Induction of Trabecular Meshwork Cells From Induced Pluripotent Stem Cells

Ding, Qiong; Zhu, Wei; Cook, Amy C.; Anfinson, Kristin R.; Tucker, Budd A.; Kuehn, Markus H.

doi:10.1167/iovs.14-14800

Cited by 60 publications

(64 citation statements)

References 43 publications

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“…As we have shown previously, iPSC can be induced to differentiate into a cell type (iPSC-TM) that strongly resembles pTM morphologically, functionally, and compositionally (23). Here, mouse iPSC-TM were induced from iPSC derived from fibroblasts isolated from transgenic animals constitutively expressing the cellular marker dsRed.…”

Section: Resultsmentioning

confidence: 96%

“…We've also previously demonstrated that iPSC-TM respond to exposure to glucocorticoids with enhanced synthesis and secretion of myocilin (23). Another well-characterized response of TM cells to glucocorticoid exposure is the formation of cross-linked actin networks (CLANs) (26).…”

Section: Resultsmentioning

confidence: 99%

“…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). Indeed, recently published data have indicated that iPSC can restore some functional aspects in an organ culture system.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that induced pluripotent stem cells (iPSC) can be differentiated into a cell type, designated iPSC-TM, which resembles primary TM cells (pTM) (23). iPSC-TM are morphologically very similar to pTM, express a large number of proteins characteristic of TM, and functionally respond to various stimuli in a manner typical of TM cells.…”

Section: Significancementioning

confidence: 99%

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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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131

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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: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

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

131

View full text Add to dashboard Cite

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“…iPS cells are able to differentiate into TM cells after culture on TM cell-derived extracellular matrix (ECM) 58 or co-culture with TM cells. 59 The induced TM cells from iPS fully restored intraocular pressure homeostatic function in an ex vivo perfused human organ culture model. 58 After co-culturing with human TM cells for up to 21 days, mouse iPS cells became TM-like cells (iPSC-TM) resembling cultured human TM cells morphologically.…”

Section: Other Stem Cell Sources For Tm Regenerationmentioning

confidence: 96%

Stem Cells in the Trabecular Meshwork for Regulating Intraocular Pressure

Yun

Zhou

Wills

et al. 2016

Journal of Ocular Pharmacology and Therapeutics

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Intraocular pressure (IOP) is still the main treatment target for glaucoma. Outflow resistance mainly exists at the trabecular meshwork (TM) outflow pathway, which is responsible for IOP regulation. Changes of TM cellularity and TM extracellular matrix turnover may play important roles in IOP regulation. In this article, we review basic anatomy and physiology of the outflow pathway and TM stem cell characteristics regarding the location, isolation, identification and function. TM stem cells are localized at the insert region of the TM and are label-retaining in vivo. They can be isolated by side-population cell sorting, cloning culture, or sphere culture. TM stem cells are multipotent with the ability to home to the TM region and differentiate into TM cells in vivo. Other stem cell types, such as adipose-derived stem cells, mesenchymal stem cells and induced pluripotent stem cells have been discovered for TM cell differentiation and TM regeneration. We also review glaucomatous animal models, which are suitable to study stem cell-based therapies for TM regeneration.

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Characterizing differences between MSCs and TM cells: Toward autologous stem cell therapies for the glaucomatous trabecular meshwork

Snider

Vannatta

Schildmeyer

et al. 2017

J Tissue Eng Regen Med

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Glaucoma, a leading cause of blindness, is characterized by an increase in intraocular pressure, which is largely determined by resistance to aqueous humour outflow through the trabecular meshwork (TM). In glaucoma, the cellularity of the TM is decreased, and, as a result, stem cell therapies for the TM represent a potential therapeutic option for restoring TM function and treating glaucoma patients. We here focus on adipose derived mesenchymal stem cells (MSCs) as a potential autologous cell source for TM regenerative medicine applications and describe characterization techniques at the messenger (reverse transcription-quantitative polymerase chain reaction), protein (western blotting, flow cytometry), and functional (contractility, phagocytosis) levels to distinguish MSCs from TM cells. We present a panel of 12 transcripts to allow: (a) suitable normalization of reverse transcription-quantitative polymerase chain reaction results across cell types and after exposure to potential differentiation stimuli; (b) distinguishing MSCs from TM cells; (c) distinguishing subtypes of TM cells; and (d) distinguishing TM cells from those in neighbouring tissue. At the protein level, dexamethasone induction of myocilin was a robust discriminating factor between MSCs and TM cells and was complemented by other protein markers. Finally, we show that contractility and phagocytosis differ between MSCs and TM cells. These methods are recommended for use in future differentiation studies to fully define if a functional TM-like phenotype is being achieved.

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Induction of Trabecular Meshwork Cells From Induced Pluripotent Stem Cells

Cited by 60 publications

References 43 publications

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

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

Stem Cells in the Trabecular Meshwork for Regulating Intraocular Pressure

Characterizing differences between MSCs and TM cells: Toward autologous stem cell therapies for the glaucomatous trabecular meshwork

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