Maximizing functional photoreceptor differentiation from adult human retinal stem cells.
Retinal stem cells (RSCs) are present in the ciliary margin of the adult human eye and can give rise to all retinal cell types. Here we show that modulation of retinal transcription factor gene expression in human RSCs greatly enriches photoreceptor progeny, and that strong enrichment was obtained with the combined transduction of OTX2 and CRX together with the modulation of CHX10. When these genetically modified human RSC progeny are transplanted into mouse eyes, their retinal integration and differentiation is superior to unmodified RSC progeny. Moreover, electrophysiologic and behavioral tests show that these transplanted cells promote functional recovery in transducin mutant mice. This study suggests that gene modulation in human RSCs may provide a source of photoreceptor cells for the treatment of photoreceptor disease.
Inoue
Tomoyuki
T
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. tinoue@ophthal.med.osaka-u.ac.jp
Coles
Brenda L K
BL
Dorval
Kim
K
Bremner
Rod
R
Bessho
Yasumasa
Y
Kageyama
Ryoichiro
R
Hino
Shinjiro
S
Matsuoka
Masao
M
Craft
Cheryl M
CM
McInnes
Roderick R
RR
Tremblay
Francois
F
Prusky
Glen T
GT
van der Kooy
Derek
D
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000235:genetics; D006085:Graft Survival / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D051857:Otx Transcription Factors / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology* / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015293:Transducin / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D014162:Transfection / Q000379:methods; D014183:Transplantation, Heterologous / Q000379:methods*
D018398:Homeodomain Proteins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C088975:Vsx2 protein, mouse; C109288:cone rod homeobox protein; D015293:Transducin