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Curr Biol. 2019 Jun 17;29(12):1963-1975.e5. doi: 10.1016/j.cub.2019.05.011. Epub 2019 May 30.

Opposing Effects of Growth and Differentiation Factors in Cell-Fate Specification.

Author information

1
Spencer Center for Vision Research, Byers Eye Institute, School of Medicine, Stanford University, Palo Alto, CA 94304, USA. Electronic address: kunche@stanford.edu.
2
Spencer Center for Vision Research, Byers Eye Institute, School of Medicine, Stanford University, Palo Alto, CA 94304, USA.
3
Spencer Center for Vision Research, Byers Eye Institute, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; Eye, Ear, Nose, & Throat Hospital, Department of Ophthalmology & Visual Science, Fudan University, 200031 Shanghai, China.
4
Shiley Eye Center, University of California San Diego, La Jolla, CA 92093, USA.
5
Spencer Center for Vision Research, Byers Eye Institute, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; Shiley Eye Center, University of California San Diego, La Jolla, CA 92093, USA; Bascom Palmer Eye Institute, University of Miami, Miami, FL 33136, USA.
6
Bascom Palmer Eye Institute, University of Miami, Miami, FL 33136, USA.

Abstract

Following ocular trauma or in diseases such as glaucoma, irreversible vision loss is due to the death of retinal ganglion cell (RGC) neurons. Although strategies to replace these lost cells include stem cell replacement therapy, few differentiated stem cells turn into RGC-like neurons. Understanding the regulatory mechanisms of RGC differentiation in vivo may improve outcomes of cell transplantation by directing the fate of undifferentiated cells toward mature RGCs. Here, we report a new mechanism by which growth and differentiation factor-15 (GDF-15), a ligand in the transforming growth factor-beta (TGF-β) superfamily, strongly promotes RGC differentiation in the developing retina in vivo in rodent retinal progenitor cells (RPCs) and in human embryonic stem cells (hESCs). This effect is in direct contrast to the closely related ligand GDF-11, which suppresses RGC-fate specification. We find these opposing effects are due in part to GDF-15's ability to specifically suppress Smad-2, but not Smad-1, signaling induced by GDF-11, which can be recapitulated by pharmacologic or genetic blockade of Smad-2 in vivo to increase RGC specification. No other retinal cell types were affected by GDF-11 knockout, but a slight reduction in photoreceptor cells was observed by GDF-15 knockout in the developing retina in vivo. These data define a novel regulatory mechanism of GDFs' opposing effects and their relevance in RGC differentiation and suggest a potential approach for advancing ESC-to-RGC cell-based replacement therapies.

KEYWORDS:

GDFs; TGF-β signaling; differentiation; retinal development; retinal ganglion cell; stem cell

PMID:
31155355
PMCID:
PMC6581615
[Available on 2020-06-17]
DOI:
10.1016/j.cub.2019.05.011

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