Thyroid hormone signaling specifies cone subtypes in human retinal organoids

Eldred, Kiara C.; Hadyniak, Sarah E.; Hussey, Katarzyna A.; Brenerman, Boris; Zhang, Ping Wu; Chamling, Xitiz; Sluch, Valentin M.; Welsbie, Derek S.; Hattar, Samer; Taylor, James; Wahlin, Karl; Zack, Donald J.; Johnston, Robert J.

doi:10.1126/science.aau6348

Cited by 220 publications

(192 citation statements)

References 58 publications

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“…There was significantly higher number of RHODOPSIN‐positive cells in WT1 organoids differentiated with Method II (Figure B); WT2 organoids differentiated with the same method showed the presence of RECOVERIN‐ and RHODOPSIN‐ positive cells and OPSIN RED/GREEN positive cells could also be observed; however, protein localization to the outer segments was not always apparent. The reported M/L‐ to S‐cone (red/green to blue) ratios range between 5 and 8 to 1 . We observed similar proportions in WT1 and WT2 Method I‐derived organoids (Figure C).…”

Section: Resultssupporting

confidence: 64%

“…The development of in vitro retinal models has been driven by a lack of adequate animal models that recapitulate the structure and function of the human retina. Induced pluripotent stem cell (IPSC)‐derived retinal organoids have been shown to have a wide range of applications, including the study of human retinogenesis, disease modeling, drug discovery, and cell therapy . Numerous protocols have been developed for the generation of retinal organoids that follow basic developmental principles of forebrain development and eye formation.…”

Section: Introductionmentioning

confidence: 99%

“…Forebrain development is orchestrated by a fine balance between a number of signaling pathways, including bone morphogenetic protein 4 (BMP4) and insulin‐like growth factor 1 (IGF1) . Long‐term maturation of retinal cells for an extended period of time is enhanced by retinoic acid (RA), taurine, and triiodothyronine (T3) . We used differentiation protocols that followed these principles in order to compare retinal differentiation efficiency of multiple iPSC lines across differentiation protocols that rely on activation of these pathways …”

Section: Introductionmentioning

confidence: 99%

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Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent

Chichagova¹,

Hilgen

Ghareeb

et al. 2019

Stem Cells

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Induced pluripotent stem cell (iPSC)-derived retinal organoids provide a platform to study human retinogenesis, disease modeling, and compound screening. Although retinal organoids may represent tissue structures with greater physiological relevance to the in vivo human retina, their generation is not without limitations. Various protocols have been developed to enable development of organoids with all major retinal cell types; however, variability across iPSC lines is often reported. Modulating signaling pathways important for eye formation, such as those involving bone morphogenetic protein 4 (BMP4) and insulin-like growth factor 1 (IGF1), is a common approach used for the generation of retinal tissue in vitro. We used three human iPSC lines to generate retinal organoids by activating either BMP4 or IGF1 signaling and assessed differentiation efficiency by monitoring morphological changes, gene and protein expression, and function. Our results showed that the ability of iPSC to give rise to retinal organoids in response to IGF1 and BMP4 activation was line-and methoddependent. This demonstrates that careful consideration is needed when choosing a differentiation approach, which would also depend on overall project aims. K E Y W O R D Sdifferentiation, induced pluripotent stem cells, organoids, retina

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Section: Resultssupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent

Chichagova¹,

Hilgen

Ghareeb

et al. 2019

Stem Cells

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“…Interestingly, CCDC136 is located next to the OPN1SW locus in humans and could possibly be co-regulated at the transcriptional level. The thyroid hormone receptor THRB is required for the development of M-cones in mice (Ng et al, 2001) and L/M-cones in humans as determined by a pluripotent stem cell model (Eldred et al, 2018). Notably, there are two known receptor isoforms for THRB (TRb1 and TRb2) and further research to determine the precise roles of THRB isoforms in subtype specification of human cones would be of great interest.…”

