Decellularised extracellular matrix-derived peptides from neural retina and retinal pigment epithelium enhance the expression of synaptic markers and light responsiveness of human pluripotent stem cell derived retinal organoids

Dorgau, Birthe; Felemban, Majed; Hilgen, Gerrit; Kiening, Martin; Zerti, Darin; Hunt, Nicola; Doherty, Mary K.; Whitfield, Phil; Hallam, Dean; White, Kathryn; Ding, Yuchun; Krasnogor, Natalio; Al‐Aama, Jumana Y.; Asfour, Hani Z.; Sernagor, Evelyne; Lako, Majlinda

doi:10.1016/j.biomaterials.2019.01.028

Cited by 56 publications

(63 citation statements)

References 61 publications

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“…1,15,16 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. 7,11,17,18…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…A number of other interphotoreceptor proteins were highlighted in recent publications, some focused on studying these proteins specifically in retinal organoids ( Felemban et al, 2018 ; Salido and Ramamurthy, 2019 ). There is a lot of interest now in these proteins among the teams, trying to use retinal organoids for modeling of retinal diseases and for cell replacement therapies ( Dorgau et al, 2019 ; Guo et al, 2019 ). This interest is guided by the expectations that these “missing factors” (interphotoreceptor matrix proteins being some of them ( Salido and Ramamurthy, 2019 )) may help to build connectivity between RPE and photoreceptors in the organoids co-cultured with RPE in vitro to improve long-term culture of organoids and recapitulate the biology and structure of RPE-photoreceptor OS niche for disease modeling, drug screening and cell/tissue replacement therapies ( Felemban et al, 2018 ; Achberger et al, 2019 ).…”

Section: Lack Of Rpe Photoreceptor Interaction In Retinal Organoidsmentioning

confidence: 99%

Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness

Singh

Nasonkin

2020

Front. Cell. Neurosci.

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The self-formation of retinal tissue from pluripotent stem cells generated a tremendous promise for developing new therapies of retinal degenerative diseases, which previously seemed unattainable. Together with use of induced pluripotent stem cells or/and CRISPR-based recombineering the retinal organoid technology provided an avenue for developing models of human retinal degenerative diseases “in a dish” for studying the pathology, delineating the mechanisms and also establishing a platform for large-scale drug screening. At the same time, retinal organoids, highly resembling developing human fetal retinal tissue, are viewed as source of multipotential retinal progenitors, young photoreceptors and just the whole retinal tissue, which may be transplanted into the subretinal space with a goal of replacing patient’s degenerated retina with a new retinal “patch.” Both approaches (transplantation and modeling/drug screening) were projected when Yoshiki Sasai demonstrated the feasibility of deriving mammalian retinal tissue from pluripotent stem cells, and generated a lot of excitement. With further work and testing of both approaches in vitro and in vivo , a major implicit limitation has become apparent pretty quickly: the absence of the uniform layer of Retinal Pigment Epithelium (RPE) cells, which is normally present in mammalian retina, surrounds photoreceptor layer and develops and matures first. The RPE layer polarize into apical and basal sides during development and establish microvilli on the apical side, interacting with photoreceptors, nurturing photoreceptor outer segments and participating in the visual cycle by recycling 11-trans retinal (bleached pigment) back to 11-cis retinal. Retinal organoids, however, either do not have RPE layer or carry patches of RPE mostly on one side, thus directly exposing most photoreceptors in the developing organoids to neural medium. Recreation of the critical retinal niche between the apical RPE and photoreceptors, where many retinal disease mechanisms originate, is so far unattainable, imposes clear limitations on both modeling/drug screening and transplantation approaches and is a focus of investigation in many labs. Here we dissect different retinal degenerative diseases and analyze how and where retinal organoid technology can contribute the most to developing therapies even with a current limitation and absence of long and functional outer segments, supported by RPE.

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“…114 This process was soon replicated in human pluripotent stem cells 115 with multiple groups using a combination of 2-and 3D protocols to generate human retinal organoids comprising all the retinal cell types within a laminated fashion that resembles the adult retina and responds to light. [116][117][118][119] Identification of each retinal cell type within these complex organoids is not easy as cell-type surface markers are far and few in between. However, gene-editing techniques have been used by Collin et al, 120 and in 2017 Phillips et al 121 to generate reporter cell lines harboring the green fluorescent protein (GFP) or td-Tomato at the Cone-Rod Homeobox (CRX) gene locus, a key transcriptional factor in retinal development.…”

Section: Scrna-seq Of Pluripotent Stem Cell-derived Retinal Organoidsmentioning

confidence: 99%

Understanding the complexity of retina and pluripotent stem cell derived retinal organoids with single cell RNA sequencing: current progress, remaining challenges and future prospective

Zerti

Collin

Cockell

et al. 2020

Current Eye Research

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Single-cell sequencing technologies have emerged as a revolutionary tool with transformative new methods to profile genetic, epigenetic, spatial, and lineage information in individual cells. Single-cell RNA sequencing (scRNA-Seq) allows researchers to collect large datasets detailing the transcriptomes of individual cells in space and time and is increasingly being applied to reveal cellular heterogeneity in retinal development, normal physiology, and disease, and provide new insights into cell-type specific markers and signaling pathways. In recent years, scRNA-Seq datasets have been generated from retinal tissue and pluripotent stem cell-derived retinal organoids. Their cross-comparison enables staging of retinal organoids, identification of specific cells in developing and adult human neural retina and provides deeper insights into cell-type sub-specification and geographical differences. In this article, we review the recent rapid progress in scRNA-Seq analyses of retina and retinal organoids, the questions that remain unanswered and the technical challenges that need to be overcome to achieve consistent results that reflect the complexity, functionality, and interactions of all retinal cell types.

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Decellularised extracellular matrix-derived peptides from neural retina and retinal pigment epithelium enhance the expression of synaptic markers and light responsiveness of human pluripotent stem cell derived retinal organoids

Cited by 56 publications

References 61 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

Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness

Understanding the complexity of retina and pluripotent stem cell derived retinal organoids with single cell RNA sequencing: current progress, remaining challenges and future prospective

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