Retinal organoids: a window into human retinal development

Abstract

Retinal development and maturation are orchestrated by a series of interacting signalling networks that drive the morphogenetic transformation of the anterior developing brain. Studies in model organisms continue to elucidate these complex series of events. However, the human retina shows many differences from that of other organisms and the investigation of human eye development now benefits from stem cell-derived organoids. Retinal differentiation methods have progressed from simple 2D adherent cultures to self-organising micro-physiological systems. As models of development, these have collectively offered new insights into the previously unexplored early development of the human retina and informed our knowledge of the key cell fate decisions that govern the specification of light-sensitive photoreceptors. Although the developmental trajectories of other retinal cell types remain more elusive, the collation of omics datasets, combined with advanced culture methodology, will enable modelling of the intricate process of human retinogenesis and retinal disease in vitro.

The Role of Small Molecules and Their Effect on the Molecular Mechanisms of Early Retinal Organoid Development

“…For example, FGF2 and FGF9 are constitutively expressed endogenously in the retina during development, and recombinant FGF2 can be added to cultures to favor the differentiation of the neural retina [150]. FGF9 expression is increased in optic vesicle stages of development, and it has been used in disease models involving optic vesicle malformation to (partially) rescue the phenotype [3,151].…”

“…Next, the area at the base of the diencephalon, on the border with the mesencephalon, forms a thickened area on either side (Figure 1Bi), which is the first sign of the bilateral separation of the optic tissue [2]. As the area continues to thicken and grow, it bulges and forms the optic sulci at embryonic day 22 (E22) [2,3]. Further in the development process, the distal area of the sulcus enlarges to form an optic vesicle at E24, whereas the proximal area restricts and forms the optic stalk (Figure 1Bii).…”

Functional 3-Dimensional Retinal Organoids: Technological Progress and Existing Challenges

“…For example, human retinal pigment epithelium (RPE) cell lines can be used to study agerelated macular degeneration (AMD) (Kozlowski, 2015), and MIO-M1 human Müller glial cell lines can be used to study diabetic retinopathy or retinal degeneration (Yong et al, 2010). Moreover, the 2D culture of reprogrammed iPSCs-derived retinal cells (Lamba et al, 2006) has been established for the study of multiple conditions-e.g., disease modeling, drug testing and discovery, and cell replacement therapies (O'Hara- Wright and Gonzalez-Cordero, 2020). Nevertheless, 2D retinal culture may not emulate important naturalistic aspects of native retinal cells in vivo, and also fails to entirely recapitulate the morphology and functional physiology of the human retina.…”

Organoids for the Study of Retinal Development and Developmental Abnormalities

“…Moreover, they are capable of achieving an advanced level of maturation, including the ability to respond to light stimulation and form functional synapses (Zhong et al, 2014 ; Wahlin et al, 2017 ; Hallam et al, 2018 ; Cowan et al, 2020 ). Remarkably, to date, the only way to achieve this high level of complexity is by harnessing the stem cells’ ability to recapitulate development ( Figure 1 ; Meyer et al, 2009 ; Eiraku et al, 2011 ; Nakano et al, 2012 ; Zhong et al, 2014 ; Volkner et al, 2016 ; O’hara-Wright and Gonzalez-Cordero, 2020 ).…”