Section: Profiling Healthy and Degenerating Human Rod Photoreceptor Smentioning

confidence: 99%

A single‐cell transcriptome atlas of the adult human retina

et al. 2019

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The retina is a specialized neural tissue that senses light and initiates image processing. Although the functional organization of specific retina cells has been well studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile the human retina, we performed single‐cell RNA sequencing on 20,009 cells from three donors and compiled a reference transcriptome atlas. Using unsupervised clustering analysis, we identified 18 transcriptionally distinct cell populations representing all known neural retinal cells: rod photoreceptors, cone photoreceptors, Müller glia, bipolar cells, amacrine cells, retinal ganglion cells, horizontal cells, astrocytes, and microglia. Our data captured molecular profiles for healthy and putative early degenerating rod photoreceptors, and revealed the loss of MALAT1 expression with longer post‐mortem time, which potentially suggested a novel role of MALAT1 in rod photoreceptor degeneration. We have demonstrated the use of this retina transcriptome atlas to benchmark pluripotent stem cell‐derived cone photoreceptors and an adult Müller glia cell line. This work provides an important reference with unprecedented insights into the transcriptional landscape of human retinal cells, which is fundamental to understanding retinal biology and disease.

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“…These different protocols have been the basis for many others that followed, and they have been replicated using mESCs, hESCs, and iPSCs (mouse and human) ( Table 1) (Osakada et al, 2008;Parameswaran et al, 2010;Tucker et al, 2011a;Tucker et al, 2011b;La Torre et al, 2012;Nakano et al, 2012;Boucherie et al, 2013;Tucker et al, 2013;Decembrini et al, 2014;Riazifar et al, 2014;Zhong et al, 2014;La Torre et al, 2015;Sluch et al, 2015;Tanaka et al, 2015;Volkner et al, 2016;Aparicio et al, 2017;Chao et al, 2017;Teotia et al, 2017;Vergara et al, 2017;Yokoi et al, 2017;Daniszewski et al, 2018;DiStefano et al, 2018;Kobayashi et al, 2018;Langer et al, 2018). Retinal organoids have also proven useful as platforms to study different aspects of development using not only mouse cells, but also human cells Phillips et al, 2014;Ohlemacher et al, 2016;Takata et al, 2017;Eldred, 2018). The latter is especially crucial since human developmental studies are often unfeasible given the limited availability of tissue and the difficulties to perform genetic manipulations.…”

Section: Stem Cell Strategies To Generate Rgcs In Vitromentioning

confidence: 99%

Retinal Ganglion Cell Replacement: Current Status and Challenges Ahead

Miltner

Torre

2018

Developmental Dynamics

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The neurons of the retina can be affected by a wide variety of inherited or environmental degenerations that can lead to vision loss and even blindness. Retinal ganglion cell (RGC) degeneration is the hallmark of glaucoma and other optic neuropathies that affect millions of people worldwide. Numerous strategies are being trialed to replace lost neurons in different degeneration models, and in recent years, stem cell technologies have opened promising avenues to obtain donor cells for retinal repair. Stem cell–based transplantation has been most frequently used for the replacement of rod photoreceptors, but the same tools could potentially be used for other retinal cell types, including RGCs. However, RGCs are not abundant in stem cell–derived cultures, and in contrast to the short‐distance wiring of photoreceptors, RGC axons take a long and intricate journey to connect with numerous brain nuclei. Hence, a number of challenges still remain, such as the ability to scale up the production of RGCs and a reliable and functional integration into the adult diseased retina upon transplantation. In this review, we discuss the recent advancements in the development of replacement therapies for RGC degenerations and the challenges that we need to overcome before these technologies can be applied to the clinic. Developmental Dynamics 248:118–128, 2019. © 2018 Wiley Periodicals, Inc.

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Thyroid hormone signaling specifies cone subtypes in human retinal organoids

Cited by 220 publications

References 58 publications

Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent

Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent

A single‐cell transcriptome atlas of the adult human retina

Retinal Ganglion Cell Replacement: Current Status and Challenges Ahead

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