TY - JOUR
T1 - Directed Differentiation of Human Embryonic Stem Cells into Functional Retinal Pigment Epithelium Cells
AU - Idelson, Maria
AU - Alper, Ruslana
AU - Obolensky, Alexey
AU - Ben-Shushan, Etti
AU - Hemo, Itzhak
AU - Yachimovich-Cohen, Nurit
AU - Khaner, Hanita
AU - Smith, Yoav
AU - Wiser, Ofer
AU - Gropp, Michal
AU - Cohen, Malkiel A.
AU - Even-Ram, Sharona
AU - Berman-Zaken, Yael
AU - Matzrafi, Limor
AU - Rechavi, Gideon
AU - Banin, Eyal
AU - Reubinoff, Benjamin
N1 - Funding Information:
We gratefully acknowledge the following members of the Hadassah Embryonic Stem Cell Research Center: Talia Mordechai, Michal Aharonowiz, and Galit Tzur for technical support and Shelly Tannenbaum for editing the manuscript. We also gratefully acknowledge Vitali Shilo from CellCure Neurosciences Ltd. for helping with cell counting and Temima Schnitzer Perlman from The Goldyne Savad Institute of Gene Therapy for helping with the deposit of the microarray data. We thank Ruth Yaul from the Hadassah Center for Retinal and Macular Degeneration for excellent technical assistance and to Israel Barzel and Marina Schulman from the department of Ophthalmology for their help in fundus imaging in vivo. We thank Michal Lotem (Sharett Institute of Oncology, Hadassah University Hospital) for her kind gift of human melanoma cell line M51 and WiCell Research Institute (Madison, WI) for providing H7 hESCs. Many thanks to John C. Saari (University of Washington, Seattle, WA) for providing the CRALBP antibody, to Micha Spira (Faculty of Science, Hebrew University, Jerusalem) for providing the green fluorescent beads, and to Naomi Feinstein and Hava Glickstein from The Department of Electron Microscopy (Hebrew University, Jerusalem) for their help in obtaining electron microscopy images. This research was supported in part by a grant to Hadassah Hebrew University Medical Center by the Israel Science Foundation (grant No. 989/07), the Chief Scientist Office of the Israel Ministry of Health (grant No. 3000003274), the Israel Ministry of Science, Yedidut Research Grant, and the Sidney Swartz Chair in Human Embryonic Stem Cell Research. N.Y.-C., H.K., M.G., and Y.B.-Z. are partially supported by a grant from CellCure Neurosciences Ltd. O.W. and L.M. are employees of CellCure Neurosciences, and B.R. is a founder, shareholder, and CSO of CellCure Neurosciences.
PY - 2009/10/2
Y1 - 2009/10/2
N2 - Dysfunction and loss of retinal pigment epithelium (RPE) leads to degeneration of photoreceptors in age-related macular degeneration and subtypes of retinitis pigmentosa. Human embryonic stem cells (hESCs) may serve as an unlimited source of RPE cells for transplantation in these blinding conditions. Here we show the directed differentiation of hESCs toward an RPE fate under defined culture conditions. We demonstrate that nicotinamide promotes the differentiation of hESCs to neural and subsequently to RPE fate. In the presence of nicotinamide, factors from the TGF-β superfamily, which presumably pattern RPE development during embryogenesis, further direct RPE differentiation. The hESC-derived pigmented cells exhibit the morphology, marker expression, and function of authentic RPE and rescue retinal structure and function after transplantation to an animal model of retinal degeneration caused by RPE dysfunction. These results are an important step toward the future use of hESCs to replenish RPE in blinding diseases.
AB - Dysfunction and loss of retinal pigment epithelium (RPE) leads to degeneration of photoreceptors in age-related macular degeneration and subtypes of retinitis pigmentosa. Human embryonic stem cells (hESCs) may serve as an unlimited source of RPE cells for transplantation in these blinding conditions. Here we show the directed differentiation of hESCs toward an RPE fate under defined culture conditions. We demonstrate that nicotinamide promotes the differentiation of hESCs to neural and subsequently to RPE fate. In the presence of nicotinamide, factors from the TGF-β superfamily, which presumably pattern RPE development during embryogenesis, further direct RPE differentiation. The hESC-derived pigmented cells exhibit the morphology, marker expression, and function of authentic RPE and rescue retinal structure and function after transplantation to an animal model of retinal degeneration caused by RPE dysfunction. These results are an important step toward the future use of hESCs to replenish RPE in blinding diseases.
KW - STEMCELL
UR - http://www.scopus.com/inward/record.url?scp=70349327681&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2009.07.002
DO - 10.1016/j.stem.2009.07.002
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C2 - 19796620
AN - SCOPUS:70349327681
SN - 1934-5909
VL - 5
SP - 396
EP - 408
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 4
ER -