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Stem Cell Therapy for Ocular Disorders

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Stem Cell Therapy for Ocular Disorders SPECIAL ARTICLE Stem Cell Therapy for Ocular Disorders Leonard A. Levin, MD, PhD; Robert Ritch, MD; Julia E. Richards, PhD; Teresa Borra´s, PhD ell injury or degeneration occurs in a number of blinding diseases. Therapy has clas- sically consisted of preventing the initial injury or increasing the resistance of cells to injury (cytoprotection). Recently, it has become possible to repopulate tissue com- partments with stem cells. This article presents a current summary of ocular stem Ccell research and applications to disease. It is based on presentations and discussions from the July 2002 international conference “Stem Cells and Glaucoma” sponsored by the Glaucoma Founda- tion. This meeting, the first of its kind, brought together ophthalmologists, geneticists, immunolo- gists, and developmental biologists working on stem cell development and applications in both human and animal models. Arch Ophthalmol. 2004;122:621-627 Stem cells are undifferentiated cells able sitates that we first gain an understanding to divide indefinitely yet maintain the abil- of their proliferation, migration, differen- ity to differentiate into specific cell types. tiation, immunogenicity, and establish- They are able to survive throughout the ment of functional cell contacts.2 It will also lifetime of the organism, while maintain- be necessary to produce these cells in con- ing their number, producing populations ditions that meet appropriate safety and of daughter cells (transit amplifying cells) effectiveness standards. Our current un- that can proceed down unique pathways derstanding of the critical factors affect- of differentiation. Stem cells may be ob- ing stem cell behavior remains limited. tained from embryonic tissues, umbilical Rapid progress is being made, and some cord blood, and some differentiated adult of the first applications of stem cells to tissues. Although the potential for stem wound repair in human eyes have pro- cell–based therapies for a variety of hu- duced successes that offer hope for the use man diseases is promising, numerous of stem cells in other ophthalmologic con- problems remain to be overcome, such as ditions. In this article, we discuss current methods for obtaining, transplanting, in- concepts in stem cells and the eye and ducing differentiation, developing func- evaluate stem cell therapy in glaucoma as tion, and eliminating immune reactions.1 a paradigm for novel approaches to the Stem cells have great potential value in treatment of eye disease. treating eye diseases characterized by ir- reversible loss of cells, such as glaucoma SOURCES OF STEM CELLS and photoreceptor degeneration. Although stem cells offer great op- The best understood stem cells are em- portunities for repair of the nervous sys- bryonic stem cells, which derive from early tem and the eye, their clinical use neces- fetal development. To our knowledge, hu- man embryonic stem cells were first char- From the Department of Ophthalmology and Visual Sciences, University of Wisconsin, acterized in 1998.3 These cells are plu- Madison (Dr Levin); Department of Ophthalmology, New York Eye and Ear Infirmary, ripotent (able to differentiate into a wide New York (Dr Ritch); Department of Ophthalmology, New York Medical College, Valhalla (Dr Ritch); Department of Ophthalmology and Visual Sciences, W. K. Kellogg variety of cell types) and relatively easy to Eye Center, University of Michigan, Ann Arbor (Dr Richards); and Department of maintain in culture, but they are neces- Ophthalmology, University of North Carolina, Chapel Hill (Dr Borra´s). The authors sarily allogeneic (from a different genetic have no relevant financial interest in this article. The Glaucoma Foundation meeting donor) to the potential recipient. Embry- attendees are listed in a box on page 626. onic stem cells are continuous cell lines (REPRINTED) ARCH OPHTHALMOL / VOL 122, APR 2004 WWW.ARCHOPHTHALMOL.COM 621 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 and have the potential to differen- of unilateral disease or allografts Embryonic stem cells are available, tiate into retinal neurons, such as from relatives or cadaver eyes for bi- but there is a substantial risk that if photoreceptors, so they might serve lateral disease. Recently, cultured transplanted into the chamber angle, as an inexhaustible source of neu- limbal stem cells have been used; a they will not differentiate but rather ral progenitors for stem cell therapy small biopsy specimen from a continue to proliferate in the cham- in the retina. Adult stem cells, as healthy limbus can be expanded ex ber angle. This would worsen, rather the name implies, are derived from vivo and then grafted to an eye with than improve, outflow. It is there- mature organisms and are present stem cell deficiency.7 Systemic im- fore necessary to identify mecha- only in restricted cellular compart- munosuppression is necessary in all nisms to induce differentiation of ments.4 They are multipotent (able cases in which allograft limbal