HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

OPEN ACCESS ARTICLE

This Article Free via Open Access: OA OA Full Text Full Text (PDF) Supplemental Data OA All Versions of this Article: 2008-0300v1 26/12/3182    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gamm, D. M. Articles by Svendsen, C. N. Search for Related Content PubMed PubMed Citation Articles by Gamm, D. M. Articles by Svendsen, C. N.

TISSUE-SPECIFIC STEM CELLS

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

^aDepartment of Ophthalmology and Visual Sciences,
^bWaisman Center Stem Cell Research Program, and
^cDepartments of Anatomy and Neurology, University of Wisconsin, Madison, Wisconsin, USA;
^dDepartment of Medicine, University of California–San Diego, La Jolla, California, USA;
^eBrain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

Key Words. Retinal progenitor cells • Retinal pigment epithelium • Mash1 • Conditioned medium • Differentiation • Culture • Human

Correspondence: Correspondence: David M. Gamm, M.D., Ph.D., 621 Waisman Center, 1,500 Highland Avenue, University of Wisconsin–Madison, Madison, Wisconsin 53705, USA. Telephone: 608-265-8668; Fax: 608-263-5267; e-mail: dgamm{at}wisc.edu

Received on April 1, 2008; accepted for publication on August 28, 2008.

First published online in STEM CELLS EXPRESS  September 18, 2008.

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.

Disclosure of potential conflicts of interest is found at the end of this article.

This article has been cited by other articles:

				S. A. Cicero, D. Johnson, S. Reyntjens, S. Frase, S. Connell, L. M. L. Chow, S. J. Baker, B. P. Sorrentino, and M. A. Dyer Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells PNAS, April 21, 2009; 106(16): 6685 - 6690. [Abstract] [Full Text] [PDF]