Regulation of Prenatal Human Retinal Neurosphere Growth and Cell Fate Potential by Retinal Pigment Epithelium and Mash1

被引:28
作者
Gamm, David M. [1 ,2 ]
Wright, Lynda S. [2 ]
Capowski, Elizabeth E. [2 ]
Shearer, Rebecca L. [2 ]
Meyer, Jason S. [2 ]
Kim, Hyun-Jung [5 ]
Schneider, Bernard L. [6 ]
Melvan, John Nicholas [2 ]
Svendsen, Clive N. [2 ,3 ,4 ]
机构
[1] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53705 USA
[2] Univ Wisconsin, Waisman Ctr, Stem Cell Res Program, Madison, WI 53705 USA
[3] Univ Wisconsin, Dept Anat, Madison, WI 53705 USA
[4] Univ Wisconsin, Dept Neurol, Madison, WI 53705 USA
[5] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[6] Ecole Polytech Fed Lausanne, Brain & Mind Inst, Lausanne, Switzerland
关键词
Retinal progenitor cells; Retinal pigment epithelium; Mash1; Conditioned medium; Differentiation; Culture; Human;
D O I
10.1634/stemcells.2008-0300
中图分类号
Q813 [细胞工程];
学科分类号
摘要
During development of the central nervous system, stem and progenitor cell proliferation and differentiation are controlled by complex inter- and intracellular interactions that orchestrate the precise spatiotemporal production of particular cell types. Within the embryonic retina, progenitor cells are located adjacent to the retinal pigment epithelium (RPE), which differentiates prior to the neurosensory retina and has the capacity to secrete a multitude of growth factors. We found that secreted proteinaceous factors in human prenatal RPE conditioned medium (RPE CM) prolonged and enhanced the growth of human prenatal retinal neurospheres. The growth-promoting activity of RPE CM was mitogen-dependent and associated with an acute increase in transcription factor phosphorylation. Expanded populations of RPE CM-treated retinal neurospheres expressed numerous neurodevelopmental and eye specification genes and markers characteristic of neural and retinal progenitor cells, but gradually lost the potential to generate neurons upon differentiation. Misexpression of Mash1 restored the neurogenic potential of long-term cultures, yielding neurons with phenotypic characteristics of multiple inner retinal cell types. Thus, a novel combination of extrinsic and intrinsic factors was required to promote both progenitor cell proliferation and neuronal multipotency in human retinal neurosphere cultures. These results support a pro-proliferative and antiapoptotic role for RPE in human retinal development, reveal potential limitations of human retinal progenitor culture systems, and suggest a means for overcoming cell fate restriction in vitro. STEM CELLS 2008;26:3182-3193
引用
收藏
页码:3182 / 3193
页数:12
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