All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids
All-trans retinoic acid (ATRA) plays an essential role during human eye development, being temporally and spatially adjusted to create gradient concentrations that guide embryonic anterior and posterior axis formation of the eye. Perturbations in ATRA signaling can result in severe ocular developmen...
| Autores: | , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:292199 |
| Acceso en línea: | https://ddd.uab.cat/record/292199 https://dx.doi.org/urn:doi:10.1186/s13287-022-03053-1 |
| Access Level: | acceso abierto |
| Palabra clave: | All-trans retinoic acid Ocular organoids Stem cells Retina Cornea Retinal pigment epithelium |
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All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoidsIsla-Magrané, Helena|||0000-0002-7203-3309Zufiaurre-Seijo, MaddalenGarcía Arumí, José|||0000-0001-8827-1160Duarri, Anna|||0000-0003-4075-5478All-trans retinoic acidOcular organoidsStem cellsRetinaCorneaRetinal pigment epitheliumAll-trans retinoic acid (ATRA) plays an essential role during human eye development, being temporally and spatially adjusted to create gradient concentrations that guide embryonic anterior and posterior axis formation of the eye. Perturbations in ATRA signaling can result in severe ocular developmental diseases. Although it is known that ATRA is essential for correct eye formation, how ATRA influences the different ocular tissues during the embryonic development of the human eye is still not well studied. Here, we investigated the effects of ATRA on the differentiation and the maturation of human ocular tissues using an in vitro model of human-induced pluripotent stem cells-derived multiocular organoids. Multiocular organoids, consisting of the retina, retinal pigment epithelium (RPE), and cornea, were cultured in a medium containing low (500 nM) or high (10 µM) ATRA concentrations for 60 or 90 days. Furthermore, retinal organoids were cultured with taurine and T3 to further study photoreceptor modulation during maturation. Histology, immunochemistry, qPCR, and western blot were used to study gene and protein differential expression between groups. High ATRA levels promote the transparency of corneal organoids and the neuroretinal development in retinal organoids. However, the same high ATRA levels decreased the pigmentation levels of RPE organoids and, in long-term cultures, inhibited the maturation of photoreceptors. By contrast, low ATRA levels enhanced the pigmentation of RPE organoids, induced the opacity of corneal organoids-due to an increase in collagen type IV in the stroma- and allowed the maturation of photoreceptors in retinal organoids. Moreover, T3 promoted rod photoreceptor maturation, whereas taurine promoted red/green cone photoreceptors. ATRA can modulate corneal epithelial integrity and transparency, photoreceptor development and maturation, and the pigmentation of RPE cells in a dose-dependent manner. These experiments revealed the high relevance of ATRA during ocular tissue development and its use as a potential new strategy to better modulate the development and maturation of ocular tissue through temporal and spatial control of ATRA signaling. The online version contains supplementary material available at 10.1186/s13287-022-03053-1.Universitat Autònoma de Barcelona 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/292199https://dx.doi.org/urn:doi:10.1186/s13287-022-03053-1reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 AC19/00080Ministerio de Economía, Industria y Competitividad https://doi.org/10.13039/501100010198 RD16/0008Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/00219open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2921992026-06-06T12:50:31Z |
| dc.title.none.fl_str_mv |
All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids |
| title |
All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids |
| spellingShingle |
All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids Isla-Magrané, Helena|||0000-0002-7203-3309 All-trans retinoic acid Ocular organoids Stem cells Retina Cornea Retinal pigment epithelium |
| title_short |
All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids |
| title_full |
All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids |
| title_fullStr |
All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids |
| title_full_unstemmed |
All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids |
| title_sort |
All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids |
| dc.creator.none.fl_str_mv |
Isla-Magrané, Helena|||0000-0002-7203-3309 Zufiaurre-Seijo, Maddalen García Arumí, José|||0000-0001-8827-1160 Duarri, Anna|||0000-0003-4075-5478 |
| author |
Isla-Magrané, Helena|||0000-0002-7203-3309 |
| author_facet |
Isla-Magrané, Helena|||0000-0002-7203-3309 Zufiaurre-Seijo, Maddalen García Arumí, José|||0000-0001-8827-1160 Duarri, Anna|||0000-0003-4075-5478 |
| author_role |
author |
| author2 |
Zufiaurre-Seijo, Maddalen García Arumí, José|||0000-0001-8827-1160 Duarri, Anna|||0000-0003-4075-5478 |
| author2_role |
author author author |
| dc.contributor.none.fl_str_mv |
Universitat Autònoma de Barcelona |
| dc.subject.none.fl_str_mv |
All-trans retinoic acid Ocular organoids Stem cells Retina Cornea Retinal pigment epithelium |
| topic |
All-trans retinoic acid Ocular organoids Stem cells Retina Cornea Retinal pigment epithelium |
| description |
All-trans retinoic acid (ATRA) plays an essential role during human eye development, being temporally and spatially adjusted to create gradient concentrations that guide embryonic anterior and posterior axis formation of the eye. Perturbations in ATRA signaling can result in severe ocular developmental diseases. Although it is known that ATRA is essential for correct eye formation, how ATRA influences the different ocular tissues during the embryonic development of the human eye is still not well studied. Here, we investigated the effects of ATRA on the differentiation and the maturation of human ocular tissues using an in vitro model of human-induced pluripotent stem cells-derived multiocular organoids. Multiocular organoids, consisting of the retina, retinal pigment epithelium (RPE), and cornea, were cultured in a medium containing low (500 nM) or high (10 µM) ATRA concentrations for 60 or 90 days. Furthermore, retinal organoids were cultured with taurine and T3 to further study photoreceptor modulation during maturation. Histology, immunochemistry, qPCR, and western blot were used to study gene and protein differential expression between groups. High ATRA levels promote the transparency of corneal organoids and the neuroretinal development in retinal organoids. However, the same high ATRA levels decreased the pigmentation levels of RPE organoids and, in long-term cultures, inhibited the maturation of photoreceptors. By contrast, low ATRA levels enhanced the pigmentation of RPE organoids, induced the opacity of corneal organoids-due to an increase in collagen type IV in the stroma- and allowed the maturation of photoreceptors in retinal organoids. Moreover, T3 promoted rod photoreceptor maturation, whereas taurine promoted red/green cone photoreceptors. ATRA can modulate corneal epithelial integrity and transparency, photoreceptor development and maturation, and the pigmentation of RPE cells in a dose-dependent manner. These experiments revealed the high relevance of ATRA during ocular tissue development and its use as a potential new strategy to better modulate the development and maturation of ocular tissue through temporal and spatial control of ATRA signaling. The online version contains supplementary material available at 10.1186/s13287-022-03053-1. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2 2022-01-01 2022 2022-01-01 |
| dc.type.none.fl_str_mv |
Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://ddd.uab.cat/record/292199 https://dx.doi.org/urn:doi:10.1186/s13287-022-03053-1 |
| url |
https://ddd.uab.cat/record/292199 https://dx.doi.org/urn:doi:10.1186/s13287-022-03053-1 |
| dc.language.none.fl_str_mv |
Inglés eng |
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Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 AC19/00080 Ministerio de Economía, Industria y Competitividad https://doi.org/10.13039/501100010198 RD16/0008 Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/00219 |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona |
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