC Y437H ) (24,25). The eyes of these mice develop normally, and structural damage to the TM is modest, but significant loss of TM cells, elevated IOP, and subsequent RGC loss is observed as animals age (24).…”

Section: Significancementioning

confidence: 99%

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Zhu

Gramlich

Laboissonniere

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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133

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Glaucoma is a common cause of vision loss or blindness and reduction of intraocular pressure (IOP) has been proven beneficial in a large fraction of glaucoma patients. The IOP is maintained by the trabecular meshwork (TM) and the elevation of IOP in open-angle glaucoma is associated with dysfunction and loss of the postmitotic cells residing within this tissue. To determine if IOP control can be maintained by replacing lost TM cells, we transplanted TM-like cells derived from induced pluripotent stem cells into the anterior chamber of a transgenic mouse model of glaucoma. Transplantation led to significantly reduced IOP and improved aqueous humor outflow facility, which was sustained for at least 9 wk. The ability to maintain normal IOP engendered survival of retinal ganglion cells, whose loss is ultimately the cause for reduced vision in glaucoma. In vivo and in vitro analyses demonstrated higher TM cellularity in treated mice compared with littermate controls and indicated that this increase is primarily because of a proliferative response of endogenous TM cells. Thus, our study provides in vivo demonstration that regeneration of the glaucomatous TM is possible and points toward novel approaches in the treatment of this disease.G laucoma is one of the most common causes of irreversible vision loss and blindness worldwide; ∼60 million suffer from this disease, and of these, 7 million are blind (1). By definition all glaucoma involves some degree of vision loss, which is because of the death of retinal ganglion cells (RGC), as well as degeneration of the optic nerve head, the optic nerve, and the lateral geniculate nucleus (2, 3). Advanced age and elevated intraocular pressure (IOP) are the two most significant risk factors for the development of glaucoma. Elevated IOP is typically a result of disturbances in the balance of aqueous humor production and drainage. Aqueous humor is continuously synthesized within the eye and drained primarily through the trabecular meshwork (TM), a specialized structure located anterior to the root of the iris. Although occlusion of the aqueous humor outflow pathways can occur through several mechanisms, in the United States and other Western populations the most common form of glaucoma is primary open angle glaucoma (POAG), which manifests no gross abnormalities to the anterior portion of the eye.Randomized clinical trials have shown that reduction of IOP slows the onset and progression of glaucoma, even in patients without suspicious elevation of IOP (4, 5). Although there has been increasing awareness that factors other than elevated IOP contribute to glaucomatous damage, to date all treatments for glaucoma remain aimed at reducing IOP either through surgical or medical means, which has resulted in significant preservation of vision and increased quality of life for millions of glaucoma patients (6, 7).Although the TM in eyes with POAG appears relatively normal at a gross morphological level, a number of more subtle changes influencing the mechanical properties of the TM collage...

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Section: Significancementioning

confidence: 99%

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Zhu

Gramlich

Laboissonniere

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

133

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“…The ATP release from astrocytes can result from chronic mechanical strain (stretch) as it occurs in glaucoma through the upregulation of pannexins. 113 The P2X7R in lacrimal glands interacts with M 3 muscarinic acetylcholine receptors and a 1D -adrenergic receptors to regulate tear secretion. 45 P2X7R plays an essential role in corneal epithelial cell migration and stromal organization during healing from abrasion wounds.…”

Section: P2xr Modulators As Drug Targets In the Eyementioning

confidence: 99%

Ocular Purine Receptors as Drug Targets in the Eye

Civan

2016

Journal of Ocular Pharmacology and Therapeutics

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Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A 1 , A 2A , and A 3 . An A 1 AR agonist is in clinical trials for glaucoma, A 2A AR reduces neuroinflammation, A 3 AR protects retinal ganglion cells from apoptosis, and both A 3 AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y 2 and P2Y 6 , lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.

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“…ATP and nucleotides are present in the aqueous humor (5). Nucleotides are released from various tissues and cells, including lens (6), trabecular meshwork (7), whole retina (8), corneal endothelial cells (9), retinal ganglion cells (RGCs) (10), retinal astrocytes (11), and ciliary body (CB) (12). ATP levels in the aqueous humor are highly elevated in glaucoma patients (13,14), and although IOP and ATP levels in the aqueous humor are positively correlated in patients (14), their interaction is undefined.…”

Section: Introductionmentioning

confidence: 99%

“…P2Y 4 and P2Y 6 receptors are present in cornea, ciliary processes, photoreceptors, and ganglion cells. P2Y 11 receptor is expressed in the retinal pigmented epithelium. Of these, P2Y 1 (17,18), P2Y 2 (19), and P2Y 6 receptors (20) have been shown to control IOP; however, it is unclear how these receptors control IOP and what the pathophysiological consequence of their dysregulation is.…”

Section: Introductionmentioning

confidence: 99%