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EMBRYONIC STEM CELLS

Retinal Incorporation and Differentiation of Neural Precursors Derived from Human Embryonic Stem Cells

^a Department of Ophthalmology, The Hadassah Human Embryonic Stem Cell Research Center of the Goldyne Savad Institute of Gene Therapy, and the
^b Departments of Gynecology,
^c Neurology, and
^d Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Key Words. Human embryonic stem cells • Differentiation • Retina • Transplantation • Photoreceptors

Correspondence: Benjamin Reubinoff, M.D., Ph.D., The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy & Department of Gynecology, Hadassah University Hospital, P.O. Box 12,000, Ein-Kerem, Jerusalem 91120, Israel. Telephone: +972-2-6778589; Fax: +972-2-6430982; e-mail: reubinof{at}md.huji.ac.il

Retinal and macular degenerations are a major cause of blindness. Cell transplantation is a possible therapeutic approach for the replacement of degenerating retinal cells. Here, we studied the potential of human embryonic stem cells (hESCs) to survive, integrate, and differentiate into retinal cells after intraocular transplantation. Highly enriched cultures of neural precursors (NPs) expressing transcripts of key regulatory genes of retinal development were developed from the hESCs. After spontaneous differentiation in vitro, the NPs gave rise to progeny expressing markers of retinal progenitors and photoreceptor development, though this was uncommon and cells expressing markers of mature photoreceptors were not observed. After transplantation into rat eyes, the NPs survived for 16 weeks, migrated large distances, and integrated in the host retina. Teratoma tumors were not observed. Human cells expressing rhodopsin, blue cone opsin, and neural retina leucine zipper transcription factor were observed in subretinal grafts, but not within vitreal and inner retinal grafts. The results suggest that hESCs have the potential to differentiate into retinal cells and that the subretinal microenvironment supports their differentiation toward a photoreceptor fate. This may be the first step toward further developments that eventually may allow the use of hESCs for transplantation in retinal degenerations.

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