Stem cells in the trabecular meshwork: Present and future promises

Kelley, Mary J.; Rose, Anastasia Y.; Keller, Kate E.; Hessle, H.; Samples, John R.; Acott, Ted S.

doi:10.1016/j.exer.2008.10.024

Cited by 90 publications

(88 citation statements)

References 61 publications

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“…In the normal eye, resident endothelial cells of the TM maintain its structure by continuously remodeling the TM beams and by degrading debris that might otherwise accumulate and occlude the outflow pathways. Loss of TM cells has been suspected to contribute to aqueous humor outflow deficiencies and, conversely, it has been hypothesized that replacing lost cells can restore function to the eye (39). Previous studies by this and other laboratories have indicated that either multipotent cells isolated from the TM (40,41) or iPSC may be useful for this purpose (23,42).…”

Section: Discussionmentioning

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.

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: Discussionmentioning

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.

133

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“…They also expressed AnkG, a putative marker for PET cells [13][14][15]. On the contrary, the primary cells only expressed Pax6.…”

Section: Discussionmentioning

confidence: 99%

“…Kelley et al [14] reported exclusive immunostaining of AnkG and BA46 in the human TM insert cells post-laser trabeculoplasty in an organ culture model. Cultured human TM insert cells were found to express BA46 [15]. It was speculated that the Schwalbe's line cells, novel cells, and TM insert cells may be one and the same and represent the putative stem cells in the transition zone at the posterior limbus.…”

mentioning

confidence: 99%

“…Our data suggest that the spheres had a bipotent potential and were more prone to adopt their original lineage, indicating that they may be more appropriate for regeneration purposes than pluripotent or multipotent stem cells. The evidence suggesting the presence of stem cells in the human TM has been accumulating for some time [6,7,9,12,15]. To date, there have been five studies that successfully cultivated the TM stem cells in vitro [16][17][18]72,73].…”

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confidence: 99%

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Bovine Posterior Limbus: An Evaluation of an Alternative Source for Corneal Endothelial and Trabecular Meshwork Stem/Progenitor Cells

Grierson

Sheridan

et al. 2015

Stem Cells and Development

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A growing body of evidence has revealed that stem-like cells in the posterior limbus of the eye between the corneal endothelium (CE) and trabecular meshwork (TM) may be able to rejuvenate these tissues in disease. However, these cells have not been clearly defined and we have named them PET cells (progenitor cells of the endothelium and trabeculum). A good and inexpensive animal model for PET cells is lacking, so we investigated bovine eyes as an effective large tissue source. We showed the presence of stem/progenitor cells in the bovine CE, transition zone, and TM in situ. Floating spheres cultured from the CE and TM showed similar stem cell marker expression patterns. Both the CE and TM spheres were bipotent and highly proliferative, but with limited secondary sphere-forming capability. They were highly prone to differentiate back into the cell type of their tissue of origin. It is speculated that the PET cells become more tissue-specific as they migrate away from their niche. Here, we showed that PET cells are present in the posterior limbus of bovine eyes and that they can be successfully cultured and expanded. PET cells represent an attractive target for developing new treatments to regenerate both the CE and TM, thereby reducing the requirement for donor tissue for corneal transplant and invasive treatments for glaucomatous patients.

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“…However, reduced TM cellularity is significantly associated with OAG [14]. Although no experimental evidence that this TM cell loss is physiologically significant has been presented previously, it has been assumed that this would compromise outflow pathway function, that is, IOP regulation [15]. OAG is a disease of aging, with incidence increasing after 40, and the outflow pathway is subjected to numerous cellular insults.…”

Section: Introductionmentioning

confidence: 99%

Induced Pluripotent Stem Cells Restore Function in a Human Cell Loss Model of Open-Angle Glaucoma

DW¹,

X²

2016

J Clin Exp Ophthalmol

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Normally, trabecular meshwork (TM) and Schlemm's canal inner wall endothelial cells within the aqueous humor outflow pathway maintain intraocular pressure within a narrow safe range. Elevation in intraocular pressure, because of the loss of homeostatic regulation by these outflow pathway cells, is the primary risk factor for vision loss due to glaucomatous optic neuropathy. A notable feature associated with glaucoma is outflow pathway cell loss. Using controlled cell loss in ex vivo perfused human outflow pathway organ culture, we developed compelling experimental evidence that this level of cell loss compromises intraocular pressure homeostatic function. This function was restored by repopulation of the model with fresh TM cells. We then differentiated induced pluripotent stem cells (iPSCs) and used them to repopulate this cell depletion model. These differentiated cells (TM-like iPSCs) became similar to TM cells in both morphology and expression patterns. When transplanted, they were able to fully restore intraocular pressure homeostatic function. This successful transplantation of TM-like iPSCs establishes the conceptual feasibility of using autologous stem cells to restore intraocular pressure regulatory function in open-angle glaucoma patients, providing a novel alternative treatment option. STEM CELLS 2015;33:751-761

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Stem cells in the trabecular meshwork: Present and future promises

Cited by 90 publications

References 61 publications

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

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

Bovine Posterior Limbus: An Evaluation of an Alternative Source for Corneal Endothelial and Trabecular Meshwork Stem/Progenitor Cells

Induced Pluripotent Stem Cells Restore Function in a Human Cell Loss Model of Open-Angle Glaucoma

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