Future Directions
The embryologic study of how a single cell (zygote) gives rise to a multitude of cell and tissue types led to the field of stem cell biology. The first successful culture of human embryonic stem cell (hESC) lines derived from spare in vitro fertilization blastocysts was reported in 1998. Stem cells range from totipotent to pluripotent to multipotent as they become more limited in their potential to form the entire range of cell and tissue types.
The strict definition of stem cells refers to cells that have the ability to self-renew via asymmetric cell division; the more colloquial and common definition refers to multipotent but lineage-restricted progenitor cells (eg, limbal stem cells). Although stem cell research has generally depended on the study of hESCs, the advent of induced pluripotent stem cell (iPSC) technology has allowed stem cells to be grown from a small sample of adult somatic cells, such as skin cells, and provided a more easily accessible and less politically charged model for the study of pluripotency. Stem cell models have been extremely useful in the study of organogenesis, tissue differentiation, and associated genetic cascades.
A breakthrough in ophthalmic research was reported in 2012 by Nakano and colleagues, who demonstrated the ability to generate 3-dimensional neural retina from hESCs, called retinal organoids, entirely in vitro. As they grow, retinal organoids follow the steps of normal embryonic development, including invagination of the optic vesicle and formation of the optic cup, in giving rise to complex, stratified retinal tissue opposed by retinal pigment epithelium (Video 4-2). This has allowed researchers to study human retinal development and disease outside the organism using simple retinal networks that function like a developing human retina. Human retinal organoids have already been used successfully to model retinal diseases and conditions affecting the retina, such as microphthalmia, Best vitelliform macular dystrophy, gyrate atrophy, Leber congenital amaurosis, and retinitis pigmentosa. Future therapies employing regenerative transplantation approaches, however, are more likely to utilize lineage-restricted progenitor cells so as to increase the likelihood of proper regeneration of function while reducing the risk of cancer.
VIDEO 4-2 Invagination of hESC-derived neural retina.
Used with permission from Nakano T, Ando S, Takata N, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012;10(6):771–785.
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Eiraku M, Takata N, Ishibashi H, et al. Self-organizing optic-cup morphogenesis in threedimensional culture. Nature. 2011;472:51–56.
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Forrester JV, Dick AD, McMenamin PG, Roberts F, Pearlman E. Embryology and early development of the eye and adnexa. In: The Eye, Basic Sciences in Practice. 4th ed. New York: Elsevier; 2016:103–129.
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Swaroop A, Kim D, Forrest D. Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat Rev Neurosci. 2010;11(8):563–576.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.