stem embryonic stem cells to cells that to differentiate into a restricted num- cells are transplanted, although some express the trabecular meshwork ber of cell types). Stem cells de- patients may eventually achieve a phenotype. rived from the central nervous sys- state of immunologic tolerance and tem (CNS) and ocular tissues have immunosuppression can be discon- DIFFERENTIATION been identified as sources for cells tinued. Future studies will focus on OF STEM CELLS that may someday be used to repair the potential use of adult pluripo- damaged brain, spinal cord, and tent stem cells for ocular surface re- To obtain large numbers of en- retina. Stem cells within the eye have construction and also strategies for grafted stem cells that differentiate received attention because of the promoting a state of tolerance in al- in a desired way, strategies are possibility that they could be ob- lograft limbal transplantation.8,9 needed to channel cells into de- tained from a patient with eye dis- Autologous conjunctival bi- sired phenotypes.15 Modification of ease and used autologously. opsy specimens obtained in the su- the microenvironment and/or inhi- perior fornix, where conjunctival bition of intracellular signaling Retinal Stem Cells stem cells reside, can be expanded cascades in engrafted cells will in tissue culture by using amniotic be needed for appropriate cell- Stem cells have been discovered at membrane as a carrier and can then specific differentiation into injured the pigmented ciliary margin of the be surgically transplanted to the ocu- tissue.16 adult mouse retina.5 A mouse eye lar surface. These tissue equiva- There are several likely sources contains about 100 of these cells, lents have been used successfully in of neural progenitors with retinal po- while the human eye contains about conjunctival replacement after pte- tential that may make stem cell 10000. They can be isolated from rygium surgery and for repair of therapy for eye disease possible.17 eye bank eyes, even from elderly pa- leaking from a scarred filtering bleb. Progenitors isolated from later stages tients. Retinal stem cells do not dif- This use of conjunctival stem cells of retinal development, which nor- ferentiate to form brain cells yet are suggests additional future applica- mally do not give rise to retinal gan- capable of producing all of the dif- tions for these tissue equivalents. glion cells (RGCs), can develop into ferent retinal cell types. Although The corneal endothelium may RGCs in conducive conditions.18 human brain stem cells grow slowly, contain regions for storage (most pe- These cells extend processes to tec- retinal stem cells require no growth ripheral), regeneration (paracen- tal explants (a target for the RGC factors and grow easily and rap- tral), and migration of stem cells. An axon) and appear to function like idly, even in completely defined se- area of corneal endothelial cells ad- RGCs. Stem cells derived from adult rum-free media. Retinal stem cells jacent to the Schwalbe line may be pigmented ciliary epithelium are an can also be isolated from fetal reti- able to transit amplifying cells and excellent source of retinal progeni- nas.6 Both types of retinal stem cells slow-cycling cells.10 Endothelial cell tors because they can differentiate could lead the way for stem cell ocu- density is markedly increased in this along photoreceptors and RGC lin- lar therapies, such as implanting area, as compared with central en- eages.19 Another readily accessible photoreceptors grown in culture into dothelial cell density.11,12 and promising source of neural pro- the blind eye of an individual with Although cell division in the genitors for autologous stem cell retinitis pigmentosa or other reti- normal primate trabecular mesh- therapy is the adult limbal epithe- nal degenerative disorders. work is rare, a niche for trabecular lium (also discussed in the earlier meshwork stem cells might exist at subsection on anterior segment stem Anterior Segment Stem Cells the Schwalbe line in monkeys. Cells cells). Although nonneural in ori- at the Schwalbe line appear differ- gin, progenitors from limbal epithe- Limbal stem cells located in the basal ent from trabecular meshwork cells, lium can generate both neurons and limbal area are involved in renewal and cells with a similar phenotype glia.20 of the corneal epithelium. Defi- to the former seem to migrate to the The influence of the age of the ciency due to aniridia, chemical trabecular meshwork.13,14 Transplan- host on the fate of stem cells after burns, Stevens-Johnson syndrome, tation of trabecular meshwork stem transplantation has been studied in or pemphigoid leads to conjuncti- cells to glaucomatous eyes might im- the Brazilian opossum, a small valization, neovascularization, scar- prove aqueous outflow. Theoreti- pouchless marsupial whose young ring, and ulceration of the cornea. cally, trabecular meshwork stem are born in an immature state.21 Limbal stem cells can be trans- cells might be isolated from adult or Brain progenitor cells from mice ex- planted by using autografts in cases embryonic trabecular meshwork.
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