Transplantation of Adult Mouse iPS Cell-Derived Photoreceptor Precursors Restores Retinal Structure and Function in Degenerative Mice

Tucker, Budd A.; Park, In‐Hyun; Qi, Sara D.; Klassen, Henry; Jiang, Caihui; Yao, Jing; Redenti, Stephen; Daley, George Q.; Young, Michael J.

doi:10.1371/journal.pone.0018992

Cited by 291 publications

(280 citation statements)

References 37 publications

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“…Mouse iPSC were generated by reprogramming fifth passage fibroblasts of 6-wk-old transgenic mice expressing the marker protein dsRed [B6.Cg-Tg(ACTB-DsRed*MST)1Nagy/J, Jackson Laboratory] using a set of ecotropic retrovirus (mouse OKSM), as described previously (49,50). Mouse iPSC were cultured on 0.2% matrigel coated plates in mouse iPSC media [DEME/F12, 15% (vol/vol) heat-inactivated FBS, 1% NEAA, 1% L-glutamine, 1% Pen/Strep, 0.2% Fungizone, 0.0008% BME], which was exchanged daily.…”

Section: Methodsmentioning

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: Methodsmentioning

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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“…iPSCs were generated from adult human dermal fibroblasts (RP MAK and RP control) by lentiviral transduction of the four transcription factors Oct4, Sox2, Klf4, and c-MYC as previously described (20). At 5 d postinfection, cells were passaged onto a monolayer of inactive mouse embryonic fibroblasts and fed daily with pluripotency media [DMEM F-12 media (Gibco), 15% heat-inactivated FBS (Lifeblood Medical Inc.), 0.0008% β-mercaptoethanol (Sigma-Aldrich), 1% 100× nonessential amino acids (NEAA) (Gibco), 1 × 10 6 units/L leukemia inhibitory factor (LIF/ESGRO; Millipore), 1% penicillin/ streptomycin (Gibco), 0.2% Fungizone (Gibco)].…”

Section: Methodsmentioning

confidence: 99%

“…3 B and C). iPSC lines were differentiated to a retinal cell lineage using our previously published stepwise differentiation protocol (20) (Fig. 3D).…”

Section: Mak Is Expressed In Both Rod and Cone Photoreceptors In The mentioning

confidence: 99%

Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase ( MAK ) as a cause of retinitis pigmentosa

Tucker

Scheetz

Mullins

et al. 2011

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

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Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non-MAK-associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies.

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“…Retinal prostheses typically consist of arrays of photodiodes that are surgically implanted beneath or above the retina to electrically stimulate the remaining inner retinal cells (Loudin et al 2007;Zrenner et al 2011). Another strategy that is being pursued for patients with very advanced disease is a three-dimensional transplants consisting of stem-cell-derived sheets of photoreceptors and RPE cells grown on a biocompatible polymer scaffold (Zhang et al 2007;Yao et al 2011;Tucker et al 2011a;Shepherd et al 2013). …”

Section: Stem Cells and Genetics Of Retinal Degenerationsmentioning

confidence: 